111 results on '"Ishrat T"'
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2. Progesterone is neuroprotective against ischemic brain injury through its effects on the phosphoinositide 3-kinase/protein kinase B signaling pathway
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Ishrat, T., primary, Sayeed, I., additional, Atif, F., additional, Hua, F., additional, and Stein, D.G., additional
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- 2012
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3. Paraquat induced acute kidney injury and lung fibrosis: a case report from Bangladesh
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Ishrat Tahsin Isha, Z. H. M. Nazmul Alam, Bidur Kanti Shaha, Md. Shafiqul Bari, Mohammad Zabed Jillul Bari, and Fazle Rabbi Chowdhury
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Paraquat ,Poisoning ,Bangladesh ,Acute kidney injury ,Lung fibrosis ,Medicine ,Biology (General) ,QH301-705.5 ,Science (General) ,Q1-390 - Abstract
Abstract Background Since Bangladesh government issued a ban on the use of highly toxic WHO Class I pesticides, annual consumption of herbicides like Paraquat have been sharply increasing in the markets. Paraquat poisoning is an emerging public health threat and its high mortality rate is responsible for a significant number of deaths. Diagnostic limitations and unavailable sample at presentation have resulted in under-reporting and lack of awareness among the treating physicians, making Paraquat poisoning one of the most neglected toxicological emergencies. Herein, we present a case of Paraquat induced multi-organ failure and emphasis on pitfalls in the management. Case presentation An 18-years-old healthy male was admitted in Sylhet M.A.G Osmani Medical College Hospital with history of attempted suicide by Paraquat ingestion. On admission, he had high serum creatinine but otherwise asymptomatic. He was discharged on day 10 when his renal functions returned to normal. But On day 15, he started having respiratory symptoms—unresponsive to any of the local treatments he received, and by day 30, he developed overt lung fibrosis. We present sequential blood picture, radiographs and CT scans demonstrating Paraquat induced kidney and lung injury over the course of 30 days. Conclusion Paraquat poisoning can lead to death and fatal long-term consequences. All cases of Paraquat poisoning, regardless of symptoms, must be hospitalized and observed for early detection of complications. Distribution of Paraquat should be restricted and/or banned as 38 other countries have done so, which we believe will greatly reduce poisoning related mortality.
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- 2018
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4. Behavioral and histologic neuroprotection of aqueous garlic extract after reversible focal cerebral ischemia.
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Saleem S, Ahmad M, Ahmad AS, Yousuf S, Ansari MA, Khan MB, Ishrat T, and Islam F
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- 2006
5. Effect of saffron (Crocus sativus) on neurobehavioral and neurochemical changes in cerebral ischemia in rats.
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Saleem S, Ahmad M, Ahmad AS, Yousuf S, Ansari MA, Khan MB, Ishrat T, and Islam F
- Published
- 2006
6. Wasp stings (Vespa affinis) induced acute kidney injury following rhabdomyolysis in a 25-year-old woman
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Parash Ullah, Ishrat Tahsin Isha, Sultan Mahmood, Fazle Rabbi Chowdhury, Mohammad Ismail Patwary, Alamgir Chowdhury, Mohammad Zeesan-ul- Abir, and Aziz Al Manna
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acute kidney injury ,rhabdomyolysis ,wasp venom ,Medical emergencies. Critical care. Intensive care. First aid ,RC86-88.9 - Abstract
Wasp sting is a relatively common arthropod assault. This usually results in pain and mild allergic reactions, but sometimes may cause severe systemic reaction and multiorgan dysfunction including rhabdomyolysis, hemolysis, coagulopathy, hepatic, renal and cardiac complications. Along with several other pathomechanisms, rhabdomyolysis is a distinguished cause of acute kidney injury (AKI) in patients with wasp sting. We herein report a case in which the patient developed rhabdomyolysis followed by AKI due to multiple wasp stings. The offending wasp was brought to the hospital and the species was confirmed by a zoologist (Vespa affinis).
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- 2016
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7. Extracellular Vesicles: A Possible Link between HIV and Alzheimer’s Disease-Like Pathology in HIV Subjects?
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Sunitha Kodidela, Kelli Gerth, Sanjana Haque, Yuqing Gong, Saifudeen Ismael, Ajay Singh, Ishrat Tauheed, and Santosh Kumar
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HIV ,exosomes ,extracellular vesicles (EVs) ,beta-amyloid ,Alzheimer’s disease ,neurodegeneration ,HAND ,HIV-TAT ,Cytology ,QH573-671 - Abstract
The longevity of people with HIV/AIDS has been prolonged with the use of antiretroviral therapy (ART). The age-related complications, especially cognitive deficits, rise as HIV patients live longer. Deposition of beta-amyloid (Aβ), a hallmark of Alzheimer’s disease (AD), has been observed in subjects with HIV-associated neurocognitive disorders (HAND). Various mechanisms such as neuroinflammation induced by HIV proteins (e.g., Tat, gp120, Nef), excitotoxicity, oxidative stress, and the use of ART contribute to the deposition of Aβ, leading to dementia. However, progressive dementia in older subjects with HIV might be due to HAND, AD, or both. Recently, extracellular vesicles (EVs)/exosomes, have gained recognition for their importance in understanding the pathology of both HAND and AD. EVs can serve as a possible link between HIV and AD, due to their ability to package and transport the toxic proteins implicated in both AD and HIV (Aβ/tau and gp120/tat, respectively). Given that Aß is also elevated in neuron-derived exosomes isolated from the plasma of HIV patients, it is reasonable to suggest that neuron-to-neuron exosomal transport of Aβ and tau also contributes to AD-like pathology in HIV-infected subjects. Therefore, exploring exosomal contents is likely to help distinguish HAND from AD. However, future prospective clinical studies need to be conducted to compare the exosomal contents in the plasma of HIV subjects with and without HAND as well as those with and without AD. This would help to find new markers and develop new treatment strategies to treat AD in HIV-positive subjects. This review presents comprehensive literatures on the mechanisms contributing to Aβ deposition in HIV-infected cells, the role of EVs in the propagation of Aβ in AD, the possible role of EVs in HIV-induced AD-like pathology, and finally, possible therapeutic targets or molecules to treat HIV subjects with AD.
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- 2019
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8. Genomic profile of Toll-like receptor pathways in traumatically brain-injured mice: effect of exogenous progesterone
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Sayeed Iqbal, Atif Fahim, Wei Wenjing, Ishrat Tauheed, Wang Jun, Hua Fang, and Stein Donald G
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Toll-like receptors ,progesterone ,traumatic brain injury ,inflammation ,mouse ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Background Traumatic brain injury (TBI) causes acute inflammatory responses that result in an enduring cascade of secondary neuronal loss and behavioral impairments. It has been reported that progesterone (PROG) can inhibit the increase of some inflammatory cytokines and inflammation-related factors induced by TBI. Toll-like receptors (TLRs) play a critical role in the induction and regulation of immune/inflammatory responses. Therefore, in the present study, we examined the genomic profiles of TLR-mediated pathways in traumatically injured brain and PROG's effects on these genes. Methods Bilateral cortical impact injury to the medial frontal cortex was induced in C57BL/6J mice. PROG was injected (i.p., 16 mg/kg body weight) at 1 and 6 h after surgery. Twenty-four hours post-surgery, mice were killed and peri-contusional brain tissue was harvested for genomic detection and protein measurement. RT-PCR arrays were used to measure the mRNA of 84 genes in TLR-mediated pathways. Western blot, ELISA and immunohistochemistry were used to confirm the protein expression of genes of interest. Results We found that 2 TLRs (TLR1 and 2), 5 adaptor/interacting proteins (CD14, MD-1, HSPA1a, PGRP and Ticam2) and 13 target genes (Ccl2, Csf3, IL1a, IL1b, IL1r1, IL6, IL-10, TNFa, Tnfrsf1a, Cebpb, Clec4e, Ptgs2 and Cxcl10) were significantly up-regulated after injury. Administration of PROG significantly down-regulated three of the 13 increased target genes after TBI (Ccl-2, IL-1b and Cxcl-10), but did not inhibit the expression of any of the detected TLRs and adaptor/interacting proteins. Rather, PROG up-regulated the expression of one TLR (TLR9), 5 adaptor/interacting proteins, 5 effectors and 10 downstream target genes. We confirmed that Ccl-2, Cxcl-10, TLR2 and TLR9 proteins were expressed in brain tissue, a finding consistent with our observations of mRNA expression. Conclusion The results demonstrate that TBI can increase gene expression in TLR-mediated pathways. PROG does not down-regulate the increased TLRs or their adaptor proteins in traumatically injured brain. Reduction of the observed inflammatory cytokines by PROG does not appear to be the result of inhibiting TLRs or their adaptors in the acute stage of TBI.
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- 2011
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9. Modulation of p75 neurotrophin receptor mitigates brain damage following ischemic stroke in mice.
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Mirzahosseini G and Ishrat T
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- 2024
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10. LM11A-31, a modulator of p75 neurotrophin receptor, suppresses HIV-1 replication and inflammatory response in macrophages.
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Mirzahosseini G, Sinha N, Zhou L, Godse S, Kodidela S, Singh UP, Ishrat T, and Kumar S
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- Humans, Oxidative Stress drug effects, Inflammation drug therapy, Inflammation metabolism, Darunavir pharmacology, HIV Infections drug therapy, HIV Infections virology, Receptors, Nerve Growth Factor metabolism, Cytokines metabolism, Isoleucine analogs & derivatives, Nerve Tissue Proteins, HIV-1 drug effects, Virus Replication drug effects, Macrophages drug effects, Macrophages metabolism, Macrophages virology, Morpholines pharmacology
- Abstract
Antiretroviral drugs have made significant progress in treating HIV-1 and improving the quality of HIV-1-infected individuals. However, due to their limited permeability into the brain HIV-1 replication persists in brain reservoirs such as perivascular macrophages and microglia, which cause HIV-1-associated neurocognitive disorders. Therefore, it is highly desirable to find a novel therapy that can cross the blood-brain barrier (BBB) and target HIV-1 pathogenesis in brain reservoirs. A recently developed 2-amino-3-methylpentanoic acid [2-morpholin-4-yl-ethyl]-amide (LM11A-31), which is a p75 neutrotrophin receptor (p75
NTR ) modulator, can cross the BBB. In this study, we examined whether LM11A-31 treatment can suppress HIV-1 replication, oxidative stress, cytotoxicity, and inflammatory response in macrophages. Our results showed that LM11A-31 (100 nM) alone and/or in combination with positive control darunavir (5.5 µM) significantly suppresses viral replication and reduces cytotoxicity. Moreover, the HIV-1 suppression by LM11A-31 was comparable to the HIV-1 suppression by darunavir. Although p75NTR was upregulated in HIV-1-infected macrophages compared to uninfected macrophages, LM11A-31 did not significantly reduce the p75NTR expression in macrophages. Furthermore, our study illustrated that LM11A-31 alone and/or in combination with darunavir significantly suppress pro-inflammatory cytokines including IL-1β, IL-8, IL-18, and TNF-α and chemokines MCP-1 in HIV-induced macrophages. The suppression of these cytokines and chemokines by LM11A-31 was comparable to darunavir. In contrast, LM11A-31 did not significantly alter oxidative stress, expression of antioxidant enzymes, or autophagy marker proteins in U1 macrophages. The results suggest that LM11A-31, which can cross the BBB, has therapeutic potential in suppressing HIV-1 and inflammatory response in brain reservoirs, especially in macrophages., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Mirzahosseini, Sinha, Zhou, Godse, Kodidela, Singh, Ishrat and Kumar.)- Published
- 2024
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11. Intranasal Delivery of Mitochondria Attenuates Brain Injury by AMPK and SIRT1/PGC-1α Pathways in a Murine Model of Photothrombotic Stroke.
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Salman M, Stayton AS, Parveen K, Parveen A, Puchowicz MA, Parvez S, Bajwa A, and Ishrat T
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- Animals, Male, Mice, Oxidative Stress drug effects, Mice, Inbred C57BL, Brain Injuries pathology, Brain Injuries drug therapy, Brain Injuries metabolism, Inflammasomes metabolism, Infarction, Middle Cerebral Artery complications, Infarction, Middle Cerebral Artery pathology, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Thrombosis pathology, Sirtuin 1 metabolism, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha metabolism, Administration, Intranasal, Mitochondria metabolism, Mitochondria drug effects, Disease Models, Animal, Signal Transduction drug effects, AMP-Activated Protein Kinases metabolism, Stroke pathology, Stroke drug therapy, Stroke metabolism
- Abstract
Ischemic stroke is one of the major causes of morbidity and mortality worldwide. Mitochondria play a vital role in the pathological processes of cerebral ischemic injury, but its transplantation and underlying mechanisms remain unclear. In the present study, we examined the effects of mitochondrial therapy on the modulation of AMPK and SIRT1/PGC-1α signaling pathway, oxidative stress, and NLRP3 inflammasome activation after photothrombotic ischemic stroke (pt-MCAO). The adult male mice were subjected to the pt-MCAO in which the proximal-middle cerebral artery was exposed with a 532-nm laser beam for 4 min by retro-orbital injection of a photosensitive dye (Rose Bengal: 15 mg/kg) before the laser light exposure and isolated mitochondria (100 μg protein) were administered intranasally at 30 min, 24 h, and 48 h following post-stroke. After 72 h, mice were tested for neurobehavioral outcomes and euthanized for infarct volume, brain edema, and molecular analysis. First, we found that mitochondria therapy significantly decreased brain infarct volume and brain edema, improved neurological dysfunction, attenuated ischemic stroke-induced oxidative stress, and neuroinflammation. Second, mitochondria treatment inhibited NLRP3 inflammasome activation. Finally, mitochondria therapy accelerated p-AMPKα(Thr172) and PGC-1α expression and resorted SIRT1 protein expression levels in pt-MCAO mice. In conclusion, our results demonstrate that mitochondria therapy exerts neuroprotective effects by inhibiting oxidative damage and inflammation, mainly dependent on the heightening activation of the AMPK and SIRT1/PGC-1α signaling pathway. Thus, intranasal delivery of mitochondria might be considered a new therapeutic strategy for ischemic stroke treatment., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2024
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12. Genetic and Pharmacological Modulation of P75 Neurotrophin Receptor Attenuate Brain Damage After Ischemic Stroke in Mice.
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Mirzahosseini G, Ismael S, Salman M, Kumar S, and Ishrat T
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- Mice, Animals, Receptor, Nerve Growth Factor metabolism, Mice, Inbred C57BL, Receptors, Nerve Growth Factor genetics, Receptors, Nerve Growth Factor metabolism, Brain metabolism, Infarction, Edema, Ischemic Stroke complications, Ischemic Stroke drug therapy, Brain Injuries
- Abstract
The precursor nerve growth factor (ProNGF) and its receptor p75 neurotrophin receptor (p75
NTR ) are upregulated in several brain diseases, including ischemic stroke. The activation of p75NTR is associated with neuronal apoptosis and inflammation. Thus, we hypothesized that p75NTR modulation attenuates brain damage and improves functional outcomes after ischemic stroke. Two sets of experiments were performed. (1) Adult wild-type (WT) C57BL/6 J mice were subjected to intraluminal suture-middle cerebral artery occlusion (MCAO) to induce cerebral ischemia. Pharmacological inhibitor of p75NTR , LM11A-31 (50 mg/kg), or normal saline was administered intraperitoneally (IP) 1 h post-MCAO, and animals survived for 24 h. (2) Adult p75NTR heterozygous knockout (p75NTR+/- ) and WT were subjected to photothrombotic (pMCAO) to induce ischemic stroke, and the animals survived for 72 h. The sensory-motor function of animals was measured using Catwalk XT. The brain samples were collected to assess infarction volume, edema, hemorrhagic transformation, neuroinflammation, and signaling pathway at 24 and 72 h after the stroke. The findings described that pharmacological inhibition and genetic knocking down of p75NTR reduce infarction size, edema, and hemorrhagic transformation following ischemic stroke. Additionally, p75NTR modulation significantly decreased several anti-apoptosis markers and improved sensory motor function compared to the WT mice following ischemic stroke. Our observations exhibit that the involvement of p75NTR in ischemic stroke and modulation of p75NTR could improve the outcome of ischemic stroke by increasing cell survival and enhancing motor performance. LM11A-31 has the potential to be a promising therapeutic agent for ischemic stroke. However, more evidence is needed to illuminate the efficacy of LM11A-31 in ischemic stroke., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)- Published
- 2024
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13. Lost in Translation: Neurotrophins Biology and Function in the Neurovascular Unit.
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Mirzahosseini G, Adam JM, Nasoohi S, El-Remessy AB, and Ishrat T
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- Humans, Neurons metabolism, Retina metabolism, Apoptosis physiology, Biology, Receptor, Nerve Growth Factor metabolism, Brain-Derived Neurotrophic Factor metabolism
- Abstract
The neurovascular unit (NVU) refers to the functional building unit of the brain and the retina, where neurons, glia, and microvasculature orchestrate to meet the demand of the retina's and brain's function. Neurotrophins (NTs) are structural families of secreted proteins and are known for exerting neurotrophic effects on neuronal differentiation, survival, neurite outgrowth, synaptic formation, and plasticity. NTs include several molecules, such as nerve growth factor, brain-derived neurotrophic factor, NT-3, NT-4, and their precursors. Furthermore, NTs are involved in signaling pathways such as inflammation, apoptosis, and angiogenesis in a nonneuronal cell type. Interestingly, NTs and the precursors can bind and activate the p75 neurotrophin receptor (p75
NTR ) at low and high affinity. Mature NTs bind their cognate tropomyosin/tyrosine-regulated kinase receptors, crucial for maintenance and neuronal development in the brain and retina axis. Activation of p75NTR results in neuronal apoptosis and cell death, while tropomysin receptor kinase upregulation contributes to differentiation and cell growth. Recent findings indicate that modulation of NTs and their receptors contribute to neurovascular dysfunction in the NVU. Several chronic metabolic and acute ischemic diseases affect the NVU, including diabetic and ischemic retinopathy for the retina, as well as stroke, acute encephalitis, and traumatic brain injury for the brain. This work aims to review the current evidence through published literature studying the impact of NTs and their receptors, including the p75NTR receptor, on the injured and healthy brain-retina axis., Competing Interests: Declaration of Conflicting InterestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: A.B.E. is listed as an inventor on patents relating to LM11A-31, which are assigned to the VA Medical Center. A.B.E. is the Founder of Nour Therapeutics LLC with interest to develop neurotrophin therapeutics.- Published
- 2023
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14. A modified murine photothrombotic stroke model: a minimally invasive and reproducible cortical and sub-cortical infarct volume and long-term deficits.
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Salman M, Ismael S, and Ishrat T
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- Animals, Mice, Reproducibility of Results, Brain, Cognition, Infarction, Stroke complications
- Abstract
Ischemic stroke is one of the major causes of devastating neurological disabilities and mortality worldwide. Despite extensive research for treatment approaches, there remains limited therapy in the stroke field. Therefore, more research is required for reproducibility to understand stroke pathology in pre-clinical studies. In the current modified method, mice were subjected to photothrombotic stroke (pt-MCA; proximal-middle cerebral artery was exposed with a 532 nm laser beam for 4 min) by retro-orbital injection of photosensitive dye, Rose Bengal (15 mg/kg) before the laser light exposure. Sensorimotor deficits were assessed by rotarod and catwalk test at 72 h following post-pt-MCAO, and brain samples were collected for infarct volume and hemorrhagic transformation (HT) assessments. Cognitive impairments were assessed by a novel objective recognition and Morris's water maze tests at the end of the follow-up. pt-MCAO animals significantly reduced body weight and impaired motor and cognitive functions. Furthermore, pt-MCAO animals showed apparent infarction, brain edema, and increased HT compared to the sham animals. Additionally, this method enables concurrent measurement of short-term and long-term neurological dysfunction with relatively larger cortical and sub-cortical infarct volume following pt-MCAO. With respect to the other models, this modified model offers enhanced reproducibility regarding infarct volume and cognitive/functional outcomes and avoids complications associated with critical surgeries and craniotomy. In conclusion, this modified model helps to understand stroke pathogenesis and minimize the animals' numbers which help to increase the scientific and statistical potential in pre-clinical studies., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
- Published
- 2023
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15. Intra-arterial verapamil improves functional outcomes of thrombectomy in a preclinical model of extended hyperglycemic stroke.
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Nasoohi S, Alehossein P, Jorjani M, Brown CM, and Ishrat T
- Abstract
The abrupt hyperglycemic reperfusion following thrombectomy has been shown to harm the efficacy of the intervention in stroke patients with large vessel occlusion. Studies of ours and others have shown thioredoxin-interacting protein (TXNIP) is critically involved in hyperglycemic stroke injury. We recently found verapamil ameliorates cerebrovascular toxicity of tissue plasminogen activators in hyperglycemic stroke. The present study aims to answer if verapamil exerts direct neuroprotective effects and alleviates glucose toxicity following thrombectomy in a preclinical model of hyperglycemic stroke. Primary cortical neural (PCN) cultures were exposed to hyperglycemic reperfusion following oxygen-glucose deprivation (OGD), with or without verapamil treatment. In a mouse model of intraluminal stroke, animals were subjected to 4 h middle cerebral artery occlusion (MCAO) and intravenous glucose infusion. Glucose infusion lasted one more hour at reperfusion, along with intra-arterial (i.a.) verapamil infusion. Animals were subjected to sensorimotor function tests and histological analysis of microglial phenotype at 72 h post-stroke. According to our findings, glucose concentrations (2.5-20 mM) directly correlated with TXNIP expression in OGD-exposed PCN cultures. Verapamil (100 nM) effectively improved PCN cell neurite growth and reduced TXNIP expression as well as interaction with NOD-like receptor pyrin domain-containing-3 (NLRP3) inflammasome, as determined by immunoblotting and immunoprecipitation. In our mouse model of extended hyperglycemic MCAO, i.a. verapamil (0.5 mg/kg) could attenuate neurological deficits induced by hyperglycemic stroke. This was associated with reduced microglial pro-inflammatory transition. This finding encourages pertinent studies in hyperglycemic patients undergoing thrombectomy where the robust reperfusion may exacerbate glucose toxicity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Nasoohi, Alehossein, Jorjani, Brown and Ishrat.)
- Published
- 2023
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16. Transplantation of Exercise-Induced Extracellular Vesicles as a Promising Therapeutic Approach in Ischemic Stroke.
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Alehossein P, Taheri M, Tayefeh Ghahremani P, Dakhlallah D, Brown CM, Ishrat T, and Nasoohi S
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- Humans, Prospective Studies, Brain metabolism, Ischemic Stroke metabolism, Stroke therapy, Stroke metabolism, Extracellular Vesicles metabolism
- Abstract
Clinical evidence affirms physical exercise is effective in preventive and rehabilitation approaches for ischemic stroke. This sustainable efficacy is independent of cardiovascular risk factors and associates substantial reprogramming in circulating extracellular vesicles (EVs). The intricate journey of pluripotent exercise-induced EVs from parental cells to the whole-body and infiltration to cerebrovascular entity offers several mechanisms to reduce stroke incidence and injury or accelerate the subsequent recovery. This review delineates the potential roles of EVs as prospective effectors of exercise. The candidate miRNA and peptide cargo of exercise-induced EVs with both atheroprotective and neuroprotective characteristics are discussed, along with their presumed targets and pathway interactions. The existing literature provides solid ground to hypothesize that the rich vesicles link exercise to stroke prevention and rehabilitation. However, there are several open questions about the exercise stressors which may optimally regulate EVs kinetic and boost brain mitochondrial adaptations. This review represents a novel perspective on achieving brain fitness against stroke through transplantation of multi-potential EVs generated by multi-parental cells, which is exceptionally reachable in an exercising body., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2023
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17. Protective Role of Short-Chain Fatty Acids against Ang- II-Induced Mitochondrial Dysfunction in Brain Endothelial Cells: A Potential Role of Heme Oxygenase 2.
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Kassan M, Kwon Y, Munkhsaikhan U, Sahyoun AM, Ishrat T, Galán M, Gonzalez AA, Abidi AH, Kassan A, and Ait-Aissa K
- Abstract
Objectives: Short-chain fatty acids (SCFAs), the main metabolites released from the gut microbiota, are altered during hypertension and obesity. SCFAs play a beneficial role in the cardiovascular system. However, the effect of SCFAs on cerebrovascular endothelial cells is yet to be uncovered. In this study, we use brain endothelial cells to investigate the in vitro effect of SCFAs on heme oxygenase 2 (HO-2) and mitochondrial function after angiotensin II (Ang-II) treatment., Methods: Brain human microvascular endothelial cells were treated with Ang-II (500 nM for 24 h) in the presence and absence of an SCFAs cocktail (1 μM; acetate, propionate, and butyrate) and/or HO-2 inhibitor (SnPP 5 μM). At the end of the treatment, HO-2, endothelial markers (p-eNOS and NO production), inflammatory markers (TNFα, NFκB-p50, and -p65), calcium homeostasis, mitochondrial membrane potential, mitochondrial ROS and H
2 O2 , and mitochondrial respiration were determined in all groups of treated cells., Key Results: Our data showed that SCFAs rescued HO-2 after Ang-II treatment. Additionally, SCFAs rescued Ang-II-induced eNOS reduction and mitochondrial membrane potential impairment and mitochondrial respiration damage. On the other hand, SCFAs reduced Ang-II-induced inflammation, calcium dysregulation, mitochondrial ROS, and H2 O2 . All of the beneficial effects of SCFAs on endothelial cells and mitochondrial function occurred through HO-2., Conclusions: SCFAs treatment restored endothelial cells and mitochondrial function following Ang-II-induced oxidative stress. SCFAs exert these beneficial effects by acting on HO-2. Our results are opening the door for more studies to investigate the effect the of SCFAs/HO-2 axis on hypertension and obesity-induced cerebrovascular diseases.- Published
- 2023
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18. Pro-survival Phenotype of HIF-1α: Neuroprotection Through Inflammatory Mechanisms.
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Puchowicz MA, Parveen K, Sethuraman A, Ishrat T, Xu K, and LaManna J
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- Humans, Signal Transduction, Inflammation genetics, Phenotype, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Neuroprotection, Gene Expression Regulation
- Abstract
Hypoxia-inducible factor 1 (HIF-1) is a major player in the oxygen sensor system as well as a transcription factor. HIF-1 is also associated in the pathogenesis of many brain diseases including Alzheimer's disease (AD), epilepsy and stroke. HIF-1 regulates the expression of many genes such as those involved in glycolysis, erythropoiesis, angiogenesis and proliferation in hypoxic condition. Despite several studies, the mechanism through which HIF-1 confers neuroprotection remains unclear, one of them is modulating metabolic profiles and inflammatory pathways. Characterization of the neuroprotective role of HIF-1 may be through its stabilization and the regulation of target genes that aid in the early adaptation to the oxidative stressors. It is interesting to note that mounting data from recent years point to an additional crucial regulatory role for hypoxia-inducible factors (HIFs) in inflammation. HIFs in immune cells regulate the production of glycolytic energy as well as innate immunity, pro-inflammatory gene expression, and mediates activation of pro-survival pathways. The present review highlights the contribution of HIF-1 to neuroprotection where inflammation is the crucial factor in the pathogenesis contributing to neural death. The potential mechanisms that contribute to neuroprotection as a result of the downstream targets of HIF-1α are discussed. Such mechanisms include those mediated through IL-10, an anti-inflammatory molecule involved in activating pro-survival signaling mechanisms via AKT/ERK and JAK/STAT pathways., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)
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- 2023
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19. The p75 neurotrophin receptor inhibitor, LM11A-31, ameliorates acute stroke injury and modulates astrocytic proNGF.
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Nasoohi S, Tayefeh Ghahremani P, Alehossein P, Elyasizadeh S, BaniArdalan S, Ismael S, Vatanpour H, Ahmadiani A, and Ishrat T
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- Mice, Humans, Animals, Nerve Growth Factor metabolism, Astrocytes metabolism, Receptors, Nerve Growth Factor genetics, Receptors, Nerve Growth Factor metabolism, Receptor, Nerve Growth Factor metabolism, Stroke drug therapy
- Abstract
The precursor form of nerve growth factor (proNGF) is essential to maintain NGF survival signaling. ProNGF is also among endogenous ligands for p75 neurotrophin receptor (p75ntr). Mounting evidence implies that p75ntr signaling contributes to neural damage in ischemic stroke. The present study examines the therapeutic effect of the p75ntr modulator LM11A-31. Adult mice underwent transient distal middle cerebral artery occlusion (t-dMCAO) followed by LM11A-31 treatment (25 mg/kg, i.p., twice daily) either for 72 h post-injury (acute phase) or afterward till two weeks post-stroke (subacute phase). LM11A-31 reduced blood-brain barrier permeability, cerebral tissue injury, and sensorimotor function in the acute phase of stroke. Ischemic brain samples showed repressed proNGF/P75ntr signaling and Caspase 3 activation in LM11A-31 treated mice, where we observed less reactive microglia and IL-1β production. LM11A-31 (20-80 nM) also mitigated neural injury induced by oxygen-glucose deprivation (OGD) in sandwich co-cultures of primary cortical neurons (PCN) and astrocytes. This concurred with JNK/PARP downregulation and reduced caspase-3 cleavage in the PCNs and was associated with repressed proNGF generation in astrocytes. Further in vitro experiments indicated human proNGF suppresses the pro-inflammatory phenotype in microglial cultures, as determined by a sharp decline in HMGB-1 production and moderate arginase-1 upregulation. Despite significant protection in acute stroke, LM11A-31 treatment did not improve cortical atrophy and sensorimotor function in the subacute phase. Our findings provide preclinical evidence supporting LM11A-31 as a promising therapy for acute stroke injury. Further investigations may elucidate if reduced astrocytic proNGF, an endogenous reservoir of pro-neurotrophins, may restrict the therapeutic window., (Copyright © 2022. Published by Elsevier Inc.)
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- 2023
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20. Verapamil inhibits TXNIP-NLRP3 inflammasome activation and preserves functional recovery after intracerebral hemorrhage in mice.
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Ismael S, Patrick D, Salman M, Parveen A, Stanfill AG, and Ishrat T
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- Mice, Male, Animals, Verapamil pharmacology, Verapamil therapeutic use, Mice, Inbred C57BL, Cerebral Hemorrhage drug therapy, Cerebral Hemorrhage metabolism, Carrier Proteins, Thioredoxins metabolism, Inflammasomes, NLR Family, Pyrin Domain-Containing 3 Protein metabolism
- Abstract
Intracerebral hemorrhage (ICH) is the second most common type of stroke with no satisfactory treatment. Recent studies from our group and others indicated a potential positive effect of verapamil, a commonly prescribed calcium channel blocker, with thioredoxin-interacting protein (TXNIP) inhibitor properties, in ischemic stroke and cognitive disorders. It is unclear whether there would be a beneficial effect of verapamil administration in ICH. Therefore, this study was designed to determine the neuroprotective effects of verapamil in a murine ICH model. ICH was induced by stereotactic injection of collagenase type VII (0.075 U) into the right striatum of adult male C57BL/6 mice. Verapamil (0.15 mg/kg) or saline was administered intravenously at 1 h post-ICH followed by oral (1 mg/kg/d) administration in drinking water for 28 days. Motor and cognitive function were assessed using established tests for motor coordination, spatial learning, short- and long-term memory. A subset of animals was sacrificed at 72 h after ICH for molecular analysis. Verapamil treatment reduced expression of TXNIP and NOD-like receptor pyrin domain-containing-3 inflammasome activation in the perihematomal area. These protective effects of verapamil were associated with decreased proinflammatory mediators, microglial activation, and blood-brain barrier permeability markers and paralleled less phosphorylated nuclear factor kappa B level. Our findings also demonstrate that long-term low-dose verapamil effectively attenuated motor and cognitive impairments. Taken together, these data indicate that verapamil has therapeutic potential in improving acute motor function after ICH. Further investigations are needed to confirm whether verapamil treatment could be a promising candidate for clinical trials., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
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- 2022
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21. A Systematic Review of Inflammatory Cytokine Changes Following Aneurysmal Subarachnoid Hemorrhage in Animal Models and Humans.
- Author
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Devlin P, Ishrat T, and Stanfill AG
- Subjects
- Animals, Humans, Cytokines, Inflammation complications, Models, Animal, Subarachnoid Hemorrhage complications, Subarachnoid Hemorrhage therapy, Intracranial Aneurysm complications
- Abstract
Aneurysmal subarachnoid hemorrhage (aSAH) is a severe form of stroke that occurs following rupture of a cerebral aneurysm. Acute inflammation and secondary delayed inflammatory responses, both largely controlled by cytokines, work together to create high mortality and morbidity for this group. The trajectory and time course of cytokine change must be better understood in order to effectively manage unregulated inflammation and improve patient outcomes following aSAH. A systematic review was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Three different search phrases ("cytokines and subarachnoid hemorrhage," "cytokine levels and subarachnoid hemorrhage," and "cytokine measurement and subarachnoid hemorrhage") were applied across three databases (PubMed, SCOPUS, and the Cochrane Library). Our procedures returned 856 papers. After application of inclusion/exclusion criteria, 95 preclinical animal studies and 41 clinical studies remained. Across studies, 22 different cytokines had been investigated, 5 different tissue types were analyzed, and 3 animal models were utilized. Three main pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) demonstrated reliable increases following aSAH across the included studies. While this is a promising area of research for potential therapeutics, there are gaps in the knowledge base that bar progress for clinical translation of this information. In particular, there is a need for investigations that explore the systemic inflammatory response following injury in a more diverse number of cytokines, the balance of specific pro-/anti- inflammatory cytokines, and how these biomarkers relate to patient outcomes and recovery over time., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2022
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22. White matter damage as a consequence of vascular dysfunction in a spontaneous mouse model of chronic mild chronic hypoperfusion with eNOS deficiency.
- Author
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Chen X, Chen L, Lin G, Wang Z, Kodali MC, Li M, Chen H, Lebovitz SG, Ortyl TC, Li L, Ismael S, Singh P, Malik KU, Ishrat T, Zhou FM, Zheng W, and Liao FF
- Subjects
- Animals, Mice, Nitric Oxide metabolism, Cerebrovascular Circulation, Disease Models, Animal, White Matter pathology, Dementia, Vascular pathology, Dementia, Vascular psychology, Cognitive Dysfunction metabolism, Alzheimer Disease metabolism
- Abstract
Vascular cognitive impairment and dementia (VCID) is the second most common form of dementia after Alzheimer's disease (AD). Currently, the mechanistic insights into the evolution and progression of VCID remain elusive. White matter change represents an invariant feature. Compelling clinical neuroimaging and pathological evidence suggest a link between white matter changes and neurodegeneration. Our prior study detected hypoperfused lesions in mice with partial deficiency of endothelial nitric oxide (eNOS) at very young age, precisely matching to those hypoperfused areas identified in preclinical AD patients. White matter tracts are particularly susceptible to the vascular damage induced by chronic hypoperfusion. Using immunohistochemistry, we detected severe demyelination in the middle-aged eNOS-deficient mice. The demyelinated areas were confined to cortical and subcortical areas including the corpus callosum and hippocampus. The intensity of demyelination correlated with behavioral deficits of gait and associative recognition memory performances. By Evans blue angiography, we detected blood-brain barrier (BBB) leakage as another early pathological change affecting frontal and parietal cortex in eNOS-deficient mice. Sodium nitrate fortified drinking water provided to young and middle-aged eNOS-deficient mice completely prevented non-perfusion, BBB leakage, and white matter pathology, indicating that impaired endothelium-derived NO signaling may have caused these pathological events. Furthermore, genome-wide transcriptomic analysis revealed altered gene clusters most related to mitochondrial respiratory pathways selectively in the white matter of young eNOS-deficient mice. Using eNOS-deficient mice, we identified BBB breakdown and hypoperfusion as the two earliest pathological events, resulting from insufficient vascular NO signaling. We speculate that the compromised BBB and mild chronic hypoperfusion trigger vascular damage, along with oxidative stress and astrogliosis, accounting for the white matter pathological changes in the eNOS-deficient mouse model. We conclude that eNOS-deficient mice represent an ideal spontaneous evolving model for studying the earliest events leading to white matter changes, which will be instrumental to future therapeutic testing of drug candidates and for targeting novel/specific vascular mechanisms contributing to VCID and AD., (© 2022. The Author(s).)
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- 2022
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23. Verapamil, a possible repurposed therapeutic candidate for stroke under hyperglycemia.
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Ismael S and Ishrat T
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- 2022
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24. Compound 21, a Direct AT2R Agonist, Induces IL-10 and Inhibits Inflammation in Mice Following Traumatic Brain Injury.
- Author
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Ismael S and Ishrat T
- Subjects
- Animals, Imidazoles, Inflammation drug therapy, Interleukin-10 therapeutic use, Mice, Mice, Inbred C57BL, Sulfonamides, Thiophenes, Brain Injuries, Traumatic drug therapy, Receptor, Angiotensin, Type 2 agonists, Receptor, Angiotensin, Type 2 therapeutic use
- Abstract
Recent studies demonstrated that the angiotensin type 2 receptor (AT2R) agonist, compound 21 (C21), provides neuroprotection and enhances recovery in experimental stroke. However, C21 has never been tested in traumatic brain injury (TBI). Here, we aim to examine whether C21 confers protection after TBI. Unilateral cortical impact injury was induced in young adult C57BL/6 mice. C21 (0.03 mg/kg, i.p.) was administered at 1 h and 3 h post-TBI. After neurological severity score (NSS) assessments, all animals were sacrificed for immunoblotting analysis at 24 h post-TBI. C21 treatment significantly ameliorated NSS and reduced TBI's biomarkers [high mobility group box 1 (HMGB1), aquaporin-4 (AQ4)] and inflammatory markers [interlukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α)] in the pericontusional areas compared to saline TBI. Further, C21 treatment induced interleukin-10 (IL-10) and phosphorylation of endothelial nitric oxide synthase (eNOS) after TBI. C21 also attenuated pro-apoptotic activation of poly (ADP-ribose) polymerase (PARP) and caspase-3. These findings support the therapeutic potential of C21 against TBI., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2022
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25. Effects of pramipexole on beta-amyloid 1-42 memory deficits and evaluation of oxidative stress and mitochondrial function markers in the hippocampus of Wistar rat.
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Salman M, Akram M, Shahrukh M, Ishrat T, and Parvez S
- Subjects
- Acetylcholinesterase metabolism, Adenosine Triphosphate metabolism, Animals, Antioxidants pharmacology, Biomarkers metabolism, Cytochromes metabolism, Cytochromes pharmacology, Glutathione metabolism, Hippocampus, Maze Learning, Memory Disorders chemically induced, Memory Disorders drug therapy, Memory Disorders metabolism, Mitochondria, Oxidative Stress, Peptide Fragments, Pramipexole adverse effects, Rats, Rats, Wistar, Reactive Oxygen Species metabolism, bcl-2-Associated X Protein metabolism, Alzheimer Disease metabolism, Amyloid beta-Peptides metabolism
- Abstract
Oxidative damage and mitochondrial dysfunction are two prominent pathological features and gradually understood as important pathogenic events for neurodegenerative diseases, including aging and Alzheimer's disease (AD). The present study was aimed to explore the prolonged treatment of pramipexole (PPX) following amyloid beta (Aβ
1-42 )-induced cognitive impairments , oxidative stress, and mitochondrial dysfunction in a Wistar rat model. We have found that PPX (1.0 mg/kg, b.wt.) improves cognitive impairments of Aβ1-42 -infused rats in Morris water maze. At the same time, PPX attenuated Aβ1-42 -induced oxidative damage and increased reduced-glutathione content level, decreased lipid peroxidation rate and suppressed the activity of acetylcholinesterase and shows antioxidant effects. Additionally, PPX treatment has shown inhibition of mitochondrial reactive oxygen species production and restored mitochondrial membrane potential, oxidative phosphorylation, and enhanced ATP levels in Aβ1-42 rats. Furthermore, PPX treatment reduced bioenergetics loss and dynamics alterations by upregulating PGC-1α protein level and mitigating translocation of Bax and Drp-1 to mitochondria and cytochrome-c release into the cytoplasm. PPX also increased mitofusin-2 protein expression, a basic element of mitochondrial fusion process. We conclude that remedial role of PPX in mitigating oxidative damage and mitochondrial perturbation that are modulated in Aβ1-42 rats may have the propensity in AD pathogenesis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)- Published
- 2022
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26. Contralesional angiotensin type 2 receptor activation contributes to recovery in experimental stroke.
- Author
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Fouda AY, Ahmed HA, Pillai B, Kozak A, Hardigan T, Ergul A, Fagan SC, and Ishrat T
- Subjects
- Animals, Diabetes Mellitus, Experimental, Imidazoles pharmacology, Infarction, Middle Cerebral Artery, Rats, Rats, Wistar, Sulfonamides, Thiophenes pharmacology, Receptor, Angiotensin, Type 2 agonists, Receptor, Angiotensin, Type 2 genetics, Receptor, Angiotensin, Type 2 metabolism, Stroke drug therapy
- Abstract
We and others have previously shown that angiotensin II receptor type 2 receptor (AT2R) is upregulated in the contralesional hemisphere after stroke in normoglycemic Wistar rats. In this study, we examined the expression of AT2R in type 2 diabetic Goto-Kakizaki (GK) rats and control Wistars after stroke. We also tested the contribution of the contralesional AT2R in recovery after stroke through a specific knockdown of the AT2R in this hemisphere only. Two experiments were conducted. In the first experiment, GK rats were subjected to middle cerebral artery occlusion (MCAO) and treated with the angiotensin II receptor type 1 receptor (AT1R) blocker candesartan or saline at reperfusion. Stroke outcomes, as well as AT2R expression, were examined and compared to control Wistars at 24 h. In the second experiment, localized AT2R knockdown was achieved through intrastriatal injection of short hairpin RNA (shRNA) lentiviral particles or non-targeting control into the left-brain hemisphere of Wistar rats. After 14 days, rats were subjected to right MCAO and treated with the AT2R agonist, Compound 21 (C21), or saline for 7 days. Behavioral outcomes were assessed for up to 10 days. In the first experiment, stroke reduced the expression of AT2R in GK rats. Candesartan treatment failed to improve the neurobehavioral outcomes, preserve vascular integrity or reduce oxidative/nitrative stress or apoptotic markers at 24 h post stroke in these animals. In the second experiment, contralesional AT2R knockdown reduced the C21-mediated functional recovery after stroke. In conclusion, contralesional AT2R upregulation after stroke is blunted in diabetic rats which show reduced sensitivity to post-stroke candesartan treatment. Contralesional AT2R could be involved in C21-mediated functional recovery after stroke., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
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- 2022
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27. Direct AT2R Stimulation Slows Post-stroke Cognitive Decline in the 5XFAD Alzheimer's Disease Mice.
- Author
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Ahmed HA, Ismael S, Salman M, Devlin P, McDonald MP, Liao FF, and Ishrat T
- Subjects
- Amyloid beta-Peptides, Animals, Disease Models, Animal, Humans, Imidazoles, Mice, Mice, Transgenic, Receptor, Angiotensin, Type 2, Sulfonamides, Thiophenes, Alzheimer Disease pathology, Cognitive Dysfunction drug therapy, Cognitive Dysfunction etiology, Neurodegenerative Diseases complications, Stroke complications
- Abstract
Alzheimer's disease (AD), currently the single leading cause of death still on the rise, almost always coexists alongside vascular cognitive impairment (VCI). In fact, the ischemic disease affects up to 90% of AD patients, with strokes and major infarctions representing over a third of vascular lesions. Studies also confirmed that amyloid plaques, typical of AD, are much more likely to cause dementia if strokes or cerebrovascular damage also exist, leading to the term "mixed pathology" cognitive impairment. Although its incidence is expected to grow, there are no satisfactory treatments. There is hence an urgent need for safe and effective therapies that preserve cognition, maintain function, and prevent the clinical deterioration that results from the progression of this irreversible, neurodegenerative disease. To our knowledge, this is the first study to investigate the effects of long-term treatment with C21, a novel angiotensin II type 2 receptor (AT2R) agonist, on the development of "mixed pathology" cognitive impairment. This was accomplished using a unique model that employs the fundamental elements of both AD and VCI. Treatment with C21/vehicle was started 1 h post-stroke and continued for 5 weeks in mice with concurrent AD pathology. Efficacy was established through a series of functional tests assessing various aspects of cognition, including spatial learning, short-term/working memory, long-term/reference memory, and cognitive flexibility, in addition to the molecular markers characteristic of AD. Our findings demonstrate that C21 treatment preserves cognitive function, maintains cerebral blood flow, and reduces Aβ accumulation and toxic tau phosphorylation in AD animals post-stroke., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2022
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28. Candesartan Effectively Preserves Cognition in Senescence Accelerated Mouse Prone 8 (SAMP8) mice.
- Author
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Ahmed HA and Ishrat T
- Abstract
Background: Alzheimer's disease (AD) has become a worldwide crisis with no effective therapeutic options. The medications currently available for AD are only palliative; their effect is temporary, and they are associated with unfavorable side effects. Even the newest medication aducanumab, granted accelerated FDA approval in 2021, failed to show cognitive benefits in clinical trials and continued approval requires verification in subsequent clinical trials. There is an urgent need for safe and effective therapies to preserve cognition and effectively manage AD. Generally, a new drug product takes several years for FDA approval and exceeds 2.5 billion dollars in research and development, with most new drug products never even reaching the market. This has led to a recent shift for repurposing/repositioning existing FDA-approved medications, to new therapeutic indications., Objective: To investigate the effects of long-term treatment with candesartan, an FDA-approved angiotensin-II type-1 receptor blocker (ARB), on the development of cognitive impairment associated with premature aging., Methods: Candesartan was given at a dose of 1 mg/kg/d in an AD model of senescence-accelerated mouse prone-8 (SAMP8) and senescence-accelerated mouse resistant (SAMR1) mice. Oral treatment with candesartan or vehicle was started, in 2-month-old mice and administered continuously for 4-months., Results: Low-dose candesartan prevented the development of cognitive impairment, otherwise associated with accelerated aging, in SAMP8 mice, by reducing inflammation and nitro-oxidative stress. Candesartan did not affect the cognitive function of control SAMR1 mice., Conclusion: Early ARB treatment might be beneficial in preventing age-related cognitive deficits in AD-prone individuals., Competing Interests: The authors declare they have no conflict of interests., (© 2022 – The authors. Published by IOS Press.)
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- 2022
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29. Repurposing verapamil for prevention of cognitive decline in sporadic Alzheimer's disease.
- Author
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Ahmed HA and Ishrat T
- Abstract
Competing Interests: None
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- 2022
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30. Acute Hyperglycemia Exacerbates Hemorrhagic Transformation after Embolic Stroke and Reperfusion with tPA: A Possible Role of TXNIP-NLRP3 Inflammasome.
- Author
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Salman M, Ismael S, Li L, Ahmed HA, Puchowicz MA, and Ishrat T
- Subjects
- Animals, Carrier Proteins physiology, Disease Models, Animal, Inflammasomes physiology, Injections, Intravenous, Male, Mice, NLR Family, Pyrin Domain-Containing 3 Protein physiology, Thioredoxins physiology, Embolic Stroke drug therapy, Embolic Stroke pathology, Hyperglycemia complications, Reperfusion, Tissue Plasminogen Activator administration & dosage
- Abstract
Objectives: Acute hyperglycemia (HG) exacerbates reperfusion injury after stroke. Our recent studies showed that acute HG upregulates thioredoxin-interacting protein (TXNIP) expression, which in turn induces inflammation and neurovascular damage in a suture model of ischemic stroke. The aim of the present study was to investigate the effect of acute HG on TXNIP-associated neurovascular damage, in a more clinically relevant murine model of embolic stroke and intravenous tissue plasminogen activator (IV-tPA) reperfusion., Materials and Methods: HG was induced in adult male mice, by intraperitoneal injection of 20% glucose. This was followed by embolic middle cerebral artery occlusion (eMCAO), with or without IV-tPA (10 mg/kg) given 3 h post embolization. Brain infarction, edema, hemoglobin content, expression of matrix metalloproteinase (MMP-9), vascular endothelial growth factor A (VEGFA), tight junction proteins (claudin-5, occluding, and zonula occludens-1), TXNIP, and NOD-like receptor protein3 (NLRP3)-inflammasome activation were evaluated at 24 h after eMCAO., Results: HG alone significantly increased TXNIP in the brain after eMCAO, and this was associated with exacerbated hemorrhagic transformation (HT; as measured by hemoglobin content). IV-tPA in HG conditions showed a trend to decrease infarct volume, but worsened HT after eMCAO, suggesting that HG reduces the therapeutic efficacy of IV-tPA. Further, HG and tPA-reperfusion did not show significant differences in expression of MMP-9, VEGFA, junction proteins, and NLRP3 inflammasome activation between the groups., Conclusion: The current findings suggest a potential role for TXNIP in the occurrence of HT in hyperglycemic conditions following eMCAO. Further studies are needed to understand the precise role of vascular TXNIP on HG/tPA-induced neurovascular damage after stroke., Competing Interests: Conflicts of Interest The authors declare no conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)
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- 2022
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31. Diabetes Mellitus during the Pandemic Covid-19: Prevalence, Pathophysiology, Mechanism, and Management: An updated overview.
- Author
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Rais N, Ahmad R, Ved A, Parveen K, Ishrat T, Prakash O, Shadab M, Bari DG, and Siddiqui NA
- Subjects
- COVID-19 Vaccines, Humans, Pandemics, Prevalence, SARS-CoV-2, COVID-19 epidemiology, COVID-19 therapy, Diabetes Mellitus epidemiology, Diabetes Mellitus therapy
- Abstract
Background: Diabetes mellitus (DM) is among the most frequently reported comorbidities in patients tainted with the pandemic coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). With a high pervasiveness of diabetes mellitus, there is an urgency to understand the special aspects of COVID-19 in hyperglycemic patients. Diabetic patients are at higher risk than the general population of viral or bacterial infections, thus require special attention since diabetes is linked with severe, critical, and lethal modes of COVID-19., Objective: The objective of this study was to focus on epidemiology, pathophysiology, mechanism, and management of DM with COVID-19., Methods: The search was carried out on databases portals such as Pubmed, EMBASE, Google Scholar, and CINAHL with the keywords, i.e., COVID-19, coronavirus, SARS-CoV-2, diabetes, covid-19, etc. Result: DM and COVID-19 disease conditions can impact each other in terms of clinical progression and outcome. Available laboratory/clinical observations suggest that hyperglycemia-induced immune dysfunction, inflated lactate grades, and cytokines storm may play critical roles in the seriousness of COVID-19 in patients with diabetes; however, the exact mechanisms linking diabetes and COVID-19 remain to be further clarified., Conclusion: Standards to constrain the disease spread at the individual and community level are the key to extenuate the speedily rising pandemic, while definitive treatment, like plasma therapy, chemoprophylaxis, or vaccine for COVID-19, has yet to be discovered., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
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- 2022
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32. Thioredoxin interacting protein, a key molecular switch between oxidative stress and sterile inflammation in cellular response.
- Author
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Mohamed IN, Li L, Ismael S, Ishrat T, and El-Remessy AB
- Abstract
Tissue and systemic inflammation have been the main culprit behind the cellular response to multiple insults and maintaining homeostasis. Obesity is an independent disease state that has been reported as a common risk factor for multiple metabolic and microvascular diseases including nonalcoholic fatty liver disease (NAFLD), retinopathy, critical limb ischemia, and impaired angiogenesis. Sterile inflammation driven by high-fat diet, increased formation of reactive oxygen species, alteration of intracellular calcium level and associated release of inflammatory mediators, are the main common underlying forces in the pathophysiology of NAFLD, ischemic retinopathy, stroke, and aging brain. This work aims to examine the contribution of the pro-oxidative and pro-inflammatory thioredoxin interacting protein (TXNIP) to the expression and activation of NLRP3-inflammasome resulting in initiation or exacerbation of sterile inflammation in these disease states. Finally, the potential for TXNIP as a therapeutic target and whether TXNIP expression can be modulated using natural antioxidants or repurposing other drugs will be discussed., Competing Interests: Conflict-of-interest statement: The authors declare that they have no personal interests., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)
- Published
- 2021
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33. Endothelial Thioredoxin-Interacting Protein Depletion Reduces Hemorrhagic Transformation in Hyperglycemic Mice after Embolic Stroke and Thrombolytic Therapy.
- Author
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Salman M, Ismael S, Li L, Ahmed HA, Puchowicz MA, and Ishrat T
- Abstract
We hypothesize that endothelial-specific thioredoxin-interacting protein knock-out (EC-TXNIP KO) mice will be more resistant to the neurovascular damage (hemorrhagic-transformation-HT) associated with hyperglycemia (HG) in embolic stroke. Adult-male EC-TXNIP KO and wild-type (WT) littermate mice were injected with-streptozotocin (40 mg/kg, i.p.) for five consecutive days to induce diabetes. Four-weeks after confirming HG, mice were subjected to embolic middle cerebral artery occlusion (eMCAO) followed by tissue plasminogen activator (tPA)-reperfusion (10 mg/kg at 3 h post-eMCAO). After the neurological assessment, animals were sacrificed at 24 h for neurovascular stroke outcomes. There were no differences in cerebrovascular anatomy between the strains. Infarct size, edema, and HT as indicated by hemoglobin (Hb)-the content was significantly higher in HG-WT mice, with or without tPA-reperfusion, compared to normoglycemic WT mice. Hyperglycemic EC-TXNIP KO mice treated with tPA tended to show lower Hb-content, edema, infarct area, and less hemorrhagic score compared to WT hyperglycemic mice. EC-TXNIP KO mice showed decreased expression of inflammatory mediators, apoptosis-associated proteins, and nitrotyrosine levels. Further, vascular endothelial growth factor-A and matrix-metalloproteinases (MMP-9/MMP-3), which degrade junction proteins and increase blood-brain-barrier permeability, were decreased in EC-TXNIP KO mice. Together, these findings suggest that vascular-TXNIP could be a novel therapeutic target for neurovascular damage after stroke.
- Published
- 2021
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34. ER stress associated TXNIP-NLRP3 inflammasome activation in hippocampus of human Alzheimer's disease.
- Author
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Ismael S, Wajidunnisa, Sakata K, McDonald MP, Liao FF, and Ishrat T
- Subjects
- Aged, Aged, 80 and over, Biomarkers, CARD Signaling Adaptor Proteins metabolism, Caspase 1 metabolism, Eukaryotic Initiation Factor-2, Female, Humans, Interleukin-1beta metabolism, Male, Middle Aged, Transcription Factor CHOP metabolism, Alzheimer Disease genetics, Carrier Proteins genetics, Endoplasmic Reticulum Stress, Hippocampus pathology, Inflammasomes, NLR Family, Pyrin Domain-Containing 3 Protein genetics
- Abstract
Although the exact etiology of Alzheimer's disease (AD) is poorly understood, experimental and clinical evidences suggest the contribution of neuroinflammation in the pathogenesis of AD. Pathologically, AD brain is characterized by an imbalance in redox status, elevated endoplasmic reticulum (ER) stress, synaptic dysfunction, inflammation, and progressive neurodegeneration. It has been noted that continuous accumulation of amyloid-beta (Aβ) and intracellular neurofibrillary tangles (NFTs) in AD brain trigger ER stress, which contributes to neurodegeneration. Similarly, experimental evidences supports the hypothesis that thioredoxin-interacting protein (TXNIP), an endogenous regulator of redox regulator thioredoxin (TRX), is activated by ER stress and contributes to activation of NLRP3 (NOD-like receptor protein 3) inflammatory cascade in hippocampus of the AD brain. Hippocampus of postmortem human AD and aged matched non-AD controls were analyzed for the expression ER stress markers and TXNIP-NLRP3 inflammasome at cellular and molecular levels. We found higher expression of TXNIP at protein and transcript levels in close association with pathological markers of AD such as Aβ and NFTs in AD hippocampus. In addition, our results demonstrated that TXNIP was co-localized in neurons and microglia. Moreover, expression of binding immunoglobulin protein (BiP), activated eukaryotic initiation factor-2α (eIf2α) and C/EBP homology protein (CHOP), proteins involved the development of ER stress, were elevated in AD hippocampus. Further, elevated expression of effector molecules of NLRP3 inflammasome activation such as apoptosis associated speck-like protein (ASC), cleaved caspase-1 and cleaved interleukin-1β were observed in the AD hippocampus. The study suggests that TXNIP could be a link that connect ER stress with neuroinflammation. Thus, TXNIP can be a possible therapeutic target to mitigate the progression of neuroinflammation in the pathogenesis of AD., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2021
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35. Verapamil as an Adjunct Therapy to Reduce tPA Toxicity in Hyperglycemic Stroke: Implication of TXNIP/NLRP3 Inflammasome.
- Author
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Ismael S, Nasoohi S, Yoo A, Mirzahosseini G, Ahmed HA, and Ishrat T
- Subjects
- Animals, Carrier Proteins antagonists & inhibitors, Drug Therapy, Combination, Fibrinolytic Agents administration & dosage, Hyperglycemia drug therapy, Male, Mice, NLR Family, Pyrin Domain-Containing 3 Protein antagonists & inhibitors, Stroke drug therapy, Thioredoxins antagonists & inhibitors, Tissue Plasminogen Activator toxicity, Vasodilator Agents administration & dosage, Carrier Proteins metabolism, Hyperglycemia metabolism, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Stroke metabolism, Thioredoxins metabolism, Tissue Plasminogen Activator administration & dosage, Verapamil administration & dosage
- Abstract
Thrombolytic therapy has remained quite challenging in hyperglycemic patients for its association with poor prognosis and increased hemorrhagic conversions. We recently showed that tissue plasminogen activator (tPA)-induced cerebrovascular damage is associated with thioredoxin-interacting protein (TXNIP) upregulation, which has an established role in the detrimental effects of hyperglycemia. In the present work, we investigated whether verapamil, an established TXNIP inhibitor, may provide protection against hyperglycemic stroke and tPA-induced blood-brain barrier (BBB) disruption. Acute hyperglycemia was induced by intraperitoneal administration of 20% glucose, 15 min prior to transient middle cerebral artery occlusion (tMCAO). Verapamil (0.15 mg/kg) or saline was intravenously infused with tPA at hyperglycemic reperfusion, 1 h post tMCAO. After 24 h of ischemia/reperfusion (I/R), mice were assessed for neurobehavioral deficits followed by sacrifice and evaluation of brain infarct volume, edema, and microbleeding. Alterations in TXNIP, inflammatory mediators, and BBB markers were further analyzed using immunoblotting or immunostaining techniques. As adjunctive therapy, verapamil significantly reduced tPA-induced BBB leakage, matrix metalloproteinase 9 (MMP-9) upregulation, and tight junction protein deregulation, which resulted in lesser hemorrhagic conversions. Importantly, verapamil strongly reversed tPA-induced TXNIP/NLRP3 (NOD-like receptor pyrin domain-containing-3) inflammasome activation and reduced infarct volume. This concurred with a remarkable decrease in high-mobility group box protein 1 (HMGB-1) and nuclear factor kappa B (NF-κB) stimulation, leading to less priming of NLRP3 inflammasome. This preclinical study supports verapamil as a safe adjuvant that may complement thrombolytic therapy by inhibiting TXNIP's detrimental role in hyperglycemic stroke., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2021
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36. Thioredoxin interacting protein regulates age-associated neuroinflammation.
- Author
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Ismael S, Nasoohi S, Li L, Aslam KS, Khan MM, El-Remessy AB, McDonald MP, Liao FF, and Ishrat T
- Subjects
- Aging genetics, Aging pathology, Animals, Brain pathology, Carrier Proteins antagonists & inhibitors, Carrier Proteins genetics, Female, Inflammation Mediators antagonists & inhibitors, Male, Maze Learning physiology, Mice, Mice, Inbred C57BL, Mice, Knockout, NLR Family, Pyrin Domain-Containing 3 Protein antagonists & inhibitors, NLR Family, Pyrin Domain-Containing 3 Protein genetics, Oxidative Stress physiology, Thioredoxins antagonists & inhibitors, Thioredoxins genetics, Aging metabolism, Brain metabolism, Carrier Proteins biosynthesis, Inflammation Mediators metabolism, NLR Family, Pyrin Domain-Containing 3 Protein biosynthesis, Thioredoxins biosynthesis
- Abstract
Immune system hypersensitivity is believed to contribute to mental frailty in the elderly. Solid evidence indicates NOD-like receptor pyrin domain containing-3 (NLRP3)-inflammasome activation intimately connects aging-associated chronic inflammation (inflammaging) to senile cognitive decline. Thioredoxin interacting protein (TXNIP), an inducible protein involved in oxidative stress, is essential for NLRP3 inflammasome activity. This study aims to find whether TXNIP/NLRP3 inflammasome pathway is involved in senile dementia. According to our studies on sex-matched mice, TXNIP was significantly upregulated in aged animals, paralleled by the NLRP3-inflammasome over-activity leading to enhanced caspase-1 cleavage and IL-1β maturation, in both sexes. This was closely associated with depletion of the anti-aging and cognition enhancing protein klotho, in aged males. Txnip knockout reversed age-related NLRP3-hyperactivity and enhanced thioredoxin (TRX) levels. Further, TXNIP inhibition along with verapamil replicated TXNIP/NLRP3-inflammasome downregulation in aged animals, with FOXO-1 and mTOR upregulation. These alterations concurred with substantial improvements in both cognitive and sensorimotor abilities. Together, these findings substantiate the pivotal role of TXNIP to drive inflammaging in parallel with klotho depletion and functional decline, and delineate thioredoxin system as a potential target to decelerate senile dementia., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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37. Manifestation of renin angiotensin system modulation in traumatic brain injury.
- Author
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Mirzahosseini G, Ismael S, Ahmed HA, and Ishrat T
- Subjects
- Angiotensin II metabolism, Animals, Humans, Inflammation Mediators metabolism, Neuroinflammatory Diseases drug therapy, Neuroinflammatory Diseases metabolism, Renin-Angiotensin System physiology, Angiotensin II pharmacology, Angiotensin II Type 1 Receptor Blockers pharmacology, Brain Injuries, Traumatic drug therapy, Renin-Angiotensin System drug effects
- Abstract
Traumatic brain injury (TBI) alters brain function and is a crucial public health concern worldwide. TBI triggers the release of inflammatory mediators (cytokines) that aggravate cerebral damage, thereby affecting clinical prognosis. The renin angiotensin system (RAS) plays a critical role in TBI pathophysiology. RAS is widely expressed in many organs including the brain. Modulation of the RAS in the brain via angiotensin type 1 (AT
1 ) and type 2 (AT2 ) receptor signaling affects many pathophysiological processes, including TBI. AT1 R is highly expressed in neurons and astrocytes. The upregulation of AT1 R mediates the effects of angiotensin II (ANG II) including release of proinflammatory cytokines, cell death, oxidative stress, and vasoconstriction. The AT2 R, mainly expressed in the fetal brain during development, is also related to cognitive function. Activation of this receptor pathway decreases neuroinflammation and oxidative stress and improves overall cell survival. Numerous studies have illustrated the therapeutic potential of inhibiting AT1 R and activating AT2 R for treatment of TBI with variable outcomes. In this review, we summarize studies that describe the role of brain RAS signaling, through AT1 R and AT2 R in TBI, and its modulation with pharmacological approaches., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)- Published
- 2021
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38. Verapamil Prevents Development of Cognitive Impairment in an Aged Mouse Model of Sporadic Alzheimer's Disease.
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Ahmed HA, Ismael S, Mirzahosseini G, and Ishrat T
- Subjects
- Aging metabolism, Alzheimer Disease chemically induced, Alzheimer Disease metabolism, Animals, Brain drug effects, Brain metabolism, Calcium Channel Blockers administration & dosage, Cognitive Dysfunction chemically induced, Cognitive Dysfunction metabolism, Drug Administration Schedule, Injections, Intraventricular, Male, Maze Learning drug effects, Maze Learning physiology, Mice, Mice, Inbred C57BL, Aging drug effects, Alzheimer Disease prevention & control, Cognitive Dysfunction prevention & control, Disease Models, Animal, Streptozocin toxicity, Verapamil administration & dosage
- Abstract
Currently, dementia is the only leading cause of death that is still on the rise, with total costs already exceeding those of cancer and heart disease and projected to increase even further in the coming years. Unfortunately, there are no satisfactory treatments and attempts to develop novel, more effective treatments have been extremely costly, albeit unsuccessful thus far. This has led us to investigate the use of established drugs, licensed for other therapeutic indications, for their potential application in cognitive disorders. This strategy, referred to as "drug repositioning," has been successful in many other areas including cancer and cardiovascular diseases. To our knowledge, this is the first study to investigate the effects of long-term treatment with verapamil, a calcium channel blocker commonly prescribed for various cardiovascular conditions and recently applied for prevention of cluster headaches, on the development of cognitive impairment in aged animals. Verapamil was studied at a low dose (1mg/kg/d) in a mouse model of sporadic Alzheimer's disease (sAD). Oral treatment with verapamil or vehicle was started, 24 h post-intracerebroventricular (ICV) streptozotocin/(STZ), in 12-month-old animals and continued for 3 months. Cognitive function was assessed using established tests for spatial learning, short-term/working memory, and long-term/reference memory. Our findings demonstrate that long-term low-dose verapamil effectively prevents development of ICV/STZ-induced cognitive impairment. It mitigates the astrogliosis and synaptic toxicity otherwise induced by ICV/STZ in the hippocampus of aged animals. These findings indicate that long-term, low-dose verapamil may delay progression of sAD in susceptible subjects of advanced age.
- Published
- 2021
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39. Renin-Angiotensin System Alterations in the Human Alzheimer's Disease Brain.
- Author
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Ismael S, Mirzahosseini G, Ahmed HA, Yoo A, Kassan M, Malik KU, and Ishrat T
- Subjects
- Aged, Aged, 80 and over, Angiotensinogen genetics, Female, Humans, Male, Peptidyl-Dipeptidase A genetics, Receptor, Angiotensin, Type 1 genetics, Alzheimer Disease physiopathology, Autopsy, Brain pathology, Cerebral Cortex pathology, Hippocampus pathology, Renin-Angiotensin System physiology
- Abstract
Background: Understanding Alzheimer's disease (AD) in terms of its various pathophysiological pathways is essential to unravel the complex nature of the disease process and identify potential therapeutic targets. The renin-angiotensin system (RAS) has been implicated in several brain diseases, including traumatic brain injury, ischemic stroke, and AD., Objective: This study was designed to evaluate the protein expression levels of RAS components in postmortem cortical and hippocampal brain samples obtained from AD versus non-AD individuals., Methods: We analyzed RAS components in the cortex and hippocampus of postmortem human brain samples by western blotting and immunohistochemical techniques in comparison with age-matched non-demented controls., Results: The expression of AT1R increased in the hippocampus, whereas AT2R expression remained almost unchanged in the cortical and hippocampal regions of AD compared to non-AD brains. The Mas receptor was downregulated in the hippocampus. We also detected slight reductions in ACE-1 protein levels in both the cortex and hippocampus of AD brains, with minor elevations in ACE-2 in the cortex. We did not find remarkable differences in the protein levels of angiotensinogen and Ang II in either the cortex or hippocampus of AD brains, whereas we observed a considerable increase in the expression of brain-derived neurotrophic factor in the hippocampus., Conclusion: The current findings support the significant contribution of RAS components in AD pathogenesis, further suggesting that strategies focusing on the AT1R and AT2R pathways may lead to novel therapies for the management of AD.
- Published
- 2021
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40. The NLRP3 inflammasome: a potential therapeutic target for traumatic brain injury.
- Author
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Ismael S, Ahmed HA, Adris T, Parveen K, Thakor P, and Ishrat T
- Abstract
Although the precise mechanisms contributing to secondary brain injury following traumatic brain injury are complex and obscure, a number of studies have demonstrated that inflammatory responses are an obvious and early feature in the pathogenesis of traumatic brain injury. Inflammasomes are multiprotein complexes that prompt the stimulation of caspase-1 and subsequently induce the maturation and secretion of proinflammatory cytokines, such as interleukin-1β and interleukin-18. These cytokines play a pivotal role in facilitating innate immune responses and inflammation. Among various inflammasome complexes, the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is the best characterized, a crucial role for NLRP3 has been demonstrated in various brain diseases, including traumatic brain injury. Several recent studies have revealed the contribution of NLRP3 inflammasome in identifying cellular damage and stimulating inflammatory responses to aseptic tissue injury after traumatic brain injury. Even more important, blocking or inhibiting the activation of the NLRP3 inflammasome may have substantial potential to salvage tissue damage during traumatic brain injury. In this review, we summarize recently described mechanisms that are involved in the activation and regulation of the NLRP3 inflammasome. Moreover, we review the recent investigations on the contribution of the NLRP3 inflammasome in the pathophysiology of TBI, and current advances and challenges in potential NLRP3-targeted therapies. A significant contribution of NLRP3 inflammasome activation to traumatic brain injury implies that therapeutic approaches focused on targeting specific inflammasome components could significantly improve the traumatic brain injury outcomes., Competing Interests: None
- Published
- 2021
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41. The Brain AT2R-a Potential Target for Therapy in Alzheimer's Disease and Vascular Cognitive Impairment: a Comprehensive Review of Clinical and Experimental Therapeutics.
- Author
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Ahmed HA and Ishrat T
- Subjects
- Animals, Brain drug effects, Humans, Renin-Angiotensin System drug effects, Alzheimer Disease drug therapy, Amyloid beta-Peptides pharmacology, Angiotensin Receptor Antagonists pharmacology, Cognitive Dysfunction drug therapy
- Abstract
Dementia is a potentially avertable tragedy, currently considered among the top 10 greatest global health challenges of the twenty-first century. Dementia not only robs individuals of their dignity and independence, it also has a ripple effect that starts with the inflicted individual's family and projects to the society as a whole. The constantly growing number of cases, along with the lack of effective treatments and socioeconomic impact, poses a serious threat to the sustainability of our health care system. Hence, there is a worldwide effort to identify new targets for the treatment of Alzheimer's disease (AD), the leading cause of dementia. Due to its multifactorial etiology and the recent clinical failure of several novel amyloid-β (Aβ) targeting therapies, a comprehensive "multitarget" approach may be most appropriate for managing this condition. Interestingly, renin angiotensin system (RAS) modulators were shown to positively impact all the factors involved in the pathophysiology of dementia including vascular dysfunction, Aβ accumulation, and associated cholinergic deficiency, in addition to tau hyperphosphorylation and insulin derangements. Furthermore, for many of these drugs, the preclinical evidence is also supported by epidemiological data and/or preliminary clinical trials. The purpose of this review is to provide a comprehensive update on the major causes of dementia including the risk factors, current diagnostic criteria, pathophysiology, and contemporary treatment strategies. Moreover, we highlight the angiotensin II receptor type 2 (AT2R) as an effective drug target and present ample evidence supporting its potential role and clinical applications in cognitive impairment to encourage further investigation in the clinical setting.
- Published
- 2020
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42. HIV Associated Risk Factors for Ischemic Stroke and Future Perspectives.
- Author
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Ismael S, Moshahid Khan M, Kumar P, Kodidela S, Mirzahosseini G, Kumar S, and Ishrat T
- Subjects
- Humans, Male, Risk Factors, Blood-Brain Barrier metabolism, Blood-Brain Barrier pathology, Blood-Brain Barrier virology, HIV Infections complications, HIV Infections metabolism, HIV Infections pathology, HIV-1 metabolism, Ischemic Stroke etiology, Ischemic Stroke metabolism, Ischemic Stroke pathology, Ischemic Stroke virology, Viral Proteins metabolism
- Abstract
Although retroviral therapy (ART) has changed the HIV infection from a fatal event to a chronic disease, treated HIV patients demonstrate high prevalence of HIV associated comorbidities including cardio/cerebrovascular diseases. The incidence of stroke in HIV infected subjects is three times higher than that of uninfected controls. Several clinical and postmortem studies have documented the higher incidence of ischemic stroke in HIV infected patients. The etiology of stroke in HIV infected patients remains unknown; however, several factors such as coagulopathies, opportunistic infections, vascular abnormalities, atherosclerosis and diabetes can contribute to the pathogenesis of stroke. In addition, chronic administration of ART contributes to the increased risk of stroke in HIV infected patients. Concurrently, experimental studies in murine model of ischemic stroke demonstrated that HIV infection worsens stroke outcome, increases blood brain barrier permeability and increases neuroinflammation. Additionally, residual HIV viral proteins, such as Trans-Activator of Transcription, glycoprotein 120 and Negative regulatory factor, contribute to the pathogenesis. This review presents comprehensive information detailing the risk factors contributing to ischemic stroke in HIV infected patients. It also outlines experimental evidence demonstrating the impact of HIV infection on stroke outcomes, in addition to possible novel therapeutic approaches to improve these outcomes.
- Published
- 2020
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43. Tissue Plasminogen Activator Promotes TXNIP-NLRP3 Inflammasome Activation after Hyperglycemic Stroke in Mice.
- Author
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Ismael S, Nasoohi S, Yoo A, Ahmed HA, and Ishrat T
- Subjects
- Animals, Blood-Brain Barrier metabolism, Blood-Brain Barrier pathology, Glucose Transporter Type 1 metabolism, Hyperglycemia complications, Hyperglycemia pathology, Inflammasomes metabolism, Mice, Stroke etiology, Stroke pathology, Up-Regulation drug effects, Carrier Proteins metabolism, Hyperglycemia metabolism, Inflammasomes drug effects, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Stroke metabolism, Thioredoxins metabolism, Tissue Plasminogen Activator pharmacology
- Abstract
Hyperglycemia has been shown to counterbalance the beneficial effects of tissue plasminogen activator (tPA) and increase the risk of intracerebral hemorrhage in ischemic stroke. Thioredoxin interacting protein (TXNIP) mediates hyperglycemia-induced oxidative damage and inflammation in the brain and reduces cerebral glucose uptake/utilization. We have recently reported that TXNIP-induced NLRP3 (NOD-like receptor pyrin domain-containing-3) inflammasome activation contributes to neuronal damage after ischemic stroke. Here, we tested the hypothesis that tPA induces TXNIP-NLRP3 inflammasome activation after ischemic stroke, in hyperglycemic mice. Acute hyperglycemia was induced in mice by intraperitoneal (IP) administration of a 20% glucose solution. This was followed by transient middle cerebral artery occlusion (t-MCAO), with or without intravenous (IV) tPA administered at reperfusion. The IV-tPA exacerbated hyperglycemia-induced neurological deficits, ipsilateral edema and hemorrhagic transformation, and accentuated peroxisome proliferator activated receptor-γ (PPAR-γ) upregulation and TXNIP/NLRP3 inflammasome activation after ischemic stroke. Higher expression of TXNIP in hyperglycemic t-MCAO animals augmented glucose transporter 1 (GLUT-1) downregulation and increased vascular endothelial growth factor-A (VEGF-A) expression/matrix metallopeptidase 9 (MMP-9) signaling, all of which result in blood brain barrier (BBB) disruption and increased permeability to endogenous immunoglobulin G (IgG). It was also associated with a discernible buildup of nitrotyrosine and accumulation of dysfunctional tight junction proteins: zonula occludens-1 (ZO-1), occludin and claudin-5. Moreover, tPA administration triggered activation of high mobility group box protein 1 (HMGB-1), nuclear factor kappa B (NF-κB), and tumor necrosis factor-α (TNF-α) expression in the ischemic penumbra of hyperglycemic animals. All of these observations suggest a powerful role for TXNIP-NLRP3 inflammasome activation in the tPA-induced toxicity seen with hyperglycemic stroke.
- Published
- 2020
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44. Dose-response, therapeutic time-window and tPA-combinatorial efficacy of compound 21: A randomized, blinded preclinical trial in a rat model of thromboembolic stroke.
- Author
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Ishrat T, Fouda AY, Pillai B, Eldahshan W, Ahmed H, Waller JL, Ergul A, and Fagan SC
- Subjects
- Animals, Behavior, Animal drug effects, Disease Models, Animal, Male, Random Allocation, Rats, Rats, Wistar, Recovery of Function drug effects, Stroke etiology, Thromboembolism complications, Fibrinolytic Agents pharmacology, Stroke pathology, Sulfonamides pharmacology, Thiophenes pharmacology, Thromboembolism pathology, Tissue Plasminogen Activator pharmacology
- Abstract
The aim of this translational, randomized, controlled, blinded preclinical trial was to determine the effect of compound 21 (C21) in embolic stroke. Rats were subjected to embolic-middle cerebral artery occlusion (eMCAO). They received C21 (0.01, 0.03 and 0.06 mg/kg/d) or saline (orally) for five days, with the first-dose given IV at 3 h post-eMCAO. For the time-window study, the optimal-dose of C21 was initiated at 3, 6 or 24 h post-eMCAO and continued for five days. For the combinatorial study, animals received IV-tissue plasminogen activator (tPA) at either 2 or 4 h, with IV-C21 (0.01 mg/kg) or saline at 3 h post-eMCAO and daily thereafter for five days. After performing the behavior tests, brains were collected for analyses. The dose-response study showed significant motor improvements with the lowest-dose (0.01 mg/kg) of C21. In the time-window study, this same dose resulted in improvements when given 6 h and 24 h post-eMCAO. Moreover, C21-treated animals performed better on the novel object recognition test. Neither the single treatment with C21 or tPA (4 h) nor the combination therapy was effective in reducing the hemorrhage or infarct size, although C21 alone lowered sensorimotor deficit scores post-eMCAO. Future studies should focus on the long-term cognitive benefits of C21, rather than acute neuroprotection.
- Published
- 2019
- Full Text
- View/download PDF
45. Angiotensin II type 2 receptor stimulation with compound 21 improves neurological function after stroke in female rats: a pilot study.
- Author
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Eldahshan W, Ishrat T, Pillai B, Sayed MA, Alwhaibi A, Fouda AY, Ergul A, and Fagan SC
- Subjects
- Animals, Brain physiopathology, Cells, Cultured, Disease Models, Animal, Endothelial Cells drug effects, Endothelial Cells metabolism, Female, Infarction, Middle Cerebral Artery diagnosis, Infarction, Middle Cerebral Artery physiopathology, Infarction, Middle Cerebral Artery psychology, Male, Microvessels drug effects, Microvessels metabolism, PPAR gamma agonists, PPAR gamma metabolism, Pilot Projects, Rats, Wistar, Receptor, Angiotensin, Type 2 genetics, Receptor, Angiotensin, Type 2 metabolism, Recovery of Function, Sex Factors, Signal Transduction, Time Factors, Behavior, Animal drug effects, Brain blood supply, Brain drug effects, Infarction, Middle Cerebral Artery drug therapy, Motor Activity drug effects, Neuroprotective Agents pharmacology, Receptor, Angiotensin, Type 2 agonists, Sulfonamides pharmacology, Thiophenes pharmacology
- Abstract
The angiotensin II type 2 receptor (AT
2 R) agonist, compound 21 (C21), has been shown to be neurovascularly protective after ischemic stroke in male rats. In the current study, we aim to study the impact of C21 treatment on female rats. Young female Wistar rats were subjected to different durations of middle cerebral artery occlusion (MCAO) (3 h, 2 h, and 1 h) using a silicone-coated monofilament, treated at reperfusion with 0.03 mg/kg ip of C21 and followed up for different times (1, 3, and 14 days) after stroke. Behavioral tests were performed (Bederson, paw grasp, beam walk, and rotarod), and animals were euthanized for infarct size analysis and Western blot analysis. In vitro, primary male and female brain microvascular endothelial cells (ECs) were grown in culture, and the expression of the AT2 R was compared between males and females. At 1 day, C21 treatment resulted in an improvement in Bederson scores. However, at 3 days and 14 days, the impact of C21 on stroke outcomes was less robust. In vitro, the expression of the AT2 R was significantly higher in female ECs compared with male ECs. In conclusion, C21 improves Bederson scores after stroke in female rats when administered early at reperfusion. The ability of C21 to exert its neuroprotective effects might be affected by fluctuating levels of female hormones. NEW & NOTEWORTHY The present study shows the neuroprotective impact of C21 on ischemic stroke in female rats and how the protective effects of C21 can be influenced by the hormonal status of female rodents.- Published
- 2019
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46. Angiotensin receptor (AT2R) agonist C21 prevents cognitive decline after permanent stroke in aged animals-A randomized double- blind pre-clinical study.
- Author
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Ahmed HA, Ishrat T, Pillai B, Bunting KM, Vazdarjanova A, Waller JL, Ergul A, and Fagan SC
- Subjects
- Administration, Oral, Aging physiology, Aging psychology, Animals, Body Weight drug effects, Cognitive Dysfunction etiology, Cognitive Dysfunction physiopathology, Disease Models, Animal, Double-Blind Method, Drug Evaluation, Preclinical, Male, Motor Activity drug effects, Random Allocation, Rats, Wistar, Recovery of Function drug effects, Stroke complications, Stroke physiopathology, Stroke psychology, Time Factors, Aging drug effects, Cognitive Dysfunction prevention & control, Nootropic Agents pharmacology, Receptor, Angiotensin, Type 2 agonists, Stroke drug therapy, Sulfonamides pharmacology, Thiophenes pharmacology
- Abstract
Post stroke cognitive impairment (PSCI) is an understudied, long-term complication of stroke, impacting nearly 30-40% of all stroke survivors. No cure is available once the cognitive deterioration manifests. To our knowledge, this is the first study to investigate the long-term effects of C21 treatment on the development of PSCI in aged animals. Treatments with C21 or vehicle were administered orally, 24 h post-stroke, and continued for 30 days. Outcome measures for sensorimotor and cognitive function were performed using a sequence of tests, all blindly conducted and assessed at baseline as well as at different time points post-stroke. Our findings demonstrate that the angiotensin receptor (AT2R) agonist C21 effectively prevents the development of PSCI in aged animals., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
47. Thioredoxin-Interacting Protein (TXNIP) Associated NLRP3 Inflammasome Activation in Human Alzheimer's Disease Brain.
- Author
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Li L, Ismael S, Nasoohi S, Sakata K, Liao FF, McDonald MP, and Ishrat T
- Subjects
- Aged, Aged, 80 and over, Alzheimer Disease pathology, Brain pathology, Caspase 1 metabolism, Female, Humans, Interleukin-1beta metabolism, Male, Middle Aged, Plaque, Amyloid metabolism, Plaque, Amyloid pathology, tau Proteins metabolism, Alzheimer Disease metabolism, Brain metabolism, Carrier Proteins metabolism, Inflammasomes metabolism, NLR Family, Pyrin Domain-Containing 3 Protein metabolism
- Abstract
Alzheimer's disease (AD) is the most common form of age-associated dementia characterized by amyloid-β plaques and neurofibrillary tangles. Recent studies have demonstrated that thioredoxin-interacting protein (TXNIP), an endogenous regulator of redox/glucose induced stress and inflammation, is now known to be upregulated in stroke, traumatic brain injury, diabetes and AD. We hypothesized that TXNIP overexpression sustains neurodegeneration through activation of the nucleotide binding and oligomerization domain-like receptor protein 3 in human AD brains. We analyzed TXNIP and the components of the NLRP3 inflammasome in the cortex of postmortem human brain samples by western blotting, real-time PCR, and immunohistochemical techniques in comparison with age-matched non-demented controls. Our results demonstrate that TXNIP protein as well as its mRNA levels in the cortex was significantly upregulated in AD compared to control brains. Moreover, using double immunofluorescence staining, TXNIP and interlukin-1β (IL-1β) were co-localized near Aβ plaques and p-tau. These results suggest an association between TXNIP overexpression levels and AD pathogenesis. Further, a significant increased expression of cleaved caspase-1 and IL-1β, the products of inflammasome activation, was detected in the cortex of AD brains. Together, these findings suggest that TXNIP, an upstream promising new therapeutic target, is a molecular link between inflammation and AD. The significant contribution of TXNIP to AD pathology suggests that strategies focusing on specific targeting of the TXNIP-NLRP3 inflammasome may lead to novel therapies for the management of AD and other age-related dementias.
- Published
- 2019
- Full Text
- View/download PDF
48. Silencing VEGF-B Diminishes the Neuroprotective Effect of Candesartan Treatment After Experimental Focal Cerebral Ischemia.
- Author
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Ishrat T, Soliman S, Eldahshan W, Pillai B, Ergul A, and Fagan SC
- Subjects
- Animals, Benzimidazoles pharmacology, Biphenyl Compounds, Brain Ischemia drug therapy, Disease Models, Animal, Infarction, Middle Cerebral Artery drug therapy, Neuroprotective Agents pharmacology, Tetrazoles pharmacology, Brain Ischemia genetics, Infarction, Middle Cerebral Artery genetics, Vascular Endothelial Growth Factor B genetics
- Abstract
The pro-survival effect of VEGF-B has been documented in different in vivo and in vitro models. We have previously shown an enhanced VEGF-B expression in response to candesartan treatment after focal cerebral ischemia. In this study, we aimed to silence VEGF-B expression to assess its contribution to candesartan's benefit on stroke outcome. Silencing VEGF-B expression was achieved by bilateral intracerebroventricular injections of lentiviral particles containing short hairpin RNA (shRNA) against VEGF-B. Two weeks after lentiviral injections, rats were subjected to either 90 min or 3 h of middle cerebral artery occlusion (MCAO) and randomized to intravenous candesartan (1 mg/kg) or saline at reperfusion. Animals were sacrificed at 24 or 72 h and brains were collected and analyzed for hemoglobin (Hb) excess and infarct size, respectively. Functional outcome at 24, 48 and 72 h was assessed blindly. Candesartan treatment improved neurobehavioral and motor function, and decreased infarct size and Hb. While silencing VEGF-B expression diminished candesartan's neuroprotective effect, candesartan-mediated vascular protection was maintained even in the absence of VEGF-B suggesting that this growth factor is not the mediator of candesartan's vascular protective effects. However, VEGF-B is a mediator of neuroprotection achieved by candesartan and represents a potential drug target to improve stroke outcome. Further studies are needed to elucidate the underlying molecular mechanisms of VEGF-B in neuroprotection and recovery after ischemic stroke.
- Published
- 2018
- Full Text
- View/download PDF
49. Thioredoxin-Interacting Protein (TXNIP) in Cerebrovascular and Neurodegenerative Diseases: Regulation and Implication.
- Author
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Nasoohi S, Ismael S, and Ishrat T
- Subjects
- Animals, Endothelial Cells pathology, Humans, Inflammation pathology, Neurodegenerative Diseases pathology, Oxidative Stress, Stress Fibers pathology, Carrier Proteins metabolism, Neurodegenerative Diseases metabolism
- Abstract
Neurological diseases, including acute attacks (e.g., ischemic stroke) and chronic neurodegenerative diseases (e.g., Alzheimer's disease), have always been one of the leading cause of morbidity and mortality worldwide. These debilitating diseases represent an enormous disease burden, not only in terms of health suffering but also in economic costs. Although the clinical presentations differ for these diseases, a growing body of evidence suggests that oxidative stress and inflammatory responses in brain tissue significantly contribute to their pathology. However, therapies attempting to prevent oxidative damage or inhibiting inflammation have shown little success. Identification and targeting endogenous "upstream" mediators that normalize such processes will lead to improve therapeutic strategy of these diseases. Thioredoxin-interacting protein (TXNIP) is an endogenous inhibitor of the thioredoxin (TRX) system, a major cellular thiol-reducing and antioxidant system. TXNIP regulating redox/glucose-induced stress and inflammation, now is known to get upregulated in stroke and other brain diseases, and represents a promising therapeutic target. In particular, there is growing evidence that glucose strongly induces TXNIP in multiple cell types, suggesting possible physiological roles of TXNIP in glucose metabolism. Recently, a significant body of literature has supported an essential role of TXNIP in the activation of the NOD-like receptor protein (NLRP3)-inflammasome, a well-established multi-molecular protein complex and a pivotal mediator of sterile inflammation. Accordingly, TXNIP has been postulated to reside centrally in detecting cellular damage and mediating inflammatory responses to tissue injury. The majority of recent studies have shown that pharmacological inhibition or genetic deletion of TXNIP is neuroprotective and able to reduce detrimental aspects of pathology following cerebrovascular and neurodegenerative diseases. Conspicuously, the mainstream of the emerging evidences is highlighting TXNIP link to damaging signals in endothelial cells. Thereby, here, we keep the trend to present the accumulative data on CNS diseases dealing with vascular integrity. This review aims to summarize evidence supporting the significant contribution of regulatory mechanisms of TXNIP with the development of brain diseases, explore pharmacological strategies of targeting TXNIP, and outline obstacles to be considered for efficient clinical translation.
- Published
- 2018
- Full Text
- View/download PDF
50. RAS modulation prevents progressive cognitive impairment after experimental stroke: a randomized, blinded preclinical trial.
- Author
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Ahmed HA, Ishrat T, Pillai B, Fouda AY, Sayed MA, Eldahshan W, Waller JL, Ergul A, and Fagan SC
- Subjects
- Amyloid beta-Peptides pharmacology, Animals, Antihypertensive Agents pharmacology, Benzimidazoles therapeutic use, Biphenyl Compounds, Blood Pressure drug effects, Cell Hypoxia drug effects, Cells, Cultured, Cognitive Dysfunction drug therapy, Disease Models, Animal, Double-Blind Method, Endothelial Cells drug effects, Epoetin Alfa, Hippocampus drug effects, Humans, Infarction, Middle Cerebral Artery pathology, Locomotion drug effects, Male, Peptide Fragments pharmacology, Rats, Rats, Inbred SHR, Renin-Angiotensin System drug effects, Sensory Gating drug effects, Sulfonamides therapeutic use, Tetrazoles therapeutic use, Thiophenes therapeutic use, Cognitive Dysfunction etiology, Cognitive Dysfunction metabolism, Infarction, Middle Cerebral Artery complications, Renin-Angiotensin System physiology
- Abstract
Background: With the aging population, the prevalence and incidence of cerebrovascular disease will continue to rise, as well as the number of individuals with vascular cognitive impairment/dementia (VCID). No specific FDA-approved treatments for VCID exist. Although clinical evidence supports that angiotensin receptor blockers (ARBs) prevent cognitive decline in older adults, whether ARBs have a similar effect on VCID after stroke is unknown. Moreover, these agents reduce BP, which is undesirable in the acute stroke period, so we believe that giving C21 in this acute phase or delaying ARB administration would enable us to achieve the neurovascular benefits without the risk of unintended and potentially dangerous, acute BP lowering., Methods: The aim of our study was to determine the impact of candesartan (ARB) or compound-21 (an angiotensin type 2 receptor--AT2R--agonist) on long-term cognitive function post-stroke, in spontaneously hypertensive rats (SHRs). We hypothesized that AT2R stimulation, either directly with C21, or indirectly by blocking the angiotensin type 1 receptor (AT1R) with candesartan, initiated after stroke, would reduce cognitive impairment. Animals were subjected to a 60-min transient middle cerebral artery occlusion and randomly assigned to either saline/C21 monotherapy, for the full study duration (30 days), or given sequential therapy starting with saline/C21 (7 days) followed by candesartan for the remainder of the study (21 days). Outcome measures included sensorimotor/cognitive-function, amyloid-β determination, and histopathologic analyses., Results: Treatment with RAS modulators effectively preserved cognitive function, reduced cytotoxicity, and prevented chronic-reactive microgliosis in SHRs, post-stroke. These protective effects were apparent even when treatment was delayed up to 7 days post-stroke and were independent of blood pressure and β-amyloid accumulation., Conclusion: Collectively, our findings demonstrate that RAS modulators effectively prevent cognitive impairment after stroke, even when treatment is delayed.
- Published
- 2018
- Full Text
- View/download PDF
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