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This work presents the use of a high-fidelity neural network surrogate model within a Modular Optimization Framework for treatment of crud deposition as a constraint within light-water reactor core loading pattern optimization. The neural network was utilized for the treatment of crud constraints within the context of an advanced genetic algorithm applied to the core design problem. This proof-of-concept study shows that loading pattern optimization aided by a neural network surrogate model can optimize the manner in which crud distributes within a nuclear reactor without impacting operational parameters such as enrichment or cycle length. Several analysis methods were investigated. Analysis found that the surrogate model and genetic algorithm successfully minimized the deviation from a uniform crud distribution against a population of solutions from a reference optimization in which the crud distribution was not optimized. Strong evidence is presented that shows boron deposition in crud can be optimized through the loading pattern. This proof-of-concept study shows that the methods employed provide a powerful tool for mitigating the effects of crud deposition in nuclear reactors.

Vascular cognitive impairment and dementia (VCID) is the second leading cause of dementia. There is currently no effective treatment for VCID. Resveratrol (RSV) is considered an antioxidant; however, our group has observed pleiotropic effects in stroke paradigms, suggesting more effects may contribute to mechanistic changes beyond antioxidative properties. The main goal of this study was to investigate if administering RSV twice a week could alleviate cognitive declines following the induction of a VCID model. Additionally, our aim was to further describe whether this treatment regimen could decrease cell death in brain areas vulnerable to changes in cerebral blood flow, such as the hippocampus and medial septum. We hypothesized RSV treatments in a mouse model of gradual cerebral hypoperfusion protect against cognitive impairment. We utilized gradual bilateral common carotid artery stenosis (GBCCAS) via the surgical implantation of ameroid constrictor devices. RSV treatment was administered on the day of implantation and twice a week thereafter. Cerebral perfusion was measured by laser speckle contrast imaging, and cognitive functions, including the recognition memory, the spatial working memory, and associative learning, were assessed by novel object recognition (NOR), Y-maze testing, and contextual fear conditioning (CFC), respectively. RSV treatment did not alleviate cerebral perfusion deficits but mitigated cognitive deficits in CFC and NOR after GBCCAS. Despite these deficits, no hippocampal pathology was observed; however, cholinergic cell loss in the medial septum was significantly increased after GBCCAS. This cholinergic cell loss was mitigated by RSV. This study describes a novel mechanism by which chronic RSV treatments protect against a VCID-induced cognitive decline through the preservation of cholinergic cell viability to improve memory performance.

Stroke remains a leading cause of mortality; however, available therapeutics are limited. The study of ischemic tolerance, in paradigms such as resveratrol preconditioning (RPC), provides promise for the development of novel prophylactic therapies. The heavily oxidative environment following stroke promotes poly-ADP-ribose polymerase 1 (PARP1)-overactivation and parthanatos, both of which are major contributors to neuronal injury. In this study, we tested the hypothesis that RPC instills ischemic tolerance through decreasing PARP1 overexpression and parthanatos following in vitro and in vivo cerebral ischemia. To test this hypothesis, we utilized rat primary neuronal cultures (PNCs) and middle cerebral artery occlusion (MCAO) in the rat as in vitro and in vivo models, respectively. RPC was administered 2 days preceding ischemic insults. RPC protected PNCs against oxygen and glucose deprivation (OGD)-induced neuronal loss, as well as increases in total PARP1 protein, implying protection against PARP1-overactivation. Twelve hours following OGD, we observed reductions in NAD + /NADH as well as an increase in AIF nuclear translocation, but RPC ameliorated NAD + /NADH loss and blocked AIF nuclear translocation. MCAO in the rat induced AIF nuclear translocation in the ischemic penumbra after 24 h, which was ameliorated with RPC. We tested the hypothesis that RPC's neuroprotection was instilled through long-term downregulation of nuclear PARP1 protein. RPC downregulated nuclear PARP1 protein for at least 6 days in PNCs, likely contributing to RPC's ischemic tolerance. This study describes a novel mechanism by which RPC instills prophylaxis against ischemia-induced PARP1 overexpression and parthanatos, through a long-term reduction of nuclear PARP1 protein., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Perturbations in synaptic function are major determinants of several neurological diseases and have been associated with cognitive impairments after cerebral ischemia (CI). Although the mechanisms underlying CI-induced synaptic dysfunction have not been well defined, evidence suggests that early hyperactivation of the actin-binding protein, cofilin, plays a role. Given that synaptic impairments manifest shortly after CI, prophylactic strategies may offer a better approach to prevent/mitigate synaptic damage following an ischemic event. Our laboratory has previously demonstrated that resveratrol preconditioning (RPC) promotes cerebral ischemic tolerance, with many groups highlighting beneficial effects of resveratrol treatment on synaptic and cognitive function in other neurological conditions. Herein, we hypothesized that RPC would mitigate hippocampal synaptic dysfunction and pathological cofilin hyperactivation in an ex vivo model of ischemia. Various electrophysiological parameters and synaptic-related protein expression changes were measured under normal and ischemic conditions utilizing acute hippocampal slices derived from adult male mice treated with resveratrol (10 mg/kg) or vehicle 48 h prior. Remarkably, RPC significantly increased the latency to anoxic depolarization, decreased cytosolic calcium accumulation, prevented aberrant increases in synaptic transmission, and rescued deficits in long-term potentiation following ischemia. Additionally, RPC upregulated the expression of the activity-regulated cytoskeleton associated protein, Arc, which was partially required for RPC-mediated attenuation of cofilin hyperactivation. Taken together, these findings support a role for RPC in mitigating CI-induced excitotoxicity, synaptic dysfunction, and pathological over-activation of cofilin. Our study provides further insight into mechanisms underlying RPC-mediated neuroprotection against CI and implicates RPC as a promising strategy to preserve synaptic function after ischemia., (© 2023. The Author(s).)

Women have a higher risk of having an ischemic stroke and increased cognitive decline after stroke as compared to men. The female sex hormone 17β-estradiol (E2) is a potent neuro- and cognitive-protective agent. Periodic E2 or estrogen receptor subtype-beta (ER-β) agonist pre-treatments every 48 h before an ischemic episode ameliorated ischemic brain damage in young ovariectomized or reproductively senescent (RS) aged female rats. The current study aims to investigate the efficacy of post-stroke ER-β agonist treatments in reducing ischemic brain damage and cognitive deficits in RS female rats. Retired breeder (9-10 months) Sprague-Dawley female rats were considered RS after remaining in constant diestrus phase for more than a month. The RS rats were exposed to transient middle cerebral artery occlusion (tMCAO) for 90 min and treated with either ER-β agonist (beta 2, 3-bis(4-hydroxyphenyl) propionitrile; DPN; 1 mg/kg; s.c.) or DMSO vehicle at 4.5 h after induction of tMCAO. Subsequently, rats were treated with either ER-β agonist or DMSO vehicle every 48 h for ten injections. Forty-eight hours after the last treatment, animals were tested for contextual fear conditioning to measure post-stroke cognitive outcome. Neurobehavioral testing, infarct volume quantification, and hippocampal neuronal survival were employed to determine severity of stroke. Periodic post-stroke ER-β agonist treatment reduced infarct volume, improved recovery of cognitive capacity by increasing freezing in contextual fear conditioning, and decreased hippocampal neuronal death in RS female rats. These data suggest that periodic post-stroke ER-β agonist treatment to reduce stroke severity and improve post-stroke cognitive outcome in menopausal women has potential for future clinical investigation., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Cholinergic cells originating from the nuclei of the basal forebrain (BF) are critical for supporting various memory processes, yet BF cholinergic cell viability has not been explored in the context of focal cerebral ischemia. In the present study, we examined cell survival within several BF nuclei in rodents following transient middle cerebral artery occlusion. We tested the hypothesis that a previously established neuroprotective therapy-resveratrol preconditioning-would rescue BF cell loss, deficits in cholinergic-related memory performance, and hippocampal synaptic dysfunction after focal cerebral ischemia., Methods: Adult (2-3-month old) male Sprague-Dawley rats or wild-type C57Bl/6J mice were injected intraperitoneally with a single dose of resveratrol or vehicle and subjected to transient middle cerebral artery occlusion using the intraluminal suture method 2 days later. Histopathological, behavioral, and electrophysiological outcomes were measured 1-week post-reperfusion. Animals with reduction in cerebral blood flow <30% of baseline were excluded., Results: Cholinergic cell loss was observed in the medial septal nucleus and diagonal band of Broca following transient middle cerebral artery occlusion. This effect was prevented by resveratrol preconditioning, which also ameliorated transient middle cerebral artery occlusion-induced deficits in cognitive performance and hippocampal long-term potentiation., Conclusions: We demonstrate for the first time that focal cerebral ischemia induces cholinergic cell death within memory-relevant nuclei of the BF. The preservation of cholinergic cell viability may provide a mechanism by which resveratrol preconditioning improves memory performance and preserves functionality of memory-processing brain structures after focal cerebral ischemia.

Women with germline BRCA1 mutations (BRCA1 +/mut ) have increased risk for hereditary breast cancer. Cancer initiation in BRCA1 +/mut is associated with premalignant changes in breast epithelium; however, the role of the epithelium-associated stromal niche during BRCA1-driven tumor initiation remains unclear. Here we show that the premalignant stromal niche promotes epithelial proliferation and mutant BRCA1-driven tumorigenesis in trans. Using single-cell RNA sequencing analysis of human preneoplastic BRCA1 +/mut and noncarrier breast tissues, we show distinct changes in epithelial homeostasis including increased proliferation and expansion of basal-luminal intermediate progenitor cells. Additionally, BRCA1 +/mut stromal cells show increased expression of pro-proliferative paracrine signals. In particular, we identify pre-cancer-associated fibroblasts (pre-CAFs) that produce protumorigenic factors including matrix metalloproteinase 3 (MMP3), which promotes BRCA1-driven tumorigenesis in vivo. Together, our findings demonstrate that precancerous stroma in BRCA1 +/mut may elevate breast cancer risk through the promotion of epithelial proliferation and an accumulation of luminal progenitor cells with altered differentiation., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

A major concern for cardiac arrest (CA) survivors is the manifestation of long-term cognitive impairments. Physical exercise (PE) is a well-established approach to improve cognitive functions under certain pathological conditions. We previously showed that PE post-CA mitigates cognitive deficits, but the underlying mechanisms remain unknown. To define neuroprotective mechanisms, we analyzed whether PE post-CA protects neurons involved in memory. We first performed a contextual fear conditioning (CFC) test to confirm that PE post-CA preserves memory in rats. We then conducted a cell-count analysis and determined the number of live cells in the hippocampus, and septal and thalamic nuclei, all areas involved in cognitive functions. Lastly, we performed RNA-seq to determine PE post-CA effect on gene expression. Following CA, exercised rats had preserved CFC memory than sham PE animals. Despite this outcome, PE post-CA did not protect hippocampal cells from dying. However, PE ameliorated cell death in septal and thalamic nuclei compared to sham PE animals, suggesting that these nuclei are crucial in mitigating cognitive decline post-CA. Interestingly, PE affected regulation of genes related to neuroinflammation, plasticity, and cell death. These findings reveal potential mechanisms whereby PE post-CA preserves cognitive functions by protecting septal and thalamic cells via gene regulation.

Chronic diabetes may cause secondary complications like stroke and also increase post-stroke brain damage. In stroke research, the Stroke Therapy Academic Industry Roundtable (STAIR) identified criteria to increase translational value of preclinical studies, which highlighted the importance of using animal models of comorbidities. Numerous animal models have been used to study the aggravation of ischemic brain damage in diabetics. In this chapter, we discuss rat and mouse models of streptozotocin (STZ)-induced diabetes, with an efficient method provided. We also provide an overview of spontaneously diabetic rodent models. We present different pathophysiological features of diabetes in each rodent model along with the advantages and disadvantages of each model. Utilizing these models may aid the advancement of novel treatments and therapies to lower ischemic brain damage in patients of diabetes., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Smoking-derived nicotine (N) and oral contraceptive (OC) synergistically exacerbate ischemic brain damage in females, and the underlying mechanisms remain elusive. In a previous study, we showed that N + OC exposure altered brain glucose metabolism in females. Since lipid metabolism complements glycolysis, the current study aims to examine the metabolic fingerprint of fatty acids in the brain of female rats exposed to N+/-OC. Adolescent and adult Sprague-Dawley female rats were randomly (n = 8 per group) exposed to either saline or N (4.5 mg/kg) +/-OC (combined OC or placebo delivered via oral gavage) for 16-21 days. Following exposure, brain tissue was harvested for unbiased metabolomic analysis (performed by Metabolon Inc., Morrisville, NC, USA) and the metabolomic profile changes were complemented with Western blot analysis of key enzymes in the lipid pathway. Metabolomic data showed significant accumulation of fatty acids and phosphatidylcholine (PC) metabolites in the brain. Adolescent, more so than adult females, exposed to N + OC showed significant increases in carnitine-conjugated fatty acid metabolites compared to saline control animals. These changes in fatty acyl carnitines were accompanied by an increase in a subset of free fatty acids, suggesting elevated fatty acid β-oxidation in the mitochondria to meet energy demand. In support, β-hydroxybutyrate was significantly lower in N + OC exposure groups in adolescent animals, implying a complete shunting of acetyl CoA for energy production via the TCA cycle. The reported changes in fatty acids and PC metabolism due to N + OC could inhibit post-translational palmitoylation of membrane proteins and synaptic vesicle formation, respectively, thus exacerbating ischemic brain damage in female rats.

Spontaneous intracerebral hemorrhage (sICH) is a disabling stroke sub-type, and tobacco use is a prominent risk factor for sICH. We showed that chronic nicotine exposure enhances bleeding post-sICH. Reduction of hematoma growth is a promising effective therapy for sICH in smoking subjects. Red-blood-cell-derived microparticles (RMPs) are hemostatic agents that limit hematoma expansion following sICH in naïve rats. Considering the importance of testing the efficacy of experimental drugs in animal models with a risk factor for a disease, we tested RMP efficacy and the therapeutic time window in limiting hematoma growth post-sICH in rats exposed to nicotine. Young rats were chronically treated with nicotine using osmotic pumps. sICH was induced in rats using an injection of collagenase in the right striatum. Vehicle/RMPs were administered intravenously. Hematoma volume and neurological impairment were quantified ≈24 h after sICH. Hematoma volumes in male and female nicotine-exposed rats that were treated with RMPs at 2 h post-sICH were significantly lower by 26 and 31% when compared to their respective control groups. RMP therapy was able to limit hematoma volume when administered up to 4.5 h post-sICH in animals of both sexes. Therefore, RMPs may limit hematoma growth in sICH patients exposed to tobacco use.

Background: Spontaneous intracerebral hemorrhage (sICH) is the deadliest stroke subtype with no effective therapies. Limiting hematoma expansion is a promising therapeutic approach. Red blood cell-derived microparticles (RMPs) are novel hemostatic agents. Therefore, we studied the potential of RMPs in limiting hematoma growth and improving outcomes post-sICH., Methods: sICH was induced in rats by intrastriatal injection of collagenase. RMPs were prepared from human RBCs by high-pressure extrusion. Behavioral and hematoma/lesion volume assessment were done post-sICH. The optimal dose, dosing regimen, and therapeutic time window of RMP therapy required to limit hematoma growth post-sICH were determined. We also evaluated the effect of RMPs on long-term behavioral and histopathologic outcomes post-sICH., Results: RMP treatment limited hematoma growth following sICH. Hematoma volume (mm 3 ) for vehicle- and RMP- (2.66×10 10 particles/kg) treated group was 143±8 and 86±4, respectively. The optimal RMP dosing regimen that limits hematoma expansion was identified. RMPs limit hematoma volume when administered up to 4.5-hour post-sICH. Hematoma volume in the 4.5-hour post-sICH RMP treatment group was lower by 24% when compared with the control group. RMP treatment also improved long-term histopathologic and behavioral outcomes post-sICH., Conclusions: Our results demonstrate that RMP therapy limits hematoma growth and improves outcomes post-sICH in a rodent model. Therefore, RMPs have the potential to limit hematoma growth in sICH patients.

Spontaneous intracerebral hemorrhage (sICH) is a deadly stroke subtype, and tobacco use increases sICH risk. However epidemiological studies show that, there are no confirmatory studies showing the effect of tobacco use on sICH outcome. Therefore, we evaluated the effect of chronic nicotine exposure (as a surrogate for tobacco use) on outcomes following sICH. Young male and female rats were randomly assigned to either nicotine (4.5 mg/kg b.w. per day) or vehicle (saline) treatment (2-3 weeks) groups. sICH was induced by injecting collagenase into the right striatum. Neurological score and hematoma volume were determined 24 h post-sICH. The hematoma volumes in nicotine-treated male and female rats were significantly higher by 42% and 48% when compared to vehicle-treated male and female rats, respectively. Neurological deficits measured in terms of neurological score for the nicotine-treated male and female groups were significantly higher when compared to the respective vehicle-treated male and female groups. Our results show that chronic nicotine exposure increases hematoma volume post-sICH in rats of both sexes. Identifying the mechanism of nicotine-dependent increase in hematoma growth post-sICH will be crucial to understanding the detrimental effect of tobacco use on the severity of bleeding following intracerebral hemorrhage.

Diabetes is a widespread disease characterized by high blood glucose levels due to abnormal insulin activity, production, or both. Chronic diabetes causes many secondary complications including cardiovascular disease: a life-threatening complication. Cerebral ischemia-related mortality, morbidity, and the extent of brain injury are high in diabetes. However, the mechanism of increase in ischemic brain injury during diabetes is not well understood. Multiple mechanisms mediate diabetic hyperglycemia and hypoglycemia-induced increase in ischemic brain injury. Endoplasmic reticulum (ER) stress mediates both brain injury as well as brain protection after ischemia-reperfusion injury. The pathways of ER stress are modulated during diabetes. Free radical generation and mitochondrial dysfunction, two of the prominent mechanisms that mediate diabetic increase in ischemic brain injury, are known to stimulate the pathways of ER stress. Increased ischemic brain injury in diabetes is accompanied by a further increase in the activation of ER stress. As there are many metabolic changes associated with diabetes, differential activation of the pathways of ER stress may mediate pronounced ischemic brain injury in subjects suffering from diabetes. We presently discuss the literature on the significance of ER stress in mediating increased ischemia-reperfusion injury in diabetes., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Metastasis is a fatal disease where research progress has been hindered by a lack of authentic experimental models. Here, we develop a 3D tumor sphere culture-transplant system that facilitates the growth and engineering of patient-derived xenograft (PDX) tumor cells for functional metastasis assays in vivo. Orthotopic transplantation and RNA sequencing (RNA-seq) analyses show that PDX tumor spheres maintain tumorigenic potential, and the molecular marker and global transcriptome signatures of native tumor cells. Tumor spheres display robust capacity for lentiviral engineering and dissemination in spontaneous and experimental metastasis assays in vivo. Inhibition of pathways previously reported to attenuate metastasis also inhibit metastasis after sphere culture, validating our approach for authentic investigations of metastasis. Finally, we demonstrate a new role for the metabolic enzyme NME1 in promoting breast cancer metastasis, providing proof-of-principle that our culture-transplant system can be used for authentic propagation and engineering of patient tumor cells for functional studies of metastasis., (© 2021. The Author(s).)

Smoking-derived nicotine (N) and oral contraceptives (OCs) synergistically exacerbate ischemic brain damage in the female, and the underlying mechanisms remain elusive. Our published study showed that N toxicity is exacerbated by OC via altered mitochondrial electron transport chain function. Because mitochondria play an important role in cellular metabolism, we investigated the global metabolomic profile of brains of adolescent and adult female Sprague-Dawley rats exposed to N with or without OC (N+/-OC). Rats were randomly exposed to saline or N+/-OC for 16-21 days followed by random allocation into two cohorts. The first cohort was used to characterize the cortical metabolome. Pathway enrichment analysis showed a significant increase in several histamine metabolites including 1-methylhistamine, 1-methyl-4-imidazoleacetate, and 1-ribosyl-imidazleacetate, along with carnosine and homocarnosine in adolescent and adult animals treated with N and N+OC in relation to respective saline controls, which may be reflective of altered histamine metabolism with nicotine treatment. We also observed reduced levels of the neurotransmitters N-acetyl-aspartyl-glutamate (NAAG), gamma-aminobutyrate (GABA), and N-methyl-GABA in N+OC treatment in adolescent animals. The second cohort underwent bilateral carotid artery occlusion and hypotension followed by cerebral blood flow (CBF) assessment a day later. Autoradiographic images of the brain 24 h after ischemic episodes showed severe reduction in cortical and hippocampal local CBF in N+/-OC-exposed rats compared with saline treated. Because GABA and histamine are critical for CBF maintenance, altered metabolism of these neurotransmitters may be responsible for observed severe post-ischemic hypoperfusion, which in turn exacerbates ischemic brain damage., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

This comprehensive review provides an insight into the pathophysiology, epidemiology, evaluation, and treatment of sickle cell anemia (SCA)-related stroke in developed and developing countries. Vascular injury, hypercoagulability and vaso-occlusion play a role in the pathophysiology of stroke in SCA. Transcranial Doppler ultrasound (TCD) has lowered the incidence of ischemic stroke from 11% to 1% as TCD identifies children who are at risk for stroke, providing opportunities for interventions to reduce this risk. Whereas blood exchange is indicated in acute stroke, chronic transfusions (either simple or exchange on a monthly basis) are used for primary as well as secondary stroke prevention in developed countries. Children with abnormally high TCD velocities (≥ 200 cm/s) are at high risk of stroke and might benefit from hydroxyurea or hydroxycarbamide (HU) after a period of a successful transition from chronic transfusions. Hematopoietic stem cell transplant presents a cure for SCA. Gene therapy is currently investigated and may be offered to patients with SCA who had a stroke or who are at high risk of stroke if proven efficacious and safe. However, gene therapy is not likely to be implemented in low-income countries due to cost. Alternatively, HU is utilized for primary and secondary stroke prevention in developing countries. Further expansion of TCD implementation should be a priority in those settings., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Cerebral ischemia contributes to significant disabilities worldwide, impairing cognitive function and motor coordination in affected individuals. Stroke has severe neuropsychological outcomes, the major one being a stroke. Stroke survivors begin to show symptoms of depression within a few months of the incidence that overtime progresses to become a long-term ailment. As the pathophysiology for the progression of the disease is multifactorial and complex, it limits the understanding of the disease mechanism completely. Meta-analyses and randomized clinical trials have shown that intervening early with tricyclic antidepressants and selective serotonin receptor inhibitors can be effective. However, these pharmacotherapies possess several limitations that have given rise to newer approaches such as brain stimulation, psychotherapy and rehabilitation therapy, which in today's time are gaining attention for their beneficial results in post-stroke depression (PSD). The present review highlights numerous factors like lesion location, inflammatory mediators and genetic abnormalities that play a crucial role in the development of depression in stroke patients. Further, we have also discussed various mechanisms involved in post-stroke depression (PSD) and strategies for early detection and diagnosis using biomarkers that may revolutionize treatment for the affected population. Towards the end, along with the preclinical scenario, we have also discussed the various treatment approaches like pharmacotherapy, traditional medicines, psychotherapy, electrical stimulation and microRNAs being utilized for effectively managing PSD., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Studies from our lab demonstrated that 1 × 10 5 intra-arterial mesenchymal stem cells (IA MSCs) at 6 h following ischemic stroke are efficacious owing to its maximum homing due to elevated stromal derived factor 1 (SDF1) in the tissue. Further, IA MSCs could abate the infarct progression, improve functional outcome, and decrease expression of calcineurin by modifying neuronal Ca 2+ channels following ischemic stroke. Since stroke pathology also encompasses acidosis that worsens the condition; hence, the role of acid sensing ion channels (ASICs) in this context could not be overlooked. ASIC1a being the major contributor towards acidosis triggers Ca 2+ ions overload which progressively contributes towards exacerbation of neuronal injury following ischemic insult. Inflammasome involvement in ischemic stroke is well reported as activated ASIC1a increases the expression of inflammasome in a pH-dependent manner to trigger inflammatory cascade. Hence, the current study aimed to identify if IA MSCs can decrease the production of inflammasome by attenuating ASIC1a expression to render neuroprotection. Ovariectomized Sprague Dawley (SD) rats exposed to middle cerebral artery occlusion (MCAo) for 90 min were treated with phosphate-buffered saline (PBS) or 1 × 10 5 MSCs IA at 6 h to check for the expression of ASIC1a and inflammasome in different groups. Inhibition studies were carried out to explore the underlying mechanism. Our results demonstrate that IA MSCs improves functional outcome and oxidative stress parameters, and decreases the expression of ASIC1a and inflammasomes in the cortical brain region after ischemic stroke. This study offers a preliminary evidence of the role of IA MSCs in regulating inflammasome by modulating ASIC1a.

Stroke is an event causing a disturbance in cerebral function leading to death and disability worldwide. Both acute kidney injury and chronic kidney disease (CKD) are associated with an increased risk of stroke and cerebrovascular events. The underlying mechanistic approach between impaired renal function and stroke is limitedly explored and has attracted researchers to learn more for developing therapeutic intervention. Common risk factors such as hypertension, hyperphosphatemia, atrial fibrillation, arteriosclerosis, hyperhomocysteinemia, blood-brain barrier disruption, inflammation, etc. are observed in the general population, but are high in renal failure patients. Also, risk factors like bone mineral metabolism, uremic toxins, and anemia, along with the process of dialysis in CKD patients, eventually increases the risk of stroke. Therefore, early detection of risks associated with stroke in CKD is imperative, which may decrease the mortality associated with it. This review highlights mechanisms by which kidney dysfunction can lead to cerebrovascular events and increase the risk of stroke in renal impairment., (© 2020 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Neurodegeneration is characterized by gradual onset and limited availability of specific biomarkers. Apart from various aetiologies such as infection, trauma, genetic mutation, the interaction between the immune system and CNS is widely associated with neuronal damage in neurodegenerative diseases. The immune system plays a distinct role in disease progression and cellular homeostasis. It induces cellular and humoral responses, and enables tissue repair, cellular healing and clearance of cellular detritus. Aberrant and chronic activation of the immune system can damage healthy neurons. The pro-inflammatory mediators secreted by chief innate immune components, the complement system, microglia and inflammasome can augment cytotoxicity. Furthermore, these inflammatory mediators accelerate microglial activation resulting in progressive neuronal loss. Various animal studies have been carried out to unravel the complex pathology and ascertain biomarkers for these harmful diseases, but have had limited success. The present review will provide a thorough understanding of microglial activation, complement system and inflammasome generation, which lead the healthy brain towards neurodegeneration. In addition to this, possible targets of immune components to confer a strategic treatment regime for the alleviation of neuronal damage are also summarized., (© 2020 John Wiley & Sons Ltd.)

The past decade has brought tremendous progress in diagnostic and therapeutic options for cerebrovascular diseases as exemplified by the advent of thrombectomy in ischemic stroke, benefitting a steeply increasing number of stroke patients and potentially paving the way for a renaissance of neuroprotectants. Progress in basic science has been equally impressive. Based on a deeper understanding of pathomechanisms underlying cerebrovascular diseases, new therapeutic targets have been identified and novel treatment strategies such as pre- and post-conditioning methods were developed. Moreover, translationally relevant aspects are increasingly recognized in basic science studies, which is believed to increase their predictive value and the relevance of obtained findings for clinical application.This review reports key results from some of the most remarkable and encouraging achievements in neurovascular research that have been reported at the 10th International Symposium on Neuroprotection and Neurorepair. Basic science topics discussed herein focus on aspects such as neuroinflammation, extracellular vesicles, and the role of sex and age on stroke recovery. Translational reports highlighted endovascular techniques and targeted delivery methods, neurorehabilitation, advanced functional testing approaches for experimental studies, pre-and post-conditioning approaches as well as novel imaging and treatment strategies. Beyond ischemic stroke, particular emphasis was given on activities in the fields of traumatic brain injury and cerebral hemorrhage in which promising preclinical and clinical results have been reported. Although the number of neutral outcomes in clinical trials is still remarkably high when targeting cerebrovascular diseases, we begin to evidence stepwise but continuous progress towards novel treatment options. Advances in preclinical and translational research as reported herein are believed to have formed a solid foundation for this progress., 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. The reviewer AL declared a shared affiliation, though no other collaboration, with several of the authors (IK, NP) to the handling Editor., (Copyright © 2021 Boltze, Aronowski, Badaut, Buckwalter, Caleo, Chopp, Dave, Didwischus, Dijkhuizen, Doeppner, Dreier, Fouad, Gelderblom, Gertz, Golubczyk, Gregson, Hamel, Hanley, Härtig, Hummel, Ikhsan, Janowski, Jolkkonen, Karuppagounder, Keep, Koerte, Kokaia, Li, Liu, Lizasoain, Ludewig, Metz, Montagne, Obenaus, Palumbo, Pearl, Perez-Pinzon, Planas, Plesnila, Raval, Rueger, Sansing, Sohrabji, Stagg, Stetler, Stowe, Sun, Taguchi, Tanter, Vay, Vemuganti, Vivien, Walczak, Wang, Xiong and Zille.)

Spontaneous intracerebral hemorrhage (sICH) is one of the deadliest subtypes of stroke, and no treatment is currently available. One of the major risk factors is tobacco use. In this article, we review literature on how tobacco use affects the risk of sICH and also summarize the known effects of tobacco use on outcomes following sICH. Several studies demonstrate that the risk of sICH is higher in current cigarette smokers compared to non-smokers. The literature also establishes that cigarette smoking not only increases the risk of sICH but also increases hematoma growth, results in worse outcomes, and increases the risk of death from sICH. This review also discusses potential mechanisms activated by tobacco use which result in an increase in risk and severity of sICH. Exploring the underlying mechanisms may help alleviate the risk of sICH in tobacco users as well as may help better manage tobacco user sICH patients.

Ischemic stroke is one of the significant causes of morbidity and mortality, affecting millions of people across the globe. Cell injury in the infarct region is an inevitable consequence of focal cerebral ischemia. Subsequent reperfusion exacerbates the harmful effect and increases the infarct volume. These cellular injuries follow either a regulated pathway involving tightly structured signaling cascades and molecularly defined effector mechanisms or a non-regulated pathway, also known as accidental cell death, where the process is biologically uncontrolled. Classical cell death pathways are long established and well reported in several articles that majorly define apoptotic cell death. A recent focus on cell death study also considers investigation on non-classical pathways that are tightly regulated, may or may not involve caspases, but non-apoptotic. Pathological cell death is a cardinal feature of different neurodegenerative diseases. Although ischemia cannot be classified as a neurodegenerative disease, it is a cerebrovascular event where the infarct region exhibits aberrant cell death. Over the past few decades, several therapeutic options have been implicated for ischemic stroke. However, their use has been hampered owing to the number of limitations that they possess. Ischemic penumbral neurons undergo apoptosis and become dysfunctional; however, they are salvageable. Thus, understanding the role of different cell death pathways is crucial to aid in the modern treatment of protecting apoptotic neurons.

Recent advancements in tissue engineering suggest that biomaterials, such as decellularized extracellular matrix (ECM), could serve to potentiate the localization and efficacy of regenerative therapies in the central nervous system. Still, what factors and which mechanisms are required from these ECM-based biomaterials to exert their effect are not entirely understood. In this study, we use the brain as a novel model to test the effects of particular biochemical and structural properties by evaluating, for the first time, three different sections of the brain (i.e., cortex, cerebellum, and remaining areas) side-by-side and their corresponding decellularized counterparts using mechanical (4-day) and chemical (1-day) decellularization protocols. The three different brain subregions had considerably different initial conditions in terms of cell number and growth factor content, and some of these differences were maintained after decellularization. Decellularized ECM from both protocols was used as a substrate or as soluble factor, in both cases showing good cell attachment and growth capabilities. Interestingly, the 1-day protocol was capable of promoting greater differentiation than the 4-day protocol, probably due to its capacity to remove a similar amount of cell nuclei, while better conserving the biochemical and structural components of the cerebral ECM. Still, some limitations of this study include the need to evaluate the response in other biologically relevant cell types, as well as a more detailed characterization of the components in the decellularized ECM of the different brain subregions. In conclusion, our results show differences in neuronal maturation depending on the region of the brain used to produce the scaffolds. Complex organs such as the brain have subregions with very different initial cellular and biochemical conditions that should be considered for decellularization to minimize exposure to immunogenic components, while retaining bioactive factors conducive to regeneration. [Figure: see text] Impact statement The present study offers new knowledge about the production of decellularized extracellular matrix scaffolds from specific regions of the porcine brain, with a direct comparison of their effect on in vitro neuronal maturation. Our results show differences in neuronal maturation depending on the region of the brain used to produce the scaffolds, suggesting that it is necessary to consider the initial cellular content of the source tissue and its bioactive capacity for the production of an effective regenerative therapy for stroke.

Simulating a clinical condition of intracerebral hemorrhage (ICH) in animals is key to research on the development and testing of diagnostic or treatment strategies for this high-mortality disease. In order to study the mechanism, pathology, and treatment for hemorrhagic stroke, various animal models have been developed. Measurement of hematoma volume is an important assessment parameter to evaluate post-ICH outcomes. However, due to tissue preservation conditions and variables in digitization, quantification of hematoma volume is usually labor intensive and sometimes even subjective. The objective of this study is to develop an automated method that can accurately and efficiently obtain unbiased cerebral hematoma volume. We developed an application (MATLAB program) that can delineate the brain slice from the background and use the Hue information in the Hue/Saturation/Value (HSV) color space to segment the hematoma region. The segmentation threshold of Hue is calculated based on the Bayes classifier theorem so that the minimum error is mathematically ensured and automated processing is enabled. To validate the developed method, we compared the outcomes from the developed method with the hemoglobin content by the spectrophotometric assay method. The results were linearly correlated with statistical significance. The method was also validated by digital phantoms with an error less than 5% compared with the ground truth from the phantoms. Hematoma volumes yielded by the automated processing and those obtained by the operator's manual operation are highly correlated. This automated segmentation approach can be potentially used to quantify hemorrhagic outcomes in rodent stroke models in an unbiased and efficient way.

Hemorrhagic transformation is a severe complication of acute ischemic stroke owing to its limited treatment options and poor prognosis. In the last decade, the rates of hemorrhagic transformation incidence have been associated with blood glucose levels. In particular, hyperglycemia at the time of admission has been associated with increased rates of hemorrhagic transformation in acute ischemic stroke patients. Recent pilot clinical trials have attempted to use intensive insulin therapy during stroke treatment to reduce the severity of cerebral infarction and possibly alleviate the risk of hemorrhagic transformation. However, the results of these studies have shown no clear clinical benefit. In addition, intensive insulin therapy has increased rates of hypoglycemia which may be associated with larger infarct growth. We hypothesize that hypoglycemia, similarly to hyperglycemia, is a risk factor for worse outcomes in acute ischemic stroke by promoting hemorrhagic transformation. This review serves to call attention to patterns present within intensive insulin therapy trials and shed light into the pathophysiological effects of hypoglycemia. It is critical that efforts be directed toward the prevention of hemorrhagic transformation by optimizing insulin therapy during the treatment of acute ischemic stroke.

Migraine and stroke are common, disabling neurological conditions with several theories being proposed to explain this bidirectional relationship. Migraine is considered as a benign neurological disorder, but research has revealed a connection between migraine and stroke, predominantly those having migraine with aura (MA). Among migraineurs, females with MA are more susceptible to ischemic stroke and may have a migrainous infarction. Migrainous infarction mostly occurs in the posterior circulation of young women. Although there are several theories about the potential relationship between MA and stroke, the precise pathological process of migrainous infarction is not clear. It is assumed that cortical spreading depression (CSD) might be one of the essential factors for migrainous infarction. Other factors that may contribute to migrainous infarction may be genetic, hormonal fluctuation, hypercoagulation, and right to left cardiac shunts. Antimigraine drugs, such as ergot alkaloids and triptans, are widely used in migraine care. Still, they have been found to cause severe vasoconstriction, which may result in the development of ischemia. It is reported that patients with stroke develop migraines during the recovery phase. Both experimental and clinical data suggest that cerebral microembolism can act as a potential trigger for MA. Further studies are warranted for the treatment of migraine, which may lead to a decline in migraine-related stroke. In this present article, we have outlined various potential pathways that link migraine and stroke.

The preservation of mitochondrial function is a major protective strategy for cerebral ischemic injuries. Previously, our laboratory demonstrated that protein kinase C epsilon (PKCε) promotes the synthesis of mitochondrial nicotinamide adenine dinucleotide (NAD + ). NAD + along with its reducing equivalent, NADH, is an essential co-factor needed for energy production from glycolysis and oxidative phosphorylation. Yet, NAD + /NADH are impermeable to the inner mitochondrial membrane and their import into the mitochondria requires the activity of specific shuttles. The most important neuronal NAD + /NADH shuttle is the malate-aspartate shuttle (MAS). The MAS has been implicated in synaptic function and is potentially dysregulated during cerebral ischemia. The aim of this study was to determine if metabolic changes induced by PKCε preconditioning involved regulation of the MAS. Using primary neuronal cultures, we observed that the activation of PKCε enhanced mitochondrial respiration and glycolysis in vitro. Conversely, inhibition of the MAS resulted in decreased oxidative phosphorylation and glycolytic capacity. We further demonstrated that activation of PKCε increased the phosphorylation of key components of the MAS in rat brain synaptosomal fractions. Additionally, PKCε increased the enzyme activity of glutamic oxaloacetic transaminase 2 (GOT2), an effect that was dependent on the import of PKCε into the mitochondria and phosphorylation of GOT2. Furthermore, PKCε activation was able to rescue decreased GOT2 activity induced by ischemia. These findings reveal novel protective targets and mechanisms against ischemic injury, which involves PKCε-mediated phosphorylation and activation of GOT2 in the MAS.

Background Physical exercise and cognitive training have been recommended to improve cognitive outcomes poststroke, but a multifaceted strategy including aerobic, resistance, and cognitive training to facilitate poststroke recovery has not been investigated. We aimed to assess the feasibility, adherence, and safety of a combined aerobic, resistance, and cognitive training intervention (CARET+CTI) after stroke. Methods and Results We prospectively randomized patients presenting with recent stroke to a comparison of a supervised 12-week CARET+CTI program and a control group receiving sham CARET+CTI. Participants were scheduled for 3 weekly CARET and CTI sessions. All participants underwent pre- and postintervention assessments of strength, endurance, and cognition. The primary outcomes were feasibility and adherence, defined as the ratio of scheduled and observed visits, and safety. We enrolled 131 participants, of whom 37 withdrew from the study. There were 17 (20%) withdrawals in the CARET+CTI and 20 (44%) in the control group. The observed-over-expected visit ratio was significantly higher in the intervention than in the control group (0.74±0.30 versus 0.54±0.38; P =0.003). A total of 99 adverse events were reported by 59 participants, none of which were serious and related to the intervention. Greater gains in physical, cognitive, and mood outcomes were found in the CARET+CTI group than in the control group, but were not statistically significant after adjustments. Conclusions A CARET+CTI intervention, after stroke, is safe, feasible, and has satisfactory participant adherence over 12 weeks. REGISTRATION URL: https://www.clini​caltr​ials.gov. Unique identifier: NCT02272426.

Alzheimer's disease (AD) is a debilitating disorder characterized by age-related dementia, which has no effective treatment to date. β-Amyloid depositions and hyperphosphorylated tau proteins are the main pathological hallmarks, along with oxidative stress, N -methyl-d-aspartate (NMDA) receptor-mediated excitotoxicity, and low levels of acetylcholine. Current pharmacotherapy for AD only provides symptomatic relief and limited improvement in cognitive functions. Many molecules have been explored that show promising outcomes in AD therapy and can regulate cellular survival through different pathways. To have a vivid approach to strategize the treatment regimen, AD physiopathology should be better explained considering diverse etiological factors in conjunction with biochemical disturbances. This Review attempts to discuss different disease modification approaches and address the novel therapeutic targets of AD that might pave the way for new drug discovery using the well-defined targets for therapy of the disease., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

Inflammation is a devastating outcome of cerebrovascular diseases (CVD), namely stroke and atherosclerosis. Numerous studies over the decade have shown that inflammasomes play a role in mediating inflammatory reactions post cellular injury occurring after a stroke or a rupture of an atherosclerotic plaque. In view of this, targeting these inflammatory pathways using different pharmacological therapies may improve outcomes in patients with CVD. Here, we review the mechanisms by which inflammasomes drive the pathogenesis of stroke and atherosclerosis. Also, discussed here are the possible treatment strategies available for inhibiting inflammasomes or their up-stream/down-stream mediators., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: The occurrence of secondary neurodegeneration has exclusively been observed after the first incidence of stroke. In humans and rodents, post-stroke secondary neurodegeneration (SND) is an inevitable event that can lead to progressive neuronal loss at a region distant to initial infarct. SND can lead to cognitive and motor function impairment, finally causing dementia. The exact pathophysiology of the event is yet to be explored. It is seen that the thalami, in particular, are susceptible to cause SND. The reason behind this is because the thalamus functioning as the relay center and is positioned as an interlocked structure with direct synaptic signaling connection with the cortex. As SND proceeds, accumulation of misfolded proteins and microglial activation are seen in the thalamus. This leads to increased neuronal loss and worsening of functional and cognitive impairment., Objective: There is a necessity of specific interventions to prevent post-stroke SND, which are not properly investigated to date owing to sparsely reproducible pre-clinical and clinical data. The basis of this review is to investigate about post-stroke SND and its updated treatment approaches carefully., Methods: Our article presents a detailed survey of advances in studies on stroke-induced secondary neurodegeneration (SND) and its treatment., Results: This article aims to put forward the pathophysiology of SND. We have also tabulated the latest treatment approaches along with different neuroimaging systems that will be helpful for future reference to explore., Conclusion: In this article, we have reviewed the available reports on SND pathophysiology, detection techniques, and possible treatment modalities that have not been attempted to date., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Aims: Exposure to recurrent hypoglycemia (RH) is common in diabetic patients receiving glucose-lowering therapies and is implicated in causing cognitive impairments. Despite the significant effect of RH on hippocampal function, the underlying mechanisms are currently unknown. Our goal was to determine the effect of RH exposure on hippocampal metabolism in treated streptozotocin-diabetic rats., Methods: Hyperglycemia was corrected by insulin pellet implantation. Insulin-treated diabetic (ITD) rats were exposed to mild/moderate RH once a day for 5 consecutive days., Results: The effect of RH on hippocampal metabolism revealed 65 significantly altered metabolites in the RH group compared with controls. Several significant differences in metabolite levels belonging to major pathways (eg, Krebs cycle, gluconeogenesis, and amino acid metabolism) were discovered in RH-exposed ITD rats when compared to a control group. Key glycolytic enzymes including hexokinase, phosphofructokinase, and pyruvate kinase were affected by RH exposure., Conclusion: Our results demonstrate that the exposure to RH leads to metabolomics alterations in the hippocampus of insulin-treated streptozotocin-diabetic rats. Understanding how RH affects hippocampal metabolism may help attenuate the adverse effects of RH on hippocampal functions., (© 2019 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

Diabetes is a chronic metabolic disease and cerebral ischemia is a serious complication of diabetes. Anti-diabetic therapy mitigates this complication but increases the risk of exposure to recurrent hypoglycemia (RH). We showed previously that RH exposure increases ischemic brain damage in insulin-treated diabetic (ITD) rats. The present study evaluated the hypothesis that increased intra-ischemic acidosis in RH-exposed ITD rats leads to pronounced post-ischemic hypoperfusion via activation of acid-sensing (proton-gated) ion channels (ASICs). Streptozotocin-diabetic rats treated with insulin were considered ITD rats. ITD rats were exposed to RH for 5 days and were randomized into Psalmotoxin1 (PcTx1, ASIC1a inhibitor), APETx2 (ASIC3 inhibitor), or vehicle groups. Transient global cerebral ischemia was induced overnight after RH. Cerebral blood flow was measured using laser Doppler flowmetry. Ischemic brain injury in hippocampus was evaluated using histopathology. Post-ischemic hypoperfusion in RH-exposed rats was of greater extent than that in control rats. Inhibition of ASICs prevented RH-induced increase in the extent of post-ischemic hypoperfusion and ischemic brain injury. Since ASIC activation-induced store-operated calcium entry (SOCE) plays a role in vascular tone, next we tested if acidosis activates SOCE via activating ASICs in vascular smooth muscle cells (VSMCs). We observed that SOCE in VSMCs at lower pH is ASIC3 dependent. The results show the role of ASIC in post-ischemic hypoperfusion and increased ischemic damage in RH-exposed ITD rats. Understanding the pathways mediating exacerbated ischemic brain injury in RH-exposed ITD rats may help lower diabetic aggravation of ischemic brain damage.

The endoplasmic reticulum (ER) and mitochondria are fundamental organelles highly interconnected with a specialized set of proteins in cells. ER-mitochondrial interconnections form specific microdomains, called mitochondria-associated ER membranes, that have been found to play important roles in calcium signaling and lipid homeostasis, and more recently in mitochondrial dynamics, inflammation, and autophagy. It is not surprising that perturbations in ER-mitochondria connections can result in the progression of disease, especially neurological disorders; hence, their architecture and regulation are crucial in determining the fate of cells and disease. The molecular identity of the specialized proteins regulating ER-mitochondrial crosstalk remains unclear. Our discussion here describes the physical and functional crosstalk between these two dynamic organelles and emphasizes the outcome of altered ER-mitochondrial interconnections in neurological disorders., (© 2019 New York Academy of Sciences.)

Aim: Calcineurin (CaN) is a threonine/phosphatase which play roles in neuronal homeostasis. Ischemic stroke induces hyperactivation of CaN which further triggers apoptotic signaling. CaN inhibition has limited therapeutic output and neurotoxicity due to its intricate roles in the neuronal network and requires a strategic modulation. Intra-arterial (IA) mesenchymal stem cells (MSCs) have shown to interact with the milieu in a paracrine manner as compared to CaN inhibitors to ameliorate the neuronal damage triggered by ischemia/reperfusion injury. The present study investigates the role of IA MSCs in modulating neuronal CaN after stroke onset. Materials and methods: To validate, middle-aged ovariectomized female rats exposed to MCAo (90 min) were treated with IA MSCs (1 × 10 5 MSCs) or phosphate-buffered saline (PBS) at 6 hours to check CaN expression in different groups.Tests for assessing functional and motor coordination were performed along with biochemical estimations. Furthermore, an inhibition study by non-selective inhibitor of neuronal calcium channel, flunarizine, was performed to explore the possible underlying mechanism by which IA MSCs may interact with CaN. Results: The study suggests that IA MSCs seemingly reduce the expression of CaN after ischemic stroke. IA MSCs have shown to improve the functional outcome and normalize oxidative parameters. Conclusion: Our study provides a preliminary evidence of role of IA MSCs in modulating CaN expression.

Stroke remains a leading cause of death and disability in the United States. No current treatments exist to promote cognitive recovery in survivors of stroke. A previous study from our laboratory determined that an acute bout of forced treadmill exercise was able to promote cognitive recovery in 3 month old male rats after middle cerebral artery occlusion (MCAo). In this study, we tested the hypothesis that 6 days of intense acute bout of forced treadmill exercise (physical exercise - PE) promotes cognitive recovery in 11-14 month old male rats. We determined that PE was able to ameliorate cognitive deficits as determined by contextual fear conditioning. Additionally, we also tested the hypothesis that PE promotes cognitive recovery in 11-13 month old reproductive senescent female rats. In contrast to males, the same intensity of exercise that decrease cognitive deficits in males was not able to promote cognitive recovery in female rats. Additionally, we determined that exercise did not lessen infarct volume in both male and female rats. There are many factors that contribute to higher stroke mortality and morbidities in women and thus, future studies will investigate the effects of PE in aged female rats to identify sex differences., (Copyright © 2019 Cohan, Youbi, Saul, Ruiz, Furones, Patel, Perez, Raval, Dave, Zhao, Dong, Rundek, Koch, Sacco and Perez-Pinzon.)

Background: Uncontrollable bleeding is a major cause of mortality and morbidity worldwide. Effective hemostatic agents are urgently needed. Red cell microparticles (RMPs) are a highly promising hemostatic agent. This study evaluated the safety profile of RMPs preliminary to clinical trial., Methods and Results: RMPs were prepared from type O+ human red blood cell by high-pressure extrusion. Male rats were treated with RMPs either a 1 × bolus, or 4 × or 20 × administered over 60 minutes. The vehicle-treated group was used as a control. Effects on physiological parameters were evaluated; namely, blood pressure, body and head temperature, hematocrit, and blood gases. We did not observe any adverse effects of RMPs on these physiological parameters. In addition, brain, heart, and lungs of rats treated with 4 × dose (bolus followed by infusion over 60 minutes) or vehicle were examined histologically for signs of thrombosis or other indications of toxicity. No thrombosis or indications of toxicity in brain, heart, or lungs were observed. Studies revealed that RMPs were distributed mainly in liver, spleen, and lymph nodes, and were potentially excreted through the kidneys., Conclusions: Our study indicates that RMP administration appears not to have any negative impact on the parameters studied and did not produce thrombosis in heart, brain, and lungs. However, more detailed long-term studies confirming the safety of RMP as a hemostatic agent are warranted.

Neurodegenerative diseases are among the leading causes of mortality and disability worldwide. However, current therapeutic approaches have failed to reach significant results in their prevention and cure. Protein Kinase Cs (PKCs) are kinases involved in the pathophysiology of neurodegenerative diseases, such as Alzheimer's Disease (AD) and cerebral ischemia. Specifically ε, δ, and γPKC are associated with the endogenous mechanism of protection referred to as ischemic preconditioning (IPC). Existing modulators of PKCs, in particular of εPKC, such as ψεReceptor for Activated C-Kinase (ψεRACK) and Resveratrol, have been proposed as a potential therapeutic strategy for cerebrovascular and cognitive diseases. PKCs change in expression during aging, which likely suggests their association with IPC-induced reduction against ischemia and increase of neuronal loss occurring in senescent brain. This review describes the link between PKCs and cerebrovascular and cognitive disorders, and proposes PKCs modulators as innovative candidates for their treatment. We report original data showing εPKC reduction in levels and activity in the hippocampus of old compared to young rats and a reduction in the levels of δPKC and γPKC in old hippocampus, without a change in their activity. These data, integrated with other findings discussed in this review, demonstrate that PKCs modulators may have potential to restore age-related reduction of endogenous mechanisms of protection against neurodegeneration.

Calreticulin (CALR), a lectin-like ER chaperone, was initially known only for its housekeeping function, but today it is recognized for many versatile roles in different compartments of a cell. Apart from canonical roles in protein folding and calcium homeostasis, it performs a variety of noncanonical roles, mostly in CNS development. In the past, studies have linked Calreticulin with various other biological components which are detrimental in deciding the fate of neurons. Many neurological disorders that differ in their etiology are commonly associated with aberrant levels of Calreticulin, that lead to modulation of apoptosis and phagocytosis, and impact on transcriptional pathways, impairment in proteostatis, and calcium imbalances. Such multifaceted properties of Calreticulin are the reason why it has been implicated in vital roles of the nervous system in recent years. Hence, understanding its role in the physiology of neurons would help to unearth its involvement in the spectrum of neurological disorders. This Review aims toward exploring the interplay of Calreticulin in neurological disorders which would aid in targeting Calreticulin for developing novel neurotherapeutics.

Neuroprotective agents administered post-cerebral ischemia have failed so far in the clinic to promote significant recovery. Thus, numerous efforts were redirected toward prophylactic approaches such as preconditioning as an alternative therapeutic strategy. Our laboratory has revealed a novel long-term window of cerebral ischemic tolerance mediated by resveratrol preconditioning (RPC) that lasts for 2 weeks in mice. To identify its mediators, we conducted an RNA-seq experiment on the cortex of mice 2 weeks post-RPC, which revealed 136 differentially expressed genes. The majority of genes (116/136) were downregulated upon RPC and clustered into biological processes involved in transcription, synaptic signaling, and neurotransmission. The downregulation in these processes was reminiscent of metabolic depression, an adaptation used by hibernating animals to survive severe ischemic states by downregulating energy-consuming pathways. Thus, to assess metabolism, we used a neuronal-astrocytic co-culture model and measured the cellular respiration rate at the long-term window post-RPC. Remarkably, we observed an increase in glycolysis and mitochondrial respiration efficiency upon RPC. We also observed an increase in the expression of genes involved in pyruvate uptake, TCA cycle, and oxidative phosphorylation, all of which indicated an increased reliance on energy-producing pathways. We then revealed that these nuclear and mitochondrial adaptations, which reduce the reliance on energy-consuming pathways and increase the reliance on energy-producing pathways, are epigenetically coupled through acetyl-CoA metabolism and ultimately increase baseline ATP levels. This increase in ATP would then allow the brain, a highly metabolic organ, to endure prolonged durations of energy deprivation encountered during cerebral ischemia.

Mitophagy and inflammasomes have a pivotal role in the development of neuropathology. Molecular mechanisms behind mitophagy and inflammasomes are well-understood, but lacunae prevail in understanding the crosstalk between them in various neurological disorders. As mitochondrial dysfunction is the prime event in neurodegeneration, the clearance of impaired mitochondria is one of the main tasks for maintaining cell integrity in the majority of neuropathologies. Along with it, inflammasome activation also plays a major role, which is usually followed by mitochondrial dysfunction. The present review highlights basics of autophagy, mitophagy, and inflammasomes and the molecular mechanisms involved, and more importantly, it tries to elaborate the interplay between mitophagy and inflammasomes in various neurological disorders. This will help in upgrading the reader's understanding in exploring the link between mitophagy and inflammasomes, which has dealt with limitations in past studies.