Search

Cerebral ischemic stroke is a major cause of death worldwide due to brain cell death resulting from ischemia-reperfusion injury. However, effective treatment approaches for patients with ischemic stroke are still lacking in clinical practice. This study investigated the potential neuroprotective effects of sildenafil, a phosphodiesterase-5 inhibitor, in a gerbil model of global brain ischemia. We investigated the effects of sildenafil on the expression of glial fibrillary acidic protein and aquaporin-4, which are markers related to astrocyte activation and water homeostasis, respectively. Immunofluorescence analysis showed that the number of cells co-expressing these markers, which was elevated in the ischemia-induced group, was significantly reduced in the sildenafil-treated groups. This suggests that sildenafil may have a potential mitigating effect on astrocyte activation induced by ischemia. Additionally, we performed various behavioral tests, including the open-field test, novel object recognition, Barnes maze, Y-maze, and passive avoidance tests, to evaluate sildenafil's effect on cognitive function impaired by ischemia. Overall, the results suggest that sildenafil may serve as a neuroprotective agent, potentially alleviating delayed neuronal cell death and improving cognitive function impaired by ischemia. [ABSTRACT FROM AUTHOR]

Background and purpose: Stress, especially immobility stress, is quite common and one of the most important and influential risk factors in neurological disorders. This study aimed to investigate the effect of acute and chronic immobility stress on the level of cortical and hippocampal oxidative stress indicators and memory impairment following global cerebral ischemia. Experimental approach: In this study, 48 male Wistar rats were randomly divided into 6 groups: 1, sham (S); 2, sham-acute stress (SSA); 3, sham-chronic stress (SSC); 4, ischemia (IS); 5, ischemia-acute stress (ISA); 6, ischemia-chronic stress (ISC). The Morris water maze (MWM) test was performed 14 days after surgery, and cortisol levels and oxidative stress factors such as malondialdehyde MDA and total thiol were measured. Findings/Results: In the MWM test, the time to find the platform (latency time) in the ISC and IS groups significantly increased compared to the S group. The time spent in the target quarter in these two groups was significantly reduced compared to the S group on the day of the probe. The results showed a significant increase in cortisol levels and malondialdehyde concentration in the ISA, ISC, and IS groups compared to the S group, but there was no significant difference in total thiol concentration. No significant difference was observed in the level of oxidative stress factors in the cortex. Conclusion and implication: Chronic immobility stress could reduce antioxidant factors in the hippocampus and exacerbate memory impairment caused by global ischemia.

Background and purpose: Stress, especially immobility stress, is quite common and one of the most important and influential risk factors in neurological disorders. This study aimed to investigate the effect of acute and chronic immobility stress on the level of cortical and hippocampal oxidative stress indicators and memory impairment following global cerebral ischemia. Experimental approach: In this study, 48 male Wistar rats were randomly divided into 6 groups: 1, sham (S); 2, sham-acute stress (SSA); 3, sham-chronic stress (SSC); 4, ischemia (IS); 5, ischemia-acute stress (ISA); 6, ischemia-chronic stress (ISC). The Morris water maze (MWM) test was performed 14 days after surgery, and cortisol levels and oxidative stress factors such as malondialdehyde MDA and total thiol were measured. Findings/Results: In the MWM test, the time to find the platform (latency time) in the ISC and IS groups significantly increased compared to the S group. The time spent in the target quarter in these two groups was significantly reduced compared to the S group on the day of the probe. The results showed a significant increase in cortisol levels and malondialdehyde concentration in the ISA, ISC, and IS groups compared to the S group, but there was no significant difference in total thiol concentration. No significant difference was observed in the level of oxidative stress factors in the cortex. Conclusion and implication: Chronic immobility stress could reduce antioxidant factors in the hippocampus and exacerbate memory impairment caused by global ischemia. [ABSTRACT FROM AUTHOR]

Cerebral ischemic stroke is a major cause of death worldwide due to brain cell death resulting from ischemia-reperfusion injury. However, effective treatment approaches for patients with ischemic stroke are still lacking in clinical practice. This study investigated the potential neuroprotective effects of sildenafil, a phosphodiesterase-5 inhibitor, in a gerbil model of global brain ischemia. We investigated the effects of sildenafil on the expression of glial fibrillary acidic protein and aquaporin-4, which are markers related to astrocyte activation and water homeostasis, respectively. Immunofluorescence analysis showed that the number of cells co-expressing these markers, which was elevated in the ischemia-induced group, was significantly reduced in the sildenafil-treated groups. This suggests that sildenafil may have a potential mitigating effect on astrocyte activation induced by ischemia. Additionally, we performed various behavioral tests, including the open-field test, novel object recognition, Barnes maze, Y-maze, and passive avoidance tests, to evaluate sildenafil’s effect on cognitive function impaired by ischemia. Overall, the results suggest that sildenafil may serve as a neuroprotective agent, potentially alleviating delayed neuronal cell death and improving cognitive function impaired by ischemia.

Recently, we demonstrated that the corpora amylacea (CA), a glycoprotein-rich aggregate frequently found in aged brains, accumulates in the ischemic hippocampus and that osteopontin (OPN) mediates the entire process of CA formation. Therefore, this study aimed to elucidate the mechanisms by which astrocytes and microglia participate in CA formation during the late phase (4-12 weeks) of brain ischemia. Based on various morphological analyses, including immunohistochemistry, in situ hybridization, immunoelectron microscopy, and correlative light and electron microscopy, we propose that astrocytes are the primary cells responsible for CA formation after ischemia. During the subacute phase after ischemia, astrocytes, rather than microglia, express Opn messenger ribonucleic acid and OPN protein, a surrogate marker and key component of CA. Furthermore, the specific localization of OPN in the Golgi complex suggests that it is synthesized and secreted by astrocytes. Astrocytes were in close proximity to type I OPN deposits, which accumulated in the mitochondria of degenerating neurons before fully forming the CA (type III OPN deposits). Throughout CA formation, astrocytes remained closely attached to OPN deposits, with their processes exhibiting well-developed gap junctions. Astrocytic cytoplasmic protein S100b, a calcium-binding protein, was detected within the fully formed CA. Additionally, ultrastructural analysis revealed direct contact between astroglial fibrils and the forming facets of the CA. Overall, we demonstrated that astrocytes play a central role inmediating CA formation fromthe initial stages of OPN deposit accumulation to the evolution of fully formed CA following transient ischemia in the hippocampus. [ABSTRACT FROM AUTHOR]

Cerebral ischemia is one of the leading causes of death and disability worldwide. The only FDA-approved treatment is recanalization with systemic tissue plasminogen activators like alteplase, although reperfusion caused by recanalization can result in neuroinflammation, which can cause brain cell apoptosis. Therefore, after an ischemic/reperfusion injury, interventions are needed to minimize the neuroinflammatory cascade. In the present study, piceatannol (PCT) was studied for its neuroprotective efficacy in a rat model of global ischemic injury by attenuating c-Jun N-terminal kinase 3 (JNK3) downstream signaling. PCT is a resveratrol analog and a polyphenolic stilbenoid naturally occurring in passion fruit and grapes. The neuroprotective efficacy of PCT (1, 5, 10 mg/kg) in ischemic conditions was assessed through pre- and post-treatment. Cerebral blood flow (CBF) and tests for functional recovery were assessed. Protein and gene expression were done for JNK3 and other inflammatory markers. A docking study was performed to identify the amino acid interaction. The results showed that PCT improved motor and memory function as measured by a functional recovery test believed to be due to an increase in cerebral blood flow. Also, the caspase signaling which promotes apoptosis was found to be down-regulated; however, nitric oxide synthase expression was up-regulated, which could explain the enhanced cerebral blood flow (CBF). According to our findings, PCT impeded c-Jun N-terminal kinase 3 (JNK3) signaling by suppressing phosphorylation and disrupting the mitochondrial apoptotic pathway, which resulted in the neuroprotective effect. Molecular docking analysis was performed to investigate the atomic-level interaction of JNK3 and PCT, which reveals that Met149, Leu206, and Lys93 amino acid residues are critical for the interaction of PCT and JNK3. According to our current research, JNK3 downstream signaling and the mitochondrial apoptosis pathway are both inhibited by PCT, which results in neuroprotection under conditions of global brain ischemia. Piceatannol attenuated JNK3 phosphorylation during the ischemic condition and prevented neuronal apoptosis [ABSTRACT FROM AUTHOR]

Recently, we demonstrated that the corpora amylacea (CA), a glycoprotein-rich aggregate frequently found in aged brains, accumulates in the ischemic hippocampus and that osteopontin (OPN) mediates the entire process of CA formation. Therefore, this study aimed to elucidate the mechanisms by which astrocytes and microglia participate in CA formation during the late phase (4–12 weeks) of brain ischemia. Based on various morphological analyses, including immunohistochemistry, in situ hybridization, immunoelectron microscopy, and correlative light and electron microscopy, we propose that astrocytes are the primary cells responsible for CA formation after ischemia. During the subacute phase after ischemia, astrocytes, rather than microglia, express Opn messenger ribonucleic acid and OPN protein, a surrogate marker and key component of CA. Furthermore, the specific localization of OPN in the Golgi complex suggests that it is synthesized and secreted by astrocytes. Astrocytes were in close proximity to type I OPN deposits, which accumulated in the mitochondria of degenerating neurons before fully forming the CA (type III OPN deposits). Throughout CA formation, astrocytes remained closely attached to OPN deposits, with their processes exhibiting well-developed gap junctions. Astrocytic cytoplasmic protein S100β, a calcium-binding protein, was detected within the fully formed CA. Additionally, ultrastructural analysis revealed direct contact between astroglial fibrils and the forming facets of the CA. Overall, we demonstrated that astrocytes play a central role in mediating CA formation from the initial stages of OPN deposit accumulation to the evolution of fully formed CA following transient ischemia in the hippocampus.

Strict metabolic regulation in discrete brain regions leads to neurochemical changes in cerebral ischemia. Accumulation of extracellular glutamate is one of the early neurochemical changes that take place during cerebral ischemia. Understanding the sequential neurochemical processes involved in cerebral ischemia-mediated excitotoxicity before the clinical intervention of revascularization and reperfusion may greatly influence future therapeutic strategies for clinical stroke recovery. This study investigated the influence of time and brain regions on excitatory neurochemical indices in the bilateral common carotid artery occlusion (BCCAO) model of global ischemia. Male Wistar rats were subjected to BCCAO for 15 and 60 min to evaluate the effect of ischemia duration on excitatory neurochemical indices (dopamine level, glutamine synthetase, glutaminase, glutamate dehydrogenase, aspartate aminotransferase, monoamine oxidase, acetylcholinesterase, and Na+ K+ ATPase activities) in the discrete brain regions (cortex, striatum, cerebellum, and hippocampus). BCCAO without reperfusion caused marked time and brain region-dependent alterations in glutamatergic, glutaminergic, dopaminergic, monoaminergic, cholinergic, and electrogenic homeostasis. Prolonged BCCAO decreased cortical, striatal, and cerebellar glutamatergic, glutaminergic, dopaminergic, cholinergic, and electrogenic activities; increased hippocampal glutamatergic, glutaminergic, dopaminergic, and cholinergic activities, increased cortical and striatal monoaminergic activity; decreased cerebellar and hippocampal monoaminergic activity; and decreased hippocampal electrogenic activity. This suggests that excitatory neurotransmitters play a major role in the tissue-specific metabolic plasticity and reprogramming that takes place between the onset of cardiac arrest-mediated global ischemia and clinical intervention of recanalization. These tissue-specific neurochemical indices may serve as diagnostic and therapeutic strategies for mitigating the progression of ischemic damage before revascularization. [ABSTRACT FROM AUTHOR]

Purpose: Chemical exchange saturation transfer (CEST) MRI is promising for detecting dilute metabolites and microenvironment properties, which has been increasingly adopted in imaging disorders such as acute stroke and cancer. However, in vivo CEST MRI quantification remains challenging because routine asymmetry analysis (MTRasym) or Lorentzian decoupling measures a combined effect of the labile proton concentration and its exchange rate. Therefore, our study aimed to quantify amide proton concentration and exchange rate independently in a cardiac arrest‐induced global ischemia rat model. Methods: The amide proton CEST (APT) effect was decoupled from tissue water, macromolecular magnetization transfer, nuclear Overhauser enhancement, guanidinium, and amine protons using the image downsampling expedited adaptive least‐squares (IDEAL) fitting algorithm on Z‐spectra obtained under multiple RF saturation power levels, before and after global ischemia. Omega plot analysis was applied to determine amide proton concentration and exchange rate simultaneously. Results: Global ischemia induces a significant APT signal drop from intact tissue. Using the modified omega plot analysis, we found that the amide proton exchange rate decreased from 29.6 ± 5.6 to 12.1 ± 1.3 s−1 (P < 0.001), whereas the amide proton concentration showed little change (0.241 ± 0.035% vs. 0.202 ± 0.034%, P = 0.074) following global ischemia. Conclusion: Our study determined the labile proton concentration and exchange rate underlying the in vivo APT MRI. The significant change in the exchange rate, but not the concentration of amide proton demonstrated that the pH effect dominates the APT contrast during tissue ischemia. [ABSTRACT FROM AUTHOR]

We previously demonstrated that osteopontin (OPN) is closely associated with calcium precipitation in response to ischemic brain insults. The present study was designed to elucidate the possible association between deposition of OPN and progressive neurodegeneration in the ischemic hippocampus. To address this, we analyzed the OPN deposits in the rat hippocampus after global cerebral ischemia in the chronic phase (4 to 12 weeks) after reperfusion using immunoelectron microscopy and correlative light and electron microscopy. We identified three different types of OPN deposits based on their morphological characteristics, numbered according to the order in which they evolved. Dark degenerative cells that retained cellular morphology were frequently observed in the pyramidal cell layer, and type I OPN deposits were degenerative mitochondria that accumulated among these cells. Type II deposits evolved into more complex amorphous structures with prominent OPN deposits within their periphery and within degenerative mitochondria-like structures. Finally, type III had large concentric laminated structures with irregularly shaped bodies in the center of the deposits. In all types, OPN expression was closely correlated with calcification, as confirmed by calcium fixation and Alizarin Red staining. Notably, type II and III deposits were highly reminiscent of corpora amylacea, glycoprotein-rich aggregates found in aged brains, or neurodegenerative disease, which was further confirmed by ubiquitin expression and periodic acid-Schiff staining. Overall, our data provide a novel link between ongoing neurodegeneration and the formation of corpora amylacea-like structures and calcium deposits in the ischemic hippocampus, suggesting that OPN may play an important role in such processes. [ABSTRACT FROM AUTHOR]

Abstract Background Targeted temperature management (TTM) of 32 to 34 °C has been the standard treatment for out-of-hospital cardiac arrest since clinical trials in 2002 indicated benefit on survival and neurological outcome. In 2013, a clinical trial showed no difference in outcome between TTM of 33 °C and TTM of 36 °C. In this meta-analysis, we investigate the evidence for TTM in animal models of cardiac arrest. Methods We searched PubMed and EMBASE for adult animal studies using TTM as a treatment in different models of cardiac arrest or global brain ischemia which reported neurobehavioural outcome, brain histology or mortality. We used a random effects model to calculate estimates of efficacy and assessed risk of bias using an adapted eight-item version of the Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CAMARADES) quality checklist. We also used a scoring system based on the recommendations of the Stroke Treatment Academic Industry Roundtable (STAIR), to assess the scope of testing in the field. Included studies which investigated a post-ischemic induction of TTM had their treatment regimens characterized with regard to depth, duration and time to treatment and scored against the modified STAIR criteria. Results The initial and updated search generated 17809 studies after duplicate removal. One hundred eighty-one studies met the inclusion criteria, including data from 1,787, 6,495 and 2,945 animals for neurobehavioural, histological and mortality outcomes, respectively. TTM was favoured compared to control for all outcomes. TTM was beneficial using short and prolonged cooling, deep and moderate temperature reduction, and early and delayed time to treatment. Median [IQR] study quality was 4 [3 to 6]. Eighteen studies checked seven or more of the eight CAMARADES quality items. There was no clear correlation between study quality and efficacy for any outcome. STAIR analysis identified 102 studies investigating post-ischemic induction of TTM, comprising 147 different treatment regimens of TTM. Only 2 and 8 out of 147 regimens investigated comorbid and gyrencephalic animals, respectively. Conclusions TTM is beneficial under most experimental conditions in animal models of cardiac arrest or global brain ischemia. However, research on gyrencephalic species and especially comorbid animals is uncommon and a possible translational gap. Also, low study quality suggests risk of bias within studies. Future animal research should focus on mimicking the clinical scenario and employ similar rigour in trial design to that of modern clinical trials.

To investigate the effects of 4-methyl-2-{[4-(toluene-4-sulfonyl)-thiomorpholine-3-carbonyl]-amino}-pentanoic acid isopropyl ester (HD5-6) against cerebral ischemia in rodents, the models with global and focal ischemia were induced by bilateral common carotid artery occlusion plus hypotension (BCAOH) and permanent cerebral artery occlusion (p-MCAO) in mice (n = 10 - 12 per group in BCAOH; n = 8 per group in p-MCAO) and rats (n = 10 - 11 in each group). HD5-6 prolonged lifetime and improved neurological function. Neurological deficits score in HD5-6 (30 mg/kg) decreased significantly. Malonaldehyde (MDA) in HD5-6-treated mice with ischemia considerably dropped. The infarction volume of the HD5-6-treated rats with MCAO-induced ischemia decreased significantly in the high dose group (P < 0.05, i.g. and P < 0.01, i.v.). Immunohistochemistry showed that Brain derived neurotrophic factor (BDNF) in the ipsilateral hemisphere increased and Vascular endothelial growth factor (VEGF) decreased with HD5-6 treatment. HD5-6 has protective effects against experimental cerebral ischemia in rodents and the action mechanism may involve anti-oxidation and neurogenesis. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the effect of Mucuna pruriens on ischemia-induced motor incoordination. Methods: Male Wistar rats were used in this study were divided into eight groups of six rats each. The bilateral common carotid artery (BCA) was occluded to induce global cerebral ischemia. Carboxymethylcellulose (CMC) was used as a vehicle for this while quercetin was used as the standard. The rats were fed with the methanol plant extract of Mucuna pruriens (MP) seeds for ten days. The treatment groups include treatment plus BCA occlusion. Various behavioral parameters such as locomotor activity, motor coordination, spatial learning, and cerebral infarction area were evaluated. Results: A decline in locomotor activity, motor coordination, and spatial learning was observed in the ischemia-induced Wistar rats. The group treated with Mucuna pruriens showed significant protection against brain damage when compared with negative control group. Conclusion: Mucuna pruriens provides effective neuroprotective activity in BCA occlusion-induced cerebral ischemia in rats, and thus a potential therapeutic agent for the clinical management of cerebral ischemia. [ABSTRACT FROM AUTHOR]

The main stem cell niche for neurogenesis in the adult mammalian brain is the subventricular zone (SVZ) that extends along the cerebral lateral ventricles. We aimed at characterizing the initial molecular responses of the macaque monkey SVZ to transient, global cerebral ischemia. We microdissected tissue lining the anterior horn of the lateral ventricle (SVZa) from 7 day post-ischemic and sham-operated monkeys. Transcriptomics shows that in ischemic SVZa, 541 genes were upregulated and 488 genes were down-regulated. The transcription data encompassing the upregulated genes revealed a profile typical for quiescent stem cells and astrocytes. In the primate brain the SVZ is morphologically subdivided in distinct and separate ependymal and subependymal regions. The subependymal contains predominantly neural stem cells (NSC) and differentiated progenitors. To determine in which SVZa region ischemia had evoked transcriptional upregulation, sections through control and ischemic SVZa were analyzed by high-throughput in situ hybridization for a total of 150 upregulated genes shown in the www.monkey-niche.org image database. The majority of the differentially expressed genes mapped to the subependymal layers on the striatal or callosal aspect of the SVZa. Moreover, a substantial number of upregulated genes was expressed in the ependymal layer, implicating a contribution of the ependyma to stem cell biology. The transcriptome analysis yielded several novel gene markers for primate SVZa including the apelin receptor that is strongly expressed in the primate SVZa niche upon ischemic insult.

The article analyses three clinical cases of patients in a permanent vegetative state due to cardiac arrest and prolonged cardiopulmonary resuscitation. All patients were admitted to Federal State Budget Scientific Institution -- Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russia. For diagnosing and prognosis for the progression of the disease a detailed examination was held, including electroencephalography, polysomnography, positron emission computed tomography, single-photon emission computed tomography, functional perfusion computed tomography, electroneuromyography, evoked potentials studies, laboratory studies, and other available tests. Instrumental diagnostics methods confirm the principal component that determines the level of consciousness in this type of damage -- diffuse damage to the cerebral cortex. To conclude realization of the rehabilitation potential of such patients is impossible without the control of nutritional support. Amino acid profile is one of the markers and ways to control metabolic function. [ABSTRACT FROM AUTHOR]

Global cerebral ischemia induced by cardiac arrest usually leads to poor neurological outcomes. Numerous studies have focused on ways to prevent ischemic damage in the brain, however clinical therapies are still limited. Our previous studies revealed that delta opioid receptor (DOR) activation with [d-Ala2, d-Leu5] enkephalin (DADLE), a DOR agonist, not only significantly promotes neuronal survival on day 3, but also improves spatial memory deficits on days 5-9 after ischemia. However, the neurological mechanism underlying DADLE-induced cognitive recovery remains unclear. This study first examined the changes in neuronal survival in the CA1 region at the advanced time point (day 7) after ischemia/reperfusion (I/R) injury and found a significant amelioration of damaged CA1 neurons in the rats treated with DADLE (2.5 nmol) when administered at the onset of reperfusion. The structure and function of CA1 neurons on days 3 and 7 post-ischemia showed significant improvements in both the density of the injured dendritic spines and the basic transmission of the impaired CA3-CA1 synapses following DADLE treatment. The molecular changes involved in DADLE-mediated synaptic modulation on days 3 and 7 post-ischemia implied the time-related differential regulation of PKCα-MARCKS on the dendritic spine structure and of BDNF- ERK1/2-synapsin I on synaptic function, in response to ischemic/reperfusion injury as well as to DADLE treatment. Importantly, all the beneficial effects of DADLE on ischemia-induced cellular, synaptic, and molecular deficits were eliminated by the DOR inhibitor naltrindole (2.5 nmol). Taken together, this study suggested that DOR activation-induced protective signaling pathways of PKCα-MARCKS involved in the synaptic morphology and BDNF-ERK-synapsin I in synaptic transmission may be engaged in the cognitive recovery in rats suffering from advanced cerebral ischemia. [ABSTRACT FROM AUTHOR]

Brain stroke is one of the causes of human death and disability worldwide. Global ischemia results in the accumulation of free radicals in the neurons. It leads to histologically brain damage. The CA1 region of the hippocampus is a sensitive area for free radicals. This study investigated the combined therapy of the Granulocyte colony stimulating factor (G-CSF) and the Intravenous lipid emulsion (ILE). These neuroprotective agents play a role in the regeneration of neurons. They improve the learning ability and memory in rats induced global ischemia. We divided 35 rats into five groups. The groups were sham group, ischemia group, G-CSF group, ILE group, and G-CSF plus ILE group. Ischemia was induced by occlusion of the bilateral common carotid about 10 min. The drugs applied on days 1, 3 and 7. The treated groups received subcutaneous injection of 20 μg/kg G-CSF and intravenous injection of 5 ml/kg ILE. After two weeks, the memory and learning ability of the rats was evaluated by the shuttle box. Hematoxylin and Eosin and Nissl and TUNEL stainings were used to determine the necrosis, normal and apoptotic cells. The combined therapy increased normal cells compared to the ischemia group. They decreased the number of necrotic and apoptosis cells in other groups. The combined group improved the passive avoidance test compared to the other groups. The combination therapy of G-CSF plus ILE is more effective than each alone. [ABSTRACT FROM AUTHOR]

Background Systemic innate immune priming is a recognized sequela of post‐ischemic neuroinflammation and contributor to delayed neurodegeneration. Given mounting evidence linking acute stroke with reactive lung inflammation, we asked whether enhanced expression of the endogenous antioxidant extracellular superoxide dismutase 3 (SOD3) produced by alveolar type II pneumocytes would protect the lung from transient global cerebral ischemia and the brain from the delayed effects of ischemia‐reperfusion. Methods and Results Following 15 minutes of global cerebral ischemia or sham conditions, transgenic SOD3 and wild‐type mice were followed daily for changes in weight, core temperature, and neurological function. Three days after reperfusion, arterial and venous samples were collected for complete blood counts, flow cytometry, and SOD3 protein blotting, and immunohistochemistry was performed on lung and brain tissue to assess tissue injury, blood‐brain barrier permeability, and neutrophil transmigration. Relative to ischemic controls, transgenic SOD3 mice performed better on functional testing and exhibited reduced peripheral neutrophil activation, lung inflammation, and blood‐brain barrier leak. Once released from the lung, SOD3 was predominantly not cell associated and depleted in the venous phase of circulation. Conclusions In addition to reducing the local inflammatory response to cerebral ischemia, targeted enrichment of SOD3 within the lung confers distal neuroprotection against ischemia‐reperfusion injury. These data suggest that therapies geared toward enhancing adaptive lung‐neurovascular coupling may improve outcomes following acute stroke and cardiac arrest.

Disturbances in mitochondrial biogenesis and bioenergetics, combined with neuroinflammation, play cardinal roles in the cognitive impairment during aging that is further exacerbated by transient cerebral ischemia. Both near-infrared (NIR) photobiomodulation (PBM) and Coenzyme Q10 (CoQ10) administration are known to stimulate mitochondrial electron transport that potentially may reverse the effects of cerebral ischemia in aged animals. We tested the hypothesis that the effects of PBM and CoQ10, separately or in combination, improve cognition in a mouse model of transient cerebral ischemia superimposed on a model of aging. We modeled aging by 6-week administration of D-galactose (500 mg/kg subcutaneous) to mice. We subsequently induced transient cerebral ischemia by bilateral occlusion of the common carotid artery (BCCAO). We treated the mice with PBM (810 nm transcranial laser) or CoQ10 (500 mg/kg by gavage), or both, for 2 weeks after surgery. We assessed cognitive function by the Barnes and Lashley III mazes and the What-Where-Which (WWWhich) task. PBM or CoQ10, and both, improved spatial and episodic memory in the mice. Separately and together, the treatments lowered reactive oxygen species and raised ATP and general mitochondrial activity as well as biomarkers of mitochondrial biogenesis, including SIRT1, PGC-1α, NRF1, and TFAM. Neuroinflammatory responsiveness declined, as indicated by decreased iNOS, TNF-α, and IL-1β levels with the PBM and CoQ10 treatments. Collectively, the findings of this preclinical study imply that the procognitive effects of NIR PBM and CoQ10 treatments, separately or in combination, are beneficial in a model of transient global brain ischemia superimposed on a model of aging in mice.

Background: Targeted temperature management (TTM) of 32 to 34 °C has been the standard treatment for out-of-hospital cardiac arrest since clinical trials in 2002 indicated benefit on survival and neurological outcome. In 2013, a clinical trial showed no difference in outcome between TTM of 33 °C and TTM of 36 °C. In this meta-analysis, we investigate the evidence for TTM in animal models of cardiac arrest. Methods: We searched PubMed and EMBASE for adult animal studies using TTM as a treatment in different models of cardiac arrest or global brain ischemia which reported neurobehavioural outcome, brain histology or mortality. We used a random effects model to calculate estimates of efficacy and assessed risk of bias using an adapted eight-item version of the Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CAMARADES) quality checklist. We also used a scoring system based on the recommendations of the Stroke Treatment Academic Industry Roundtable (STAIR), to assess the scope of testing in the field. Included studies which investigated a post-ischemic induction of TTM had their treatment regimens characterized with regard to depth, duration and time to treatment and scored against the modified STAIR criteria. Results: The initial and updated search generated 17809 studies after duplicate removal. One hundred eighty-one studies met the inclusion criteria, including data from 1,787, 6,495 and 2,945 animals for neurobehavioural, histological and mortality outcomes, respectively. TTM was favoured compared to control for all outcomes. TTM was beneficial using short and prolonged cooling, deep and moderate temperature reduction, and early and delayed time to treatment. Median [IQR] study quality was 4 [3 to 6]. Eighteen studies checked seven or more of the eight CAMARADES quality items. There was no clear correlation between study quality and efficacy for any outcome. STAIR analysis identified 102 studies investigating post-ischemic induction of TTM, comprising 147 different treatment regimens of TTM. Only 2 and 8 out of 147 regimens investigated comorbid and gyrencephalic animals, respectively. Conclusions: TTM is beneficial under most experimental conditions in animal models of cardiac arrest or global brain ischemia. However, research on gyrencephalic species and especially comorbid animals is uncommon and a possible translational gap. Also, low study quality suggests risk of bias within studies. Future animal research should focus on mimicking the clinical scenario and employ similar rigour in trial design to that of modern clinical trials. [ABSTRACT FROM AUTHOR]

• We previously discovered palmitic acid methyl ester (a C16:0 saturated fatty acid) is a novel and potent vasodilator. • We investigated the therapeutic potential of palmitic acid methyl ester against cardiac arrest-induced brain injury and neurological deficits. • We found that post-treatment of palmitic acid methyl ester after cardiac arrest can enhance cerebral blood flow and neuronal cell survival ultimately improving functional learning/memory. We previously discovered that palmitic acid methyl ester (PAME) is a potent vasodilator first identified and released from the superior cervical ganglion and remain understudied. Thus, we investigated PAME's role in modulating cerebral blood flow (CBF) and neuroprotection after 6 min of cardiac arrest (model of global cerebral ischemia). Our results suggest that PAME can enhance CBF under normal physiological conditions, while administration of PAME (0.02 mg/kg) immediately after cardiopulmonary resuscitation can also enhance CBF in vivo. Additionally, functional learning and spatial memory assessments (via T-maze) 3 days after asphyxial cardiac arrest (ACA) suggest that PAME-treated rats have improved learning and memory recovery versus ACA alone. Furthermore, improved neuronal survival in the CA1 region of the hippocampus were observed in PAME-treated, ACA-induced rats. Altogether, our findings suggest that PAME can enhance CBF, alleviate neuronal cell death, and promote functional outcomes in the presence of ACA. [ABSTRACT FROM AUTHOR]

Ischemic stroke is responsible for a large number of neurological deficits including memory impairment. Deep brain stimulation (DBS), a well established therapeutic modality for the treatment of movement disorders, has recently shown potential beneficial effects on memory in animals and patients with Alzheimer's disease. Here, we test DBS for its ability to improve memory impairments by stimulating the entorhinal cortex (EC) in a rat model of global ischemia (GI). Two weeks after GI, adult male rats received high-frequency EC DBS for 1 h, and animals were assessed for changes in locomotor activity, learning, and memory 6 weeks later. GI produced spatial memory impairment that was ameliorated by DBS, with no difference between the group that received DBS for GI (GI-DBS ON group) and nonstroke control groups. Although GI led to a dramatic CA1 neuronal loss that could not be rescued with DBS, stimulation attenuated the reduction of CA1 synaptophysin expression after GI. Further, in vitro slice recordings showed a restoration of typical evoked synaptic dendritic fields in GI-DBS ON animals, indicating that the DBS-induced memory rescue is associated with increased synaptophysin expression and enhanced synaptic function. These results suggest that DBS may ameliorate the functional consequences of cerebral ischemia and point to be a potential new therapeutic approach. [ABSTRACT FROM AUTHOR]

Disturbances in mitochondrial biogenesis and bioenergetics, combined with neuroinflammation, play cardinal roles in the cognitive impairment during aging that is further exacerbated by transient cerebral ischemia. Both near-infrared (NIR) photobiomodulation (PBM) and Coenzyme Q10 (CoQ10) administration are known to stimulate mitochondrial electron transport that potentially may reverse the effects of cerebral ischemia in aged animals. We tested the hypothesis that the effects of PBM and CoQ10, separately or in combination, improve cognition in a mouse model of transient cerebral ischemia superimposed on a model of aging. We modeled aging by 6-week administration of D-galactose (500 mg/kg subcutaneous) to mice. We subsequently induced transient cerebral ischemia by bilateral occlusion of the common carotid artery (BCCAO). We treated the mice with PBM (810 nm transcranial laser) or CoQ10 (500 mg/kg by gavage), or both, for 2 weeks after surgery. We assessed cognitive function by the Barnes and Lashley III mazes and the What-Where-Which (WWWhich) task. PBM or CoQ10, and both, improved spatial and episodic memory in the mice. Separately and together, the treatments lowered reactive oxygen species and raised ATP and general mitochondrial activity as well as biomarkers of mitochondrial biogenesis, including SIRT1, PGC-1α, NRF1, and TFAM. Neuroinflammatory responsiveness declined, as indicated by decreased iNOS, TNF-α, and IL-1β levels with the PBM and CoQ10 treatments. Collectively, the findings of this preclinical study imply that the procognitive effects of NIR PBM and CoQ10 treatments, separately or in combination, are beneficial in a model of transient global brain ischemia superimposed on a model of aging in mice. [ABSTRACT FROM AUTHOR]

Purpose: Transient global ischemia arising in human due to cardiac arrest causes selective, delayed neuronal death in hippocampal CA1 and cognitive impairment. Growth arrest and DNA-damage-inducible protein 45 beta (Gadd45b) is a wellknown molecule in both DNA damage-related pathogenesis and therapies. Emerging evidence suggests that Gadd45b is an anti-apoptotic factor in nonneuronal cells and is an intrinsic neuroprotective molecule in neurons. However, the mechanism of Gadd45b pathway is not fully examined in neurodegeneration associated with global ischemia. Methods: Rats were subjected to transient global ischemia by the 4-vessel occlusion or sham operation. The animals were sacrificed at 24 hours, 48 hours, and 7 days after ischemia. The hippocampal CA1 was microdissected and processed to examine mRNA and protein level. To assess neuronal death, tissue sections were cut and processed for Fluoro-Jade and Nissl staining. Results: Here we show that ischemic insults increase abundance of Gadd45b and brain-derived neurotrophic factor, a known target of Gadd45 mediated demethylation, in selectively-vulnerable hippocampal CA1 neurons. We further show that knockdown of Gadd45b increases abundance of a pro-apoptotic Bcl-2 family member Bax while decreasing the antiapoptotic protein Bcl-2, which together promote neuronal death. Conclusions: These findings document a protective role of Gadd45b against neuronal insults associated with global ischemia and identify Gadd45b as a potential therapeutic target for the amelioration of hippocampal neurodegeneration. [ABSTRACT FROM AUTHOR]

Vascular dementia is a transversal phenomenon in different kinds of neurodegenerative diseases involving acute and chronic brain alterations. Specifically, the role of phospholipids in the pathogenesis of dementia remains unknown. In the present study, we explored phospholipid profiles a month postischemia in cognitively impaired rats. The two-vessel occlusion (2-VO) model was used to generate brain parenchyma ischemia in adult male rats confirmed by alterations in myelin, endothelium, astrocytes and inflammation mediator. A lipidomic analysis was performed via mass spectrometry in the hippocampus and serum a month postischemia. We found decreases in phospholipids (PLs) associated with neurotransmission, such as phosphatidylcholine (PC 32:0, PC 34:2, PC 36:3, PC 36:4, and PC 42:1), and increases in PLs implied in membrane structure and signaling, such as lysophosphatidylethanolamine (LPE 18:1, 20:3, and 22:6) and phosphatidylserine (PS 38:4, 36:2, and 40:4), in the hippocampus. Complementarily, PC (PC 34:2, PC 34:3, PC 38:5, and PC 36:5) and ether-PC (ePC 34:1, 34:2, 36:2, 38:2, and 38:3) decreased, while Lyso-PC (LPC 18:0, 18:1, 20:4, 20:5, and LPC 22:6) and phosphatidylinositol (PI 36:2, 38:4, 38:5, and 40:5), as neurovascular state sensors, increased in the serum. Taken together, these data suggest inverse PC/LPC-PI levels as peripheral biomarkers and inverse PC/LPE-PS as a central indicator of postischemic cognitive impairment in rats.

Cardiac arrest is one of the most dangerous health problems in the world. Outcome prognosis is largely based on cerebral performance categories determined by neurological evaluations. Few systemic tests are currently available to predict survival to hospital discharge. Here, we present the results from the preclinical studies of cardiac arrest and resuscitation (CAR) in mice to identify signatures of circulating immune cells as blood-derived biomarkers to predict outcomes after CAR. Two flow cytometry panels for circulating blood lymphocytes and myeloid-derived cells, respectively, were designed to correlate with neuroinflammation and neuronal and dendritic losses in the selectively vulnerable regions of bilateral hippocampi. We found that CD4 + CD25 + regulatory T cells, CD11b + CD11c - and CD11b + Ly6C + Ly6G + myeloid-derived cells, and cells positive for the costimulatory molecules CD80 and CD86 in the blood were correlated with activation of microglia and astrocytosis, and CD4 + CD25 + T cells are additionally correlated with neuronal and dendritic losses. A fingerprint pattern of blood T cells and monocytes is devised as a diagnostic tool to predict CAR outcomes. Blood tests aimed at identifying these immunocyte patterns in cardiac arrest patients will guide future clinical trials to establish better prognostication tools to avoid unnecessary early withdrawal from life-sustaining treatment.

Purpose: Chemical exchange saturation transfer (CEST) MRI has been used for quantitative assessment of dilute metabolites and/or pH in disorders such as acute stroke and tumor. However, routine asymmetry analysis (MTRasym) may be confounded by concomitant effects such as semisolid macromolecular magnetization transfer (MT) and nuclear Overhauser enhancement. Resolving multiple contributions is essential for elucidating the origins of in vivo CEST contrast. Methods: Here we used a newly proposed image downsampling expedited adaptive least‐squares fitting on densely sampled Z‐spectrum to quantify multipool contribution from water, nuclear Overhauser enhancement, MT, guanidinium, amine, and amide protons in adult male Wistar rats before and after global ischemia. Results: Our results revealed the major contributors to in vivo T1‐normalized MTRasym (3.5 ppm) contrast between white and gray matter (WM/GM) in normal brain (−1.96%/second) are pH‐insensitive macromolecular MT (−0.89%/second) and nuclear Overhauser enhancement (−1.04%/second). Additionally, global ischemia resulted in significant changes of MTRasym, being −2.05%/second and −1.56%/second in WM and GM, which are dominated by changes in amide (−1.05%/second, −1.14%/second) and MT (−0.88%/second, −0.62%/second). Notably, the pH‐sensitive amine and amide effects account for nearly 60% and 80% of the MTRasym changes seen in WM and GM, respectively, after global ischemia, indicating that MTRasym is predominantly pH‐sensitive. Conclusion: Combined amide and amine effects dominated the MTRasym changes after global ischemia, indicating that MTRasym is predominantly pH‐sensitive and suitable for detecting tissue acidosis following acute stroke. [ABSTRACT FROM AUTHOR]

Global ischemia in childhood often leads to poor neurologic outcomes, including learning and memory deficits. Using our novel model of childhood cardiac arrest/cardiopulmonary resuscitation (CA/CPR), we investigate the mechanism of ischemia-induced cognitive deficits and recovery. Memory is impaired seven days after juvenile CA/CPR and completely recovers by 30 days. Consistent with this remarkable recovery not observed in adults, hippocampal long-term potentiation (LTP) is impaired 7–14 days after CA/CPR, recovering by 30 days. This recovery is not due to the replacement of dead neurons (neurogenesis), but rather correlates with brain-derived neurotrophic factor (BDNF) expression, implicating BDNF as the molecular mechanism underlying impairment and recovery. Importantly, delayed activation of TrkB receptor signaling reverses CA/CPR-induced LTP deficits and memory impairments. These data provide two new insights (1) endogenous recovery of memory and LTP through development may contribute to improved neurological outcome in children compared to adults and (2) BDNF-enhancing drugs speed recovery from pediatric cardiac arrest during the critical school ages. [ABSTRACT FROM AUTHOR]

Background: Cornu ammonis 3 (CA3) hippocampal neurons are resistant to global ischemia, whereas cornu ammonis (CA1) 1 neurons are vulnerable. Hamartin expression in CA3 neurons mediates this endogenous resistance via productive autophagy. Neurons lacking hamartin demonstrate exacerbated endoplasmic reticulum stress and increased cell death. We investigated endoplasmic reticulum stress responses in CA1 and CA3 regions following global cerebral ischemia, and whether pharmacological modulation of endoplasmic reticulum stress or autophagy altered neuronal viability. Methods: In vivo: male Wistar rats underwent sham or 10 min of transient global cerebral ischemia. CA1 and CA3 areas were microdissected and endoplasmic reticulum stress protein expression quantified at 3 h and 12 h of reperfusion. In vitro: primary neuronal cultures (E18 Wistar rat embryos) were exposed to 2 h of oxygen and glucose deprivation or normoxia in the presence of an endoplasmic reticulum stress inducer (thapsigargin or tunicamycin), an endoplasmic reticulum stress inhibitor (salubrinal or 4-phenylbutyric acid), an autophagy inducer ([4'-(N-diethylamino) butyl]-2- chlorophenoxazine (10-NCP)) or autophagy inhibitor (3-methyladenine). Results: In vivo, decreased endoplasmic reticulum stress protein expression (phospho-eIF2α and ATF4) was observed at 3 h of reperfusion in CA3 neurons following ischemia, and increased in CA1 neurons at 12 h of reperfusion. In vitro, endoplasmic reticulum stress inducers and high doses of the endoplasmic reticulum stress inhibitors also increased cell death. Both induction and inhibition of autophagy also increased cell death. Conclusion: Endoplasmic reticulum stress is associated with neuronal cell death following ischemia. Neither reduction of endoplasmic reticulum stress nor induction of autophagy demonstrated neuroprotection in vitro, highlighting their complex role in neuronal biology following ischemia. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to investigate the effects of memantine on brain ischemia. Because we can measure nitric oxide (NO) production and hydroxyl radical metabolism continuously, we investigated the effect of memantine on NO production and hydroxyl radical metabolism in cerebral ischemia and reperfusion.Methods: Memantine (25 µmol/kg) was administered intraperitoneally to 6 C57BL/6 mice 30 minutes before ischemia. Seven additional mice received no injection (controls). NO production and hydroxyl radical metabolism were continuously monitored using bilateral striatal microdialysis in vivo. Hydroxyl radical formation was monitored using the salicylate trapping method. Forebrain ischemia was produced in all mice by occluding the common carotid artery bilaterally for 10 minutes. Levels of the NO metabolites nitrite (NO2-) and nitrate (NO3-) were determined using the Griess reaction. Survival rates of hippocampal CA1 neurons were calculated and 8-hydroxydeoxyguanosine (8-OHdG)-immunopositive cells were counted to evaluate the oxidative stress in hippocampal CA1 neurons 72 hours after the start of reperfusion.Results: The regional cerebral blood flow was significantly higher in the memantine group than in the control group after reperfusion. Furthermore, the level of 2,3-dihydroxybenzoic acid was significantly lower in the memantine group than in the control group during ischemia and reperfusion. Levels of NO2- and NO3- did not differ significantly between the 2 groups. Although survival rates in the CA1 did not differ significantly, there were fewer 8-OHdG-immunopositive cells in animals that had received memantine than in control animals.Conclusions: These data suggest that memantine exerts partially neuroprotective effects against cerebral ischemic injury. [ABSTRACT FROM AUTHOR]