Reduction In Cerebral Infarction Research Articles

Cell-Free Therapy as A New Treatment Strategy in An Albino Rat Model of Cerebral Ischemia [Histological Studies

The therapeutic efficacy of stem cell therapy in many diseased organs based greatly on their paracrine effect. The neural stem cells are thought to have a role in improving the neurological functional, recovery, and reduction of cerebral infarction caused by cerebral ischemia/ reperfusion [I/R] injury in rats.

Irisin Ameliorates Cerebral Vasospasm and Early Brain Injury in Rats with Experimental Subarachnoid Hemorrhage

Irisin is a cytokine mainly secreted by skeletal muscles, widely distributed in the body with functions of anti-oxidation, anti-inflammation, prevention of reperfusion injury, immune stimulation, and reduction of cerebral infarction. In this study, rats with subarachnoid hemorrhage (SAH) were used as experimental subjects, and irisin was injected intraperitoneally to investigate irisin’s effect on cerebral vasospasm and early brain injury (EBI). After establishment of the animal model of SAH, animals were administered with irisin through intraperitoneal injection. The animal tissues were taken out to assess the morphological changes, and neurons apoptosis by TUNEL staining and Nissl staining. Brain edema score was used to assess the severity of brain injury, and the relationship between related signal pathways was detected by Western blot. Administration of irisin significantly reduced cerebral vasospasm and decreased neuronal apoptosis induced by SAH. Irisin inhibited the apoptosis of prefrontal cortex mitochondrial neurons, and decreased Bax/Bcl-2 and cytochrome C in the cytoplasm. The expressions of PSD-95 and GAP-43 and BDNF in brain tissues were decreased upon SAH, but their expressions were partially restored after treatment with irisin. Irisin decreases neuronal apoptosis and mitochondrial function with up-regulation of synapse proteins, thereby exerting a protective effect on EBI and SAH.

Secreted Protein Acidic and Cysteine Rich (SPARC) Regulates the Pathological Response to Ischemic Insults and Represents a Promising Therapeutic Target for Stroke Treatment

AbstractSecreted protein acidic and cysteine rich (SPARC) is a nonstructural, multifunctional matricellular protein involved in tissue development, extracellular matrix, and immune response. In this study, by using mice deficient in SPARC, the role of SPARC in the pathogenesis of ischemic stroke is characterized. It is found that, compared to the wild‐type mice, SPARC deficient mice demonstrated 48.3% reduction in cerebral infarction after ischemia insult. Mechanistically, it is shown that SPARC deficiency significantly reduces ischemia induced cellular apoptosis, diminishes inflammatory response in the ischemic area as well as in the circulatory system, and enhances the integrity of the blood–brain barrier. It is further assessed if SPARC could be targeted for stroke treatment through intraventricular or intravenous administration of SPARC neutralizing antibody. It is found that delivery of SPARC antibody through either route effectively reduces ischemia‐induced infarction. Taken together, the study suggests that SPARC plays an important role in the pathological response to ischemic insults, and represents a promising therapeutic target for clinical management of stroke.

Citalopram attenuated neurobehavioral, biochemical, and metabolic alterations in transient middle cerebral artery occlusion model of stroke in male Wistar rats.

Oxidative stress and inflammation are implicated as cardinal mechanisms of neuronal death following stroke. In the present study citalopram (Cit) was investigated in a 2 h middle cerebral artery occlusion (MCAo) model of stroke in male Wistar rats. Pretreatment, posttreatment (Post Cit) and pre plus posttreatment (Pre + Post Cit) with Cit were evaluated for its neuroprotective effect. In pretreatment protocol, effect of Cit at three doses (2, 4, and 8 mg/kg) administered i.p., 1 h prior to MCAo was evaluated using neurological deficit score (NDS), motor deficit paradigms, and cerebral infarction 24 h post-MCAo. In posttreatment and pre plus posttreatment protocol, the effective dose of Cit (4 mg/kg) was administered i.p., 0.5 h post-reperfusion (Post Cit) only, and 1 h prior to MCAo and again at 0.5 h post-reperfusion (Pre + Post Cit), respectively. These two groups were assessed for NDS and cerebral infarction. Though NDS was significantly reduced in both Post Cit and Pre + Post Cit groups, significant reduction in cerebral infarction was evident only in Pre + Post Cit group. Infarct volume assessed by magnetic resonance imaging was significantly attenuated in Pre + Post Cit group (10.6 ± 1.1%) compared to MCAo control group (18.5 ± 3.0%). Further, Pre + Post Cit treatment significantly altered 17 metabolites along with attenuation of malondialdehyde, reduced glutathione, matrix metalloproteinases, and apoptotic markers as compared to MCAo control. These results support the neuroprotective effect of Cit, mediated through amelioration of oxidative stress, inflammation, apoptosis, and altered metabolic profile.

Neuroprotective Effects of Poly(ADP-ribose)polymerase Inhibitor Olaparib in Transient Cerebral Ischemia.

Olaparib was the first poly(ADP-ribose)polymerase inhibitor approved by Food and Drug Administration for oncology treatment. However, its neuroprotective effects have not been elucidated. This study aimed to evaluate the effects of olaparib in transient cerebral ischemia. A mouse model of transient middle cerebral artery occlusion was used. Reperfusion was performed at 2h after ischemia. Different doses of olaparib (1, 3, 5, 10 and 25mg/kg) were administered intraperitoneally immediately after reperfusion. Twenty-four hours after ischemia, the neurological score was assessed, and grip and string tests were performed to evaluate the behavioral deficits in the mice. Cresyl violet staining was used to assess cerebral edema and the lesion volume. Immunohistochemistry was performed to evaluate the expression of blood-brain barrier proteins collagen IV and claudin-5, as well as extravasation of IgG. Ischemia induced a neurological deficit, which was significantly ameliorated by olaparib at 3 and 5mg/kg. However, this neuroprotective effect was not observed in mice treated with either low-dose or high-dose olaparib. Both 3 and 5mg/kg olaparib markedly reduced cerebral infarction volume, but not cerebral edema. The expression of collagen IV decreased after cerebral ischemia, which was improved by olaparib at 3 and 5mg/kg. These results were confirmed by the reduction of IgG extravasation with olaparib. Olaparib showed clear neuroprotective effects in transient ischemic mice mainly through the reduction of cerebral infarction and blood-brain barrier damage.

Abstract TP103: Activation of the Pi3k Pathway Plays Important Roles in Reduction of Cerebral Infarction by Cilnidipine

Cerebral infarction causes permanent neuronal loss inducing severe morbidity and mortality. Because hypertension is the main risk factor for cerebral infarction and most patients with hypertension take daily antihypertensive drugs, the neuroprotective effects and mechanisms of anti-hypertensive drugs need to be investigated. Cilnidipine, a long-acting, second-generation 1,4-dihydropyridine inhibitor of both L- and N-type calcium channels, was reported to reduce oxidative stress. In this study, we investigated whether cilnidipine has therapeutic effects in an animal model of cerebral infarction. After determination of the most effective dose of cilnidipine, a total of 128 rats were subjected to middle cerebral artery occlusion (MCAO). Neurobehavioral function test and brain MRI were performed, and rats with similar sized infarcts were randomized to either the cilnidipine group or the control group. Cilnidipine treatment was performed with reperfusion after 2-hr occlusion. Western blots and immunohistochemistry were also performed after 24-hr occlusion. Initial infarct volume on DWI was not different between the cilnidipine group and the control group; however, FLAIR MRI at 24 hr showed significantly reduced infarct volume in the cilnidipine group compared with the control group. Cilnidipine treatment significantly decreased the number of TUNEL-positive cells compared to the control group. Western blot and immunohistochemistry showed increased expression of phosphorylated Akt (Ser473), phosphorylated GSK-3β, and Bcl-2 and decreased expression of Bax and cleaved caspase-3. These results suggest that cilnidipine, which is used for the treatment of hypertension, has neuroprotective effects in the ischemic brain through activation of the PI3K pathway.

Activation of the phosphatidylinositol 3-kinase pathway plays important roles in reduction of cerebral infarction by cilnidipine.

Cerebral infarction causes permanent neuronal loss inducing severe morbidity and mortality. Because hypertension is the main risk factor for cerebral infarction and most patients with hypertension take antihypertensive drugs daily, the neuroprotective effects and mechanisms of anti-hypertensive drugs need to be investigated. Cilnidipine, a long-acting, new generation 1,4-dihydropyridine inhibitor of both L- and N-type calcium channels, was reported to reduce oxidative stress. In this study, we investigated whether cilnidipine has therapeutic effects in an animal model of cerebral infarction. After determination of the most effective dose of cilnidipine, a total of 128 rats were subjected to middle cerebral artery occlusion. Neurobehavioral function test and brain MRI were performed, and rats with similar sized infarcts were randomized to either the cilnidipine group or the control group. Cilnidipine treatment was performed with reperfusion after 2-h occlusion. Western blots and immunohistochemistry were also performed after 24-h occlusion. Initial infarct volume on diffusion-weighted MRI was not different between the cilnidipine group and the control group; however, fluid-attenuated inversion recovery MRI at 24h showed significantly reduced infarct volume in the cilnidipine group compared with the control group. Cilnidipine treatment significantly decreased the number of triphosphate nick end labeling-positive cells compared to the control group. Western blot and immunohistochemistry showed increased expression of phosphorylated Akt (Ser473), phosphorylated glycogen synthase kinase-3β, and Bcl-2 and decreased expression of Bax and cleaved caspase-3. These results suggest that cilnidipine, which is used for the treatment of hypertension, has neuroprotective effects in the ischemic brain through activation of the PI3K pathway. We investigated whether cilnidipine has neuroprotective effects on ischemic stroke in an animal model. We have demonstrated that the neuroprotective effect of cilnidipine is associated with the activation of the PI3K pathway. Considering the daily use of antihypertensive drugs for patients with hypertension, cilnidipine could be beneficial for patients with ischemic stroke.

Impact of Scotland’s Comprehensive, Smoke-Free Legislation on Stroke

BackgroundPrevious studies have reported a reduction in acute coronary events following smoke-free legislation. Evidence is lacking on whether stroke is also reduced. The aim was to determine whether the incidence of stroke, overall and by sub-type, fell following introduction of smoke-free legislation across Scotland on 26 March 2006.Methods and FindingsA negative binomial regression model was used to determine whether the introduction of smoke-free legislation resulted in a step and/or slope change in stroke incidence. The model was adjusted for age-group, sex, socioeconomic deprivation quintile, urban/rural residence and month. Interaction tests were also performed. Routine hospital administrative data and death certificates were used to identify all hospital admissions and pre-hospital deaths due to stroke (ICD10 codes I61, I63 and I64) in Scotland between 2000 and 2010 inclusive. Prior to the legislation, rates of all stroke, intracerebral haemorrhage and unspecified stroke were decreasing, whilst cerebral infarction was increasing at 0.97% per annum. Following the legislation, there was a dramatic fall in cerebral infarctions that persisted for around 20 months. No visible effect was observed for other types of stroke. The model confirmed an 8.90% (95% CI 4.85, 12.77, p<0.001) stepwise reduction in cerebral infarction at the time the legislation was implemented, after adjustment for potential confounders.ConclusionsFollowing introduction of national, comprehensive smoke-free legislation there was a selective reduction in cerebral infarction that was not apparent in other types of stroke.

Blood Cholesterol Level and Risk of Stroke in Community-based or Worksite Cohort Studies: A Review of Japanese Cohort Studies in the Past 20 years

Evidence of the causal relationship between hypercholesterolemia and coronary artery disease (CAD) has been established worldwide. However, little attention has been paid to the relationship between hypercholesterolemia and stroke, despite stroke being the most common cardiovascular disease in Japan. We therefore reviewed cohort studies that investigated this relationship in the Japanese population over the past 20 years, and compared their findings with clinical trials and cohort studies in Western countries. Fourteen cohort studies were carried out in Japan during this period. The number of subjects in the studies ranged from 1621 to 91,219 and the mean follow-up period ranged from 7.6 to 32 years. The majority of studies showed no association between hypercholesterolemia and total stroke. However, one report showed a positive association between low-density lipoprotein cholesterol and atherothrombotic cerebral infarction. The relationship between hypercholesterolemia and cerebral infarction may be modified by the proportion of atherothrombotic infarctions in the population surveyed. Randomized controlled trials on statins have shown a substantial reduction in cerebral infarction, and so the discrepancy between cohort studies and clinical trials requires further study. However, some studies have reported that subjects with low blood cholesterol are more susceptible to intracerebral hemorrhage. Two hypotheses have been proposed to explain this association between low cholesterol and intracerebral hemorrhage. First, low blood cholesterol may induce angionecrosis, possibly in combination with hypertension, and second, low blood cholesterol may reflect a poor nutritional status. Either way, further continuous research in various fields of medical science is required to clarify the overall effect of blood cholesterol on stroke in humans.

Intracerebroventricular injection of human prostatic acid phosphatase has potent neuroprotective effects against transient focal cerebral ischemia in rats

Though the potential use of adenosine as a neuroprotective agent has long been realized, there are currently no adenosine-based therapies for the prevention or treatment of cerebral ischemia and reperfusion injury. Prostatic acid phosphatase (PAP), an enzyme that has long served as a diagnostic marker for prostate cancer, has been recently demonstrated to exhibit ecto-5′-nucleotidase activity, and dephosphorylate endogenous extracellular AMP to adenosine. We therefore tested the hypothesis that PAP has sustained and potent neuroprotective effects against cerebral ischemia in the rat model of middle cerebral artery occlusion. We found that hPAP produced significant neuroprotection against focal cerebral ischemia, as evident from significant reduction in cerebral infarction and neurological deficits. The therapeutic time window for hPAP in rat focal cerebral ischemia model was limited from 6 h before ischemia to 1.5 h after reperfusion. The present study suggested that PAP is a potential candidate for the prevention and treatment of cerebral ischemic injury, especially during perioperative period.

Fasudil and Ozagrel in Combination Show Neuroprotective Effects on Cerebral Infarction after Murine Middle Cerebral Artery Occlusion

Rho kinase (ROCK), one of the serine/threonine kinases, is involved in pathologic conditions, and its activation causes neuronal cell death. Fasudil, a selective ROCK inhibitor, has been reported to cause increased cerebral blood flow (CBF) in the ischemic brain and protect against neuronal cell death by inhibiting ROCK. Ozagrel, a thromboxane A(2) synthase inhibitor, inhibits platelet aggregation and causes vasodilatation, thereby increasing CBF in cerebral thrombosis. The present study evaluates the combination therapy of fasudil and ozagrel on focal brain ischemia induced by middle cerebral artery occlusion (MCAO) in mice. Each monotherapy of fasudil at 10 mg/kg i.p. and ozagrel at 30 mg/kg i.p. significantly reduced cerebral infarction. The combination therapy of fasudil (3 mg/kg i.p.) and ozagrel (10 mg/kg i.p.), which are noneffective doses, resulted in reduction of cerebral infarction, and the protective effect was observed up to 5 min, but not 3 h, after reperfusion. Regional CBF after MCAO and phosphorylation of endothelial nitric-oxide synthase (NOS) significantly increased in response to the combination therapy, whereas these effects were not observed with monotherapy of either drug. The protective effect of combination treatment was antagonized by the treatment of a NOS inhibitor, nitro-l-arginine methyl ester hydrochloride. These findings indicate that the combination treatment of fasudil and ozagrel exhibits additive effects for neuroprotection after MCAO. These findings indicate that the combination treatment of fasudil and ozagrel may be useful as a potential therapeutic strategy for the treatment of stroke.

Neanthes japonica (Iznka) fibrinolytic enzyme reduced cerebral infarction, cerebral edema and increased antioxidation in rat models of focal cerebral ischemia

Thrombolytic agent is increasingly being used in treating acute ischemic stroke. A novel protease with strong thrombolytic activity, Neanthes japonica (Iznka) fibrinolytic enzyme (NJF) discovered in our laboratory has been reported with characteristics of direct hydrolyzing fibrin and fibrinogen. The neuroprotective effect of NJF and urokinase (UK) was tested in rat models of middle cerebral artery occlusion (MCAO). The model was successfully produced by introducing an intraluminal suture into the left middle cerebral artery (MCA). NJF (0.25, 0.5, 1 mg/kg) was injected intravenously 1 h after the onset of reperfusion. Compared with vehicle group, MCAO animals treated with NJF showed dose dependent reduction in cerebral infarction with improved neurological outcome. Meanwhile, ischemia induced cerebral edema was reduced in a dose dependent manner. Treatment with NJF at 0.5 mg/kg was almost equivalent to UK at 15,000 U/kg dosage in the reduction of cerebral infarction and cerebral edema. Biomedical assay showed that NJF treatment suppressed lipid peroxidation and restored superoxide dismutase (SOD) activities in brain tissue. These results suggest that NJF posses neuroprotective potential in rat MCAO and reperfusion model. Neuroprotection shown by NJF may be attributed to inhibition of lipid peroxidation, increase in endogenous antioxidant defense enzymes.

PO11-TU-02 Reduction of cerebral infarction in rats by biliverdin associated with amelioration of oxidative stress

PO11-TU-02 Reduction of cerebral infarction in rats by biliverdin associated with amelioration of oxidative stress

Opioids modulate post-ischemic progression in a rat model of stroke

Alterations in the opioidergic system have been found in cerebral ischemia. Neuroprotection studies have demonstrated the involvement of the opioidergic system in cerebral ischemia/reperfusion (I/R). However, the neuroprotective mechanisms remain largely unclear. This study was conducted to investigate whether intracerebroventricular administration of opioidergic agonists has a neuroprotective effect against cerebral ischemia in rats and, if this proved to be the case, to determine the potential neuroprotective mechanisms. Using a focal cerebral I/R rat model, we demonstrated that the opioidergic agents, BW373U86 (δ agonist) and Dynorphin A 1–13 (κ agonist), but not TAPP (μ agonist), attenuated cerebral ischemic injury as manifested in the reduction of cerebral infarction and preservation of neurons. The antagonism assay showed that the neuroprotective effect of Dynorphin A was attenuated by nor-Binaltorphimine (κ antagonist). Surprisingly, BW373U86-induced neuroprotection was not changed by Naltrindole (δ antagonist). These findings indicate that BW373U86 and Dynorphin A exerted distinct neuroprotection against ischemia via opioid-independent and -dependent mechanisms, respectively. The post-ischemic protection in beneficial treatments was accompanied by alleviations in brain edema, inflammatory cell infiltration, and pro-inflammatory cytokine interleukin 6 (IL-6) expression. In vitro cell study further demonstrated that the opioidergic agonists, δ and κ, but not μ, attenuated IL-6 production from stimulated glial cells. Our findings indicate that opioidergic agents have a role in post-ischemic progression through both opioid-dependent and -independent mechanisms. In spite of the distinct-involved action mechanism, the potential neuroprotective effect of opioidergic compounds was associated with immune suppression. Taken together, these findings suggest a potential role for opioidergic agents in the therapeutic consideration of neuroinflammatory diseases. However, a better understanding of the mechanisms involved is necessary before this therapeutic potential can be realized.

Reduction of cerebral infarction in rats by biliverdin associated with amelioration of oxidative stress

Biliverdin (BV), one of the byproducts of heme catalysis through heme oxygenase (HO) system, is a scavenger of reactive oxygen species (ROS). We hypothesized that BV treatment could protect rat brain cells from oxidative injuries via its anti-oxidant efficacies. Cerebral infarction was induced by transient middle cerebral artery occlusion (tMCAO) for 90 min, followed by reperfusion. BV or vehicle was administered intraperitoneally immediately after reperfusion. The size of the cerebral infarction 2 days after tMCAO was evaluated by 2,3,5-triphenyltetrazolium chloride (TTC) stain. Superoxide generation 4 h after tMCAO was determined by detection of oxidized hydroethidine. In addition, the oxidative impairment of neurons were immunohistochemically assessed by stain for lipid peroxidation with 4-hydroxy-2-nonenal (4-HNE) and damaged DNA with 8-hydroxy-2′-deoxyguanosine (8-OHdG). BV treatment significantly reduced infarct volume of the cerebral cortices associated with less superoxide production and decreased oxidative injuries of brain cells. The present study demonstrated that treatment with BV ameliorated the oxidative injuries on neurons and decreased brain infarct size in rat tMCAO model.

Increased Tolerance to Ischemic Neuronal Damage by Knockdown of Na+–Ca2+ Exchanger Isoform 1

We hypothesize that stimulation of Na+-K+-Cl+ cotransporter (NKCC1) causes Na+ overload that may lead to reversal of Na+-Ca2+ exchanger isoform 1 (NCX1) and ischemic neuronal damage. NCX1 protein expression and Ca2+ influx via reversal of NCX were decreased by approximately 70% in NCX1+/- neurons. Compared to NCX1+/+ neurons, NCX1+/- neurons exhibited significantly less cell death (approximately 30%) after 3 h oxygen and glucose deprivation (OGD) and 21 h reoxygenation. Additional neuroprotection was found in NCX1+/- neurons treated with NCX inhibitor KB-R7943. Moreover, expression of NCX1 protein was approximately 40% lower in NCX1+/- brains than in NCX1+/+ brains. However, there was no significant reduction in cerebral infarction in NCX1+/- mice following middle cerebral artery occlusion (MCAO). These data suggest that moderate reduction of NCX1 protein may be not enough to exert protection. We used small RNA-interference (siRNA) approach to further elucidate the role of NCX1 in ischemic cell damage. Efficacy of anti-NCX1 siRNA was tested in astrocytes and approximately 50% knockdown of NCX1 protein expression was achieved after 24-72 h transfection. Reduction in NCX1 protein expression was also found in brains of NCX1+/- mice after the siRNA injection. NCX1+/- mice treated with siRNA showed approximately 20% less MCAO-induced infarction, compared to NCX1+/- mice. Approximately 50% neuroprotection was detected in NKCC1+/-/NCX1+/- mice following MCAO. In conclusion, these data suggest that NCX1 plays an important role in ischemia/reperfusion-induced neuronal injury.

Les antithrombotiques dans la prévention des accidents ischémiques cérébraux

Stroke prevention cannot be dissociated from cardiovascular prevention in general. It is based on the correction of vascular risk factors, particularly hypertension and tobacco smoking, and on antithrombotic drugs which tackle the thrombo-embolic process which is the immediate cause of the ischemic event. Ischemic strokes exhibit considerable etiopathogenic diversity, the underlying cause modifying thrombus composition. In atherothrombotic brain infarction, platelets play a major role and antiplatelet drugs have a benefit/risk ratio better than that of oral anticoagulants, with a 25% reduction in the combined risk of ischemic stroke, myocardial infarction and vascular death. Antiplatelet drugs are also used in small artery diseases of the brain although the role of thrombosis is unknown and no specific trial has been devoted to this variety of cerebrovascular disease. In emboligenic cardiac diseases, atrial fibrillation in particular, stasis of the dilated left atrium favors coagulation phenomena, hence the much better efficacy of oral anticoagulants (presently vitamin K antagonists) both in primary and secondary prevention with a 70% risk reduction in cerebral infarction, compared with only 20% for aspirin. The expected benefit of antithrombotic drugs must be weighed against their inherent hemorrhagic risk, which is greatest for oral anticoagulants, slightly less for association of antiplatelet drugs and even less for each antiplatelet drug given alone. The use of antithrombotic drugs allows a targeted prevention of cerebral infarction. It is based on a triple case by case evaluation: that of the cause and of the risk it carries, that of the benefit expected from antithrombotic drugs, and that of their inherent hemorrhagic risk. (J Mal Vasc 2005; 30: 267-79)

Reduction of cerebral infarction in SHR-SP by statins

Reduction of cerebral infarction in SHR-SP by statins

Reduction of Cerebral Infarction in Stroke-Prone Spontaneously Hypertensive Rats by Statins Associated With Amelioration of Oxidative Stress

This study aimed to clarify the effect of statins on spontaneous stroke and to examine the antioxidative effect in artificial transient middle cerebral artery occlusion (tMCAO). Stroke-prone spontaneous hypertensive rats (SHR-SP) were treated with pitavastatin, atorvastatin, simvastatin, or vehicle for 4 weeks. Physiological parameters, serum lipids, and infarct volumes were examined. The markers for oxidative stresses on lipids and DNA were immunohistochemically detected in vehicle-treated or simvastatin-treated SHR-SP with tMCAO. Atorvastatin and simvastatin decreased infarct volumes, with simvastatin most effective. Simvastatin significantly reduced immunoreactivities for oxidative stress markers for lipids and DNA in neurons after tMCAO. The results suggest that the antioxidative properties of statins may be implicated in their beneficial effects against neuronal damage in cerebral ischemia.

1265 Reduction of cerebral infarction in SHR-SP by statins associated with amelioration of oxidative stress

1265 Reduction of cerebral infarction in SHR-SP by statins associated with amelioration of oxidative stress