Effects of Lipoxin A4 Pretreatment on Cognitive Function of Aged Rats after Global Cerebral Ischemia Reperfusion

The aim of the present study was to investigate the effect of lipoxin A4 （LXA4） pretreatment on cognitive function of aged rats after global cerebral ischemia reperfusion, and to explore its possible mechanism. Thirty-six aged male Sprague-Dawley rats were randomly divided into three groups （n=12 each）： sham-operation group （S group）, global cerebral ischemia reperfusion group （I/R group） and LXA4-pretreatment group （L group）. The rat model of global cerebral ischemia reperfusion was established by occlusion of the bilateral common carotid artery with hypotension. The cognitive function of rats was determined by a step-down type passive avoidance test and Morris Water Maze test on the third day after reperfusion. Rats were sacrificed after Water Maze test and the pathological changes ofhippocampal CA1 region were observed and the related inflammatory mediators were determined. As compared with S group, the escape latency in I/R group was prolonged from the first day to the fifth day, while that in L group was prolonged from the first day to the third day. The retention time in I/R group and L group in the first quadrant was shortened. The reaction time, frequency of reaction mistake and frequency of escape mistake in I/R group increased, and the latent period shortened. The frequency of escape mistake in L group increased, and the damage in the hippocampal CAI region of I/R group and L group was obvious. The levels of S-10013, TNF-α, IL-1β, IL-10 and NF-κB in I/R group and L group increased. As compared with I/R group, the escape latency in L group was shortened from the first day to the fifth day, and the retention time in the first quadrant prolonged. The reaction time, frequency of reaction mistake and frequency of escape mistake in L group decreased, and the latent period prolonged. The damage in the hippocampal CA1 region of L group was alleviated as well. The levels of S-10013, TNF-α, IL-1β and NF-κB in L group decreased, and those of IL-10 increased. It can be concluded that LXA4 pretreatment can improve the cognitive function in aged rats after global cerebral ischemia reperfusion probably by inhibiting the inflammatory reaction.

Extremely low frequency electromagnetic fields promote cognitive function and hippocampal neurogenesis of rats with cerebral ischemia

Extremely low frequency electromagnetic fields(ELF-EMF) can improve the learning and memory impairment of rats with Alzheimer's disease, however, its effect on cerebral ischemia remains poorly understood.In this study, we established rat models of middle cerebral artery occlusion/reperfusion.One day after modeling, a group of rats were treated with ELF-EMF(50 Hz, 1 mT) for 2 hours daily on 28 successive days.Our results showed that rats treated with ELF-EMF required shorter swimming distances and latencies in the Morris water maze test than those of untreated rats.The number of times the platform was crossed and the time spent in the target quadrant were greater than those of untreated rats.The number of BrdU~+/NeuN~+ cells, representing newly born neurons, in the hippocampal subgranular zone increased more in the treated than in untreated rats.Up-regulation in the expressions of Notch1, Hes1, and Hes5 proteins, which are the key factors of the Notch signaling pathway, was greatest in the treated rats.These findings suggest that ELF-EMF can enhance hippocampal neurogenesis of rats with cerebral ischemia, possibly by affecting the Notch signaling pathway.The study was approved by the Institutional Ethics Committee of Sichuan University, China(approval No.2019255A) on March 5, 2019.

DNA hypomethylation promotes learning and memory recovery in a rat model of cerebral ischemia/reperfusion injury

Cerebral ischemia/reperfusion injury impairs learning and memory in patients.Studies have shown that synaptic function is involved in the formation and development of memory,and that DNA methylation plays a key role in the regulation of learning and memory.To investigate the role of DNA hypomethylation in cerebral ischemia/reperfusion injury,in this study,we established a rat model of cerebral ischemia/reperfusion injury by occlusion of the middle cerebral artery and then treated the rats with intraperitoneal 5-aza-2′-deoxycytidine,an inhibitor of DNA methylation.Our results showed that 5-aza-2′-deoxycytidine markedly improved the neurological function,and cognitive,social and spatial memory abilities,and dose-dependently increased the synaptic density and the expression of SYP and SHANK2 proteins in the hippocampus in a dose-dependent manner in rats with cerebral ischemia/reperfusion injury.The effects of 5-aza-2′-deoxycytidine were closely related to its reduction of genomic DNA methylation and DNA methylation at specific sites of the Syp and Shank2 genes in rats with cerebral ischemia/reperfusion injury.These findings suggest that inhibition of DNA methylation by 5-aza-2′-deoxycytidine promotes the recovery of learning and memory impairment in a rat model of cerebral ischemia/reperfusion injury.These results provide theoretical evidence for stroke treatment using epigenetic methods.

Effects of CXCR7-neutralizing antibody on neurogenesis in the hippocampal dentate gyrus and cognitive function in the chronic phase of cerebral ischemia

Stromal cell-derived factor-1 and its receptor CXCR4 are essential regulators of the neurogenesis that occurs in the adult hippocampal dentate gyrus.However,the effects of CXCR7,a new atypical receptor of stromal cell-derived factor-1,on hippocampal neurogenesis after a stroke remain largely unknown.Our study is the first to investigate the effect of a CXCR7-neutralizing antibody on neurogenesis in the dentate gyrus and the associated recovery of cognitive function of rats in the chronic stage of cerebral ischemia.The rats were randomly divided into sham,sham+anti-CXCR7,ischemia and ischemia+anti-CXCR7 groups.Endothelin-1 was injected in the ipsilateral motor cortex and striatum to induce focal cerebral ischemia.Sham group rats were injected with saline instead of endothelin-1 via intracranial injection.Both sham and ischemic rats were treated with intraventricular infusions of CXCR7-neutralizing antibodies for 6 days 1 week after surgery.Immunofluorescence staining with doublecortin,a marker for neuronal precursors,was performed to assess the neurogenesis in the dentate gyrus.We found that anti-CXCR7 antibody infusion enhanced the proliferation and dendritic development of doublecortin-labeled cells in the dentate gyrus in both ischemic and sham-operated rats.Spatial learning and memory functions were assessed by Morris water maze tests 30-32 days after ischemia.CXCR7-neutralizing antibody treatment significantly reduced the escape latency of the spatial navigation trial and increased the time spent in the target quadrant of spatial probe trial in animals that received ischemic insult,but not in sham operated rats.These results suggest that CXCR7-neutralizing antibody enhances the neurogenesis in the dentate gyrus and improves the cognitive function after cerebral ischemia in rats.All animal experimental protocols and procedures were approved by the Institutional Animal Care and Use Committee of China Medical University(CMU16089 R)on December 8,2016.

Dopamine and cognitive function after global cerebral ischemia-reperfusion:a brief review

Global cerebral ischemia/hypoxia may occur due to various causes such as cardiac arrest,shock,and asphyxiation.Even though the patient’s life may be saved after cardiopulmonary resuscitation,cerebral ischemia– reperfusion injury is likely to occur and often results in neurological dysfunction.Apart from motor and speech impediments,patients with such injury may also suffer from impaired higher-level cognitive functions such as learning and memory,placing a heavy burden on families and society.Brain areas associated with the limbic system include the hippocampus,corpus striatum,and amygdala,which are linked with cognitive function.Those brain regions are easily damaged by hypoxia,and since they are connected with the dopaminergic pathway,global cerebral ischemia–reperfusion can damage the dopaminergic pathway as well and affect the projection of dopaminergic neurons in the limbic system.This review article examines the feasibility of using dopamine,a neurotransmitter heavily involved in cognitive function,in experimental research and clinical treatment of global cerebral ischemia–reperfusion injury.Specifically,we examine the effects of dopamine on post-injury cognition and neuronal plasticity,with the ultimate goal of identifying a new tool for clinical treatment.

The role of Rho/Rho-kinase pathway and the neuroprotective effects of fasudil in chronic cerebral ischemia

The Rho/Rho-kinase signaling pathway plays an important role in cerebral ischemia/reperfusion injury. However, very few studies have examined in detail the changes in the Rho/Rho-kinase signaling pathway in chronic cerebral ischemia. In this study, rat models of chronic cerebral ischemia were established by permanent bilateral common carotid artery occlusion and intra- gastrically administered 9 mg/kg fasudil, a powerful ROCK inhibitor, for 9 weeks. Morris water maze results showed that cognitive impairment progressively worsened as the cerebral ischemia proceeded. Immunohistochemistry, semi-quantitative RT-PCR and western blot analysis showed that the expression levels of Rho-kinase, its substrate myosin-binding subunit, and its relat- ed protein alpha smooth muscle actin, significantly increased after chronic cerebral ischemia. TUNEL staining showed that chronic cerebral ischemia could lead to an increase in neuronal apoptosis, as well as the expression level of caspase-3 in the frontal cortex of rats subjected to chronic cerebral ischemia. Fasudil treatment alleviated the cognitive impairment in rats with chronic cerebral ischemia, and decreased the expression level of Rho-kinase, myosin-binding subunit and alpha smooth muscle actin. Furthermore, fasudil could regulate cerebral injury by reducing cell apoptosis and decreasing caspase-3 expression in the frontal cortex. These findings demonstrate that fasudil can protect against cognitive impairment induced by chronic cerebral ischemia via the Rho/Rho-kinase signaling pathway and anti-apoptosis mechanism.

Changes of hypoxia-inducible factor-1 signaling and the effect of cilostazol in chronic cerebral ischemia

Hypoxiainducible factor1 and its specific target gene heme oxygenase1, are involved in acute cerebral ischemia. However, very few studies have examined in detail the changes in the hy poxiainducible factor1/heme oxygenase1 signaling pathway in chronic cerebral ischemia. In this study, a rat model of chronic cerebral ischemia was established by permanent bilateral common carotid artery occlusion, and these rats were treated with intragastric cilostazol （30 mg/kg） for 9 weeks. Morris water maze results showed that cognitive impairment gradually worsened as the cerebral ischemia proceeded. Immunohistochemistry, semiquantitative PCR and western blot analysis showed that hypoxiainducible factorla and heme oxygenase1 expression levels in creased after chronic cerebral ischemia, with hypoxiainducible factorla expression peaking at 3 weeks and heme oxygenase1 expression peaking at 6 weeks. These results suggest that the elevated levels of hypoxiainducible factorla may upregulate heine oxygenase1 expression fol lowing chronic cerebral ischemia and that the hypoxiainducible factor1/heme oxygenase1 sig naling pathway is involved in the development of cognitive impairment induced by chronic cerebral ischemia. Cilostazol treatment alleviated the cognitive impairment in rats with chronic cerebral ischemia, decreased hypoxiainducible factorla and heme oxygenase1 expression levels, and reduced apoptosis in the frontal cortex. These findings demonstrate that cilostazol can protect against cognitive impairment induced by chronic cerebral ischemic injury through an antiapoptotic mechanism.

Flavonoids from Scutellaria baicalensis Georgi are effective to treat cerebral ischemia/reperfusion

Based on previous studies that have shown flavonoids from the stems and leaves of Scutellaria baicalensis Georgi are neuroprotective agents in a naturally senile, D-galactose, aging in vivo model, as well as an in vitro model of oxidative/hypoxic injury, we established a cerebral ischemia/reperfusion model in rats by middle cerebral artery occlusion. The light/electron microscopic observations found significant neuropathological changes including neuron loss or swelling and rough endoplasmic reticulum injury. Moreover, the activities of lactate dehydrogenase Na＋-K＋-ATPase, Ca2＋-ATPase and superoxide dismutase were significantly lowered, and the levels of malonaldehyde increased. In addition, the memory of rats worsened. However, treatment with flavonoids from Scutellaria baicalensis Georgi （35, 70 and 140 mg/kg） for 13 days dramatically improved the above abnormal changes. These results suggest that the ability of flavonoids from Scutellaria baicalensis Georgi in attenuating cerebral functional and morphological consequences after cerebral ischemia/reperfusion may be beneficial for the treatment of ischemic brain disease.

Bumetanide promotes neural precursor cell regeneration and dendritic development in the hippocampal dentate gyrus in the chronic stage of cerebral ischemia

Bumetanide has been shown to lessen cerebral edema and reduce the infarct area in the acute stage of cerebral ischemia. Few studies focus on the effects of bumetanide on neuroprotection and neurogenesis in the chronic stage of cerebral ischemia. We established a rat model of cerebral ischemia by injecting endothelin-1 in the left cortical motor area and left corpus striatum. Seven days later, bumetanide 200 μg/kg/day was injected into the lateral ventricle for 21 consecutive days with a mini-osmotic pump. Results demonstrated that the number of neuroblasts cells and the total length of dendrites increased, escape latency reduced, and the number of platform crossings increased in the rat hippocampal dentate gyrus in the chronic stage of cerebral ischemia. These findings suggest that bumetanide promoted neural precursor cell regeneration, dendritic development and the recovery of cognitive function, and protected brain tissue in the chronic stage of ischemia.

Intercellular adhesion molecule-1 expression in the hippocampal CA1 region of hyperlipidemic rats with chronic cerebral ischemia

Chronic cerebral ischemia is a pathological process in many cerebrovascular diseases and it is induced by long-term hypedipidemia, hypertension and diabetes mellitus. After being fed a high-fat diet for 4 weeks, rats were subjected to permanent occlusion of bilateral common carotid arteries to establish rat models of chronic cerebral ischemia with hypedipiclemia. Intercellular adhesion molecule-1 expression in rat hippocampal CA1 region was determined to better understand the mechanism underlying the effects of hypedipidemia on chronic cerebral ischemia. Water maze test results showed that the cognitive function of rats with hyperlipidemia or chronic cerebral ischemia, particulady in rats with hypedipidemia combined with chronic cerebral ischemia, gradually decreased between 1 and 4 months after occlusion of the bilateral common carotid arteries. This correlated with pathological changes in the hippocampal CA1 region as detected by hematoxylin-eosin staining. Immunohistochemical staining showed that intercellular adhesion molecule-1 expression in the hippocampal CA1 region was noticeably increased in rats with hyperlipidemia or chronic cerebral ischemia, in particular in rats with hyperlipidemia combined with chronic cerebral ischemia. These findings suggest that hyperlipidemia aggravates chronic cerebral ischemia-induced neurological damage and cognitive impairment in the rat hippocampal CA1 region which may be mediated, at least in part, by up-regulated expression of intercellular adhesion molecule-l.

Total flavonoid of Litsea coreana leve exerts anti-oxidative effects and alleviates focal cerebral ischemia/reperfusion injury

In this study, we hypothesized that total flavonoid of Litsea coreana leve （TFLC） protects against focal cerebral ischemia/reperfusion injury. TFLC （25, 50, 100 mg/kg） was administered orally to a rat model of focal ischemia/reperfusion injury, while the free radical scavenging agent, edaravone, was used as a positive control drug. Results of neurological deficit scoring, 2,3,5-triphenyl tetrazolium chloride staining, hematoxylin-eosin staining and biochemical tests showed that TFLC at different doses significantly alleviated cerebral ischemia-induced neurological deficits and histopathological changes, and reduced infarct volume. Moreover, it suppressed the increase in the levels of nitrates plus nitrites, malondialdehyde and lactate dehydrogenase, and it diminished the reduction in glu- tathione, superoxide dismutase and catalase activities induced by cerebral ischemia/reperfusion injury. Compared with edaravone, the protective effects of TFLC at low and medium doses （25, 50 mg/kg） against cerebral ischemia/reperfusion injury were weaker, while the protective effects at high dose （100 mg/kg） were similar. Our experimental findings suggest that TFLC exerts neuroprotective effects against focal cerebral ischemia/reperfusion injury in rats, and that the effects may be asso- ciated with its antioxidant activities.

Neuroprotection of Cyperus esculentus L. orientin against cerebral ischemia/reperfusion induced brain injury

Orientin is a flavonoid monomer.In recent years,its importance as a source of pharmacological active substance is growing rapidly due to its properties such as anti-myocardial ischemia,anti-apoptosis,anti-radiation,anti-tumor,and anti-aging.However,the neuroprotective effects of Orientin on stroke injury have not been comprehensively evaluated.The aim of the present study was thus to investigate the neuroprotective capacity and the potential mechanisms of Cyperus esculentus L.orientin(CLO)from Cyperus esculentus L.leaves against ischemia/reperfusion(I/R)injury using standard orientin as control.For in vitro studies,we treated HT22 cells with CoCl2 as an in vitro ischemic injury model.HT22 cells in the control group were treated with CoCl2.For in vivo studies,we used rat models of middle cerebral artery occlusion,and animals that received sham surgery were used as controls.We found that CLO protected CoCl2-induced HT22 cells against ischemia/reperfusion injury by lowering lipid peroxidation and reactive oxygen species formation as well as decreasing protein oxidation.However,CLO did not reduce the release of lactate dehydrogenase nor increase the activity of superoxide dismutase.Results showed that CLO could decrease neurological deficit score,attenuate brain water content,and reduce cerebral infarct volume,leading to neuroprotection during cerebral ischemia-reperfusion injury.Our studies indicate that CLO flavonoids can be taken as a natural antioxidant and bacteriostastic substance in food and pharmaceutical industry.The molecular mechanisms of CLO could be at least partially attributed to the antioxidant properties and subsequently inhibiting activation of casepase-3.All experimental procedures and protocols were approved on May 16,2016 by the Experimental Animal Ethics Committee of Xinjiang Medical University of China(approval No.IACUC20160516-57).

Paired associative stimulation improves synaptic plasticity and functional outcomes after cerebral ischemia

Paired associative stimulation is a relatively new non-invasive brain stimulation technique that combines transcranial magnetic stimulation and peripheral nerve stimulation. The effects of paired associative stimulation on the excitability of the cerebral cortex can vary according to the time interval between the transcranial magnetic stimulation and peripheral nerve stimulation. We established a model of cerebral ischemia in rats via transient middle cerebral artery occlusion. We administered paired associative stimulation with a frequency of 0.05 Hz 90 times over 4 weeks. We then evaluated spatial learning and memory using the Morris water maze. Changes in the cerebral ultra-structure and synaptic plasticity were assessed via transmission electron microscopy and a 64-channel multi-electrode array. We measured mRNA and protein expression levels of brain-derived neurotrophic factor and N-methyl-D-aspartate receptor 1 in the hippocampus using a real-time polymerase chain reaction and western blot assay. Paired associative stimulation treatment significantly improved learning and memory in rats subjected to cerebral ischemia. The ultra-structures of synapses in the CA1 area of the hippocampus in rats subjected to cerebral ischemia were restored by paired associative stimulation. Long-term potentiation at synapses in the CA3 and CA1 regions of the hippocampus was enhanced as well. The protein and mRNA expression of brain-derived neurotrophic factor and N-methyl-D-aspartate receptor 1 increased after paired associative stimulation treatment. These data indicate that paired associative stimulation can protect cog-nition after cerebral ischemia. The observed effect may be mediated by increases in the mRNA and protein expression of brain-derived neurotrophic factor and N-methyl-D-aspartate receptor 1, and by enhanced synaptic plasticity in the CA1 area of the hippocampus. The animal experiments were approved by the Animal Ethics Committee of Tongji Medical College, Huazhong University of Science & Technology, China(approval No. TJ-A20151102) on July 11, 2015.

Echinacoside Alleviates Cognitive Impairment in Cerebral Ischemia Rats through α7nAChR-Induced Autophagy

Objectives:To evaluate the effect of echinacoside(ECH)on cognitive dysfunction in post cerebral stroke model rats.Methods:The post stroke cognitive impairment rat model was created by occlusion of the transient middle cerebral artery(MCAO).The rats were randomly divided into 3 groups by a random number table:the sham group(sham operation),the MCAO group(received operation for focal cerebral ischemia),and the ECH group(received operation for focal cerebral ischemia and ECH50 mg/kg per day),with 6 rats in each group,The infarct volume and spatial learning were evaluated by triphenyl tetrazolium chloride staining and Morris water maze.The expression of α7 nAChR in the hippocampus was detected by immunohistochemistry.The contents of acetylcholine(ACh),malondialdehyde(MDA),glutathione(GSH),superoxide dismutase(SOD),activities of choline acetyltransferase(ChAT),acetylcholinesterase(AChE),and catalase(CAT)were evaluated by enzyme linked immunosorbent assay.The neural apoptosis and autophagy were determined by TUNEL staining and LC3 staining,respectively.Results:ECH significantly lessened the brain infarct volume and ameliorated neurological deficit in infarct volume and water content(both P<0.01).Compared with MCAO rats,administration of ECH revealed shorter escape latency and long retention time at 7,14 and 28 days(all P<0.01),increased the α7 nAChR protein expression,ACh content,and ChAT activity,and decreased AChE activity in MCAO rats(all P<0.01).ECH significantly decreased MDA content and increased the GSH content,SOD,and CAT activities compared with MCAO rats(all P<0.05).ECH suppressed neuronal apoptosis by reducing TUNEL-positive cells and also enhanced autophagy in MCAO rats(all P<0.01).Conclusion:ECH treatment helped improve cognitive impairment by attenuating neurological damage and enhancing autophagy in MCAO rats.

Activation of cerebral Ras-related C3 botulinum toxin substrate(Rac) 1 promotes post-ischemic stroke functional recovery in aged mice

Brain functional impairment after stroke is common;however,the molecular mechanisms of post-stroke recovery remain unclear.It is well-recognized that age is the most important independent predictor of poor outcomes after stroke as older patients show poorer functional outcomes following stroke.Mounting evidence suggests that axonal regeneration and angiogenesis,the major forms of brain plasticity responsible for post-stroke recovery,diminished with advanced age.Previous studies suggest that Ras-related C3 botulinum toxin substrate(Rac)1 enhances stroke recovery as activation of Rac1 improved behavior recovery in a young mice stroke model.Here,we investigated the role of Rac1 signaling in long-term functional recovery and brain plasticity in an aged(male,18 to 22 months old C57BL/6J)brain after ischemic stroke.We found that as mice aged,Rac1 expression declined in the brain.Delayed overexpression of Rac1,using lentivirus encoding Rac1 injected day 1 after ischemic stroke,promoted cognitive(assessed using novel object recognition test)and sensorimotor(assessed using adhesive removal tests)recovery on days 14–28.This was accompanied by the increase of neurite and proliferative endothelial cells in the periinfarct zone assessed by immunostaining.In a reverse approach,pharmacological inhibition of Rac1 by intraperitoneal injection of Rac1 inhibitor NSC23766 for 14 successive days after ischemic stroke worsened the outcome with the reduction of neurite and proliferative endothelial cells.Furthermore,Rac1 inhibition reduced the activation of p21-activated kinase 1,the protein level of brain-derived neurotrophic factor,and increased the protein level of glial fibrillary acidic protein in the ischemic brain on day 28 after stroke.Our work provided insight into the mechanisms behind the diminished plasticity after cerebral ischemia in aged brains and identified Rac1 as a potential therapeutic target for improving functional recovery in the older adults after stroke.

Offspring of rats with cerebral hypoxia-ischemia manifest cognitive dysfunction in learning and memory abilities

Neonatal hypoxic-ischemic encephalopathy is a serious neurological disease,often resulting in long-term neurodevelopmental disorders among surviving children.However,whether these neurodevelopmental issues can be passed to offspring remains unclear.The right common carotid artery of 7-day-old parental-generation rats was subjected to permanent ligation using a vessel electrocoagulator.Neonatal hypoxic-ischemic rat models were established by subjecting the rats to 8%O2–92%N2 for 2 hours.The results showed that 24 hours after hypoxia and ischemia,pathological damage,cerebral atrophy,liquefaction,and impairment were found,and Zea-Longa scores were significantly increased.The parental-generation rats were propagated at 3 months old,and offspring were obtained.No changes in the overall brain structures of these offspring rats were identified by magnetic resonance imaging.However,the escape latency was longer and the number of platform crossings was reduced among these offspring compared with normal rats.These results indicated that the offspring of hypoxic-ischemic encephalopathy model rats displayed cognitive impairments in learning and memory.This study was approved by the Animal Care&Welfare Committee of Kunming Medical University,China in 2018(approval No.kmmu2019072).

Effects of Yinxingdamo Injection Combined with Oxiracetam Capsule on Cognitive Function and Neurological Deficit in Patients with Acute Cerebral Infarction

OBJETTIVE: To observe the effects of Yinxingdamo Injection combined with oxiracetam capsule on cognitive function and neurological deficit in patients with acute cerebral infarction. METHODS: A total of 76 patients with acute cerebral infarction were randomly divided into observation group and control group, with 38 patients in each group. Patients in the control group were treated with conventional western medicine and oxiracetam capsules while patients in the observation group were given Yinxingdamo injection intravenous drip treatment on the basis of the same treatment. After 4 weeks of treatment, the cognitive function of the two groups before and after treatment was observed [Simple Intelligence Scale(MMSE Score), Montreal Cognitive Assessment Scale(MoCA Score)], Neurological Deficit [Chinese Stroke Scale(CSS Score), Daily Life Activity ability(ADL score)], free radical biochemical indicators [malondialdehyde(MDA), oxide dismutase(SOD)] changes, and statistical effects of two groups. RESULTS: After treatment, the total effective rate of the observation group was 92.1%, which was significantly higher than 73.7% of the control group(P < 0.05). The MMSE score and MoCA score of the two groups were significantly increased after treatment(P < 0.05), and the MMSE score and MoCA score inobservation group were significantly increased after treatment than the control group(P < 0.05). The CSS scores of the two groups were significantly decreased after treatment(P < 0.05), and the ADL scores were significantly increased(P < 0.05). The improvement of CSS score and ADL score in the observation group were significantly better than those in the control group(P < 0.05), and serum MDA levels were significantly decreased in both groups after treatment(P < 0.05), and SOD levels were significantly increased(P < 0.05), and the improvement of MDA and SOD levels in the observation group was significantly better than that in the control group group(P < 0.05). CONCLUSION: Yinxingdamo injection combined with oxiracetam capsule can effectively inhibit the oxygen free radical reaction injury in patients with acute cerebral infarction, and significantly improve the symptoms of cognitive dysfunction and neurological deficit in patients. Its curative effect is exact and worthy of clinical application.

Therapeutic time window of flurbiprofen axetil＇s neuroprotective effect in a rat model of transient focal cerebral ischemia

Background The neuroprotective effect of the cyclooxygenase （COX） inhibitor has been demonstrated in acute and chronic neurodegenerative processes. But its function under cerebral ischemic conditions is unclear. This study was designed to evaluate the neuroprotective efficacy of emulsified flurbiprofen axetil （FA, COX inhibitor） and its therapeutic time window in a model of transient middle cerebral artery occlusion （MCAO） in rats. Methods Forty-eight male SD rats were randomly assigned into six groups （n=8 in each group）; three FA groups, vehicle, sham and ischemia/reperfusion （I/R） groups. Three doses of FA （5, 10 or 20 mg/kg, intravenous infusion） were administered just after cerebral ischemia/reperfusion （I/R）. The degree of neurological outcome was measured by the neurologic deficit score （NDS） at 24, 48 and 72 hours after I/R. Mean brain infarct volume percentage （MBIVP） was determined with 2,3,5-triphenyltetrazolium chloride （TTC） staining at 72 hours after I/R. In three other groups （n=8 in each group）, the selected dosage of 10 mg/kg was administrated intravenously at 6, 12 and 24 hours after I/R. Results The three different doses of FA improved NDS at 24, 48 and 72 hours after I/R and significantly reduced MBIVP. However, the degree of MBIVP in the FA 20 mg/kg group differed from that in FA 10 mg/kg group. Of interest is the finding that the neuroprotective effect conferred by 10 mg/kg of FA was also observed when treatment was delayed until 12-24 hours after ischemia reperfusion. Conclusion COX inhibitor FA is a promising therapeutic strategy for cerebral ischemia and its therapeutic time window could last for 12-24 hours after cerebral ischemia reperfusion, which would help in lessening the initial ischemic brain damage.

Flurbiprofen axetil promotes neuroprotection by activation of cerebral peroxisome proliferator-activated receptor gamma after focal cerebral ischemia in rats

Background Our previous papers indicate that flurbiprofen axetil （FA）, a cyclooxygenase inhibitor, is a promising therapeutic strategy for cerebral ischemia in rats. This study aimed to investigate whether FA could promote a neuroprotective effect by activation of peroxisome proliferator-activated receptor-y （PPAR-y） after focal cerebral ischemia in rats. Methods Totally 48 male Sprague-Dawley （SD） rats were randomly assigned into six groups （n=8 in each group）： animals in group ischemia/reperfusion （I/R） only received 120-minute transient middle cerebral artery occlusion （tMCAO）; animals in group I/R ＋FA were administered FA （10 mg/kg） by caudal vein just after 120-minute tMCAO; animals in group I/R ＋FA＋GW9662 were administered GW9662 （a PPAR-Y inhibitor, 1 mg/kg） intraperitoneally 30 minutes before cerebral ischemia onset and FA （10 mg/kg） by caudal vein just after 120-minute tMCAO; animals in group I/R ＋GW9662 were administered GW9662 （1 mg/kg） intraperitoneally 30 minutes before cerebral ischemia onset; animals in group I/R ＋DMSO were administered 3% DMSO （vehicle of GW9662, 1 ml/kg） intraperitoneally 30 minutes before cerebral ischemia onset; animals in sham group experienced the identical surgery apart from the insertion of the nylon filament. The neurologic deficit score （NDS） were performed at 72 hours after reperfusion, and then mean brain infarct volume percentage （MBIVP） was determined with 2,3,5-triphenyltetrazolium chloride （TTC） 10 g/L staining. Results NDS was significantly increased in group I/R＋FA （12.0 （10.0-15.0））, group I/R＋FA＋GW9662 （10.0 （8.0-12.0））, and in group I/R＋FA＋DMSO （12.0 （9.0-14.0）） at 72 hours after reperfusion compared with those in group I/R （7.5 （6.0-10.0））. NDS was conspicuously different between group I/R＋FA （12.0 （10.0-15.0）） and group I/R＋FA＋GW9662 （10.0 （8.0-12.0））. MBIVP in group I/R （（45.82±8.83）%） was significantly greater than that in group I/R＋FA （（23.52±9.90）%）, group I/R＋FA＋GW9662 （（33.17±7.15）%）; MBIVP in group I/R＋FA （（23.52±9.90）%） was significantly smaller than that in group I/R＋FA＋GW9662 （（33.17±7.15）%）. Conclusions FA confers the neuroprotective effect on tMCAO in rats and the selective PPAR-Y antagonist GW9662 attenuates the effect of FA. FA could promote a neuroprotective effect by, or in part, activation of PPAR-y after focal cerebral ischemia in rats.

Meta-Analysis of Risk Factors of Vascular Cognitive Disorder in Acute Cerebral Infarction Patients

Objectives: To identify the main risk factors of vascular cognitive impairment in patients with acute cerebral infarction by Meta-analysis, and provide references for the effective prevention of the cognitive impairment in stroke patients. Methods: To retrieve the observational research literatures that refer to the risk factors of vascular cognitive impairment in patients with ischemic stroke, which are published on China National Knowledge Infrastructure (CNKI), Wanfang and Weipu Chinese databases. The screening and data extraction of these literatures are independently completed by two researchers, who also give the quality evaluation of the literatures according to the evaluation criterion of the Australian JBI Evidence-Based Health Care Center. Then, Meta-analysis is conducted by using Revman5.3 software. Results: There are twenty-eight articles selected from 1507 literatures, with a total of 10,711 cases and 50 risk factors included. Among them, there are combined effects of ten factors which have statistical significance, such as infarction area, alcohol consumption, smoking, hyper homocysteinemia, hypertension, diabetes mellitus, age, history of cerebral infarction, hyperlipoidemia and education level. The relational merging OR value and 95% CI between the type-variable factors and cognitive impairment are 3.25 (1.84, 5.76);2.98 (2.58, 3.45);2.79 (1.69, 4.59);2.35 (1.93, 2.85);2.25 (1.86, 2.71);2.14 (2.10, 2.18);1.82 (1.62, 2.03);1.54 (1.24, 1.92);1.45 (1.34, 1.56);0.83 (0.78, 0.89). Conclusion: Infarction area, alcohol consumption, smoking, hyper homocysteinemia, hypertension, diabetesmellitus, age, history of cerebral infarction, hyperlipoidemia and low education level are the main risk factors for vascular cognitive impairment in patients with acute cerebral infarction. Clinical nursing staff should include it into the routine assessment of patients with acute cerebral infarction and actively prevent and intervene.