Predictors of post stroke cognitive impairment: VITATOPS cognition substudy.

INTRODUCTION: Post stroke cognitive impairment (PSCI) is a common complication of ischemic stroke. PSCI can involve different depending on clinical and stroke related characteristics. The aim of this study is to determine the factors associated with impairments in specific cognitive domains. METHODS: The Vitamins to Prevent Stroke (VITATOPS) trial is a large, multinational randomised controlled trial. In this substudy, consecutive patients admitted for ischaemic stroke or transient ischaemic attack (TIA) at a tertiary hospital in Singapore were included. PSCI was defined as impairment of any of the six cognitive subgroups - visuoconstruction, attention, verbal memory, language, visual memory and visuomotor function - that were assessed annually for up to five years. Univariate and multivariate Cox proportional hazard models were used to determine factors associated with impairments in each of these cognitive domains. RESULTS: A total of 736 patients were included in this study, of which 173 (23.5 %) developed cognitive impairment. Out of the six cognitive domains, the greatest proportion of patients had an impairment in visuoconstruction (26.4 %) followed by attention (19.8 %), verbal memory (18.3 %), language (17.5 %), visual memory (17.3 %) and visuomotor function (14.8 %). Patients with posterior circulation cerebral infarction (POCI) as the index stroke subtype had higher rates of cognitive impairment. Further subgroup analyses show that Indian race and advanced age were predictive of language impairment, whilst fewer years of education and POCI were predictive of verbal memory impairment. POCI was predictive of visual memory impairment, and advanced age and POCI were predictive of visuomotor function impairment. CONCLUSION: We identified visuoconstruction and attention domains to be the most affected in our Asian cohort of PSCI. Advanced age, lower levels of education, posterior circulation strokes and concomitant comorbidities such as peripheral artery disease are independent predictors of PSCI.

Long-Term Outcomes After Stenting in Extracranial vs. Intracranial Stenosis.

Objective: The purpose of this pilot study is to explore the difference in safety and effectiveness after stenting in patients with extracranial or intracranial vertebral artery stenosis. Methods: The study involved 26 patients treated with stents for ≥70% stenosis between January 1, 2017, and September 8, 2020. The patients were divided into intracranial and extracranial groups based on the location of the target vessel stenosis. The incidence of stroke or death within 30 days, long-term recurrence of ischemic symptoms, and restenosis during follow-up were monitored. Results: Within 30 days, no stroke or death was observed in the 26 patients, During the follow-up period, the risk of recurrence of posterior circulation stroke or transient ischemic attack was 23.1% (6/26). Vascular-related complications were 5.6% vs. 12.5% (P = .529) in the intracranial vs. extracranial stenosis group. After 1 year, stroke or transient ischemic attack of posterior circulation was observed in 12.5% (1/8) vs. 16.7% (3/18) in the intracranial and extracranial stenosis group, respectively. The restenosis rate in the intracranial stenosis group was higher than the extracranial stenosis group (37.5% vs. 28.6%, P > .05). This trend was also found in the asymptomatic restenosis rate (25% vs. 7.1%, P = .527). Conclusions: The study results showed that there was no significant difference in the safety and effectiveness after stenting in extracranial and intracranial vertebral artery stenosis, but intracranial vertebral artery stenosis has a low rate of symptomatic restenosis. Symptomatic restenosis may be an important problem that limits the efficacy of extracranial vertebral artery stenting.

Early initiation of rivaroxaban after reperfusion therapy for stroke patients with nonvalvular atrial fibrillation.

BACKGROUND: The optimal timing of initiating oral anticoagulants after reperfusion therapy for ischemic stroke is unknown. Factors related to early initiation of rivaroxaban and differences in clinical outcomes of stroke patients with nonvalvular atrial fibrillation (NVAF) who underwent reperfusion therapy was investigated. METHODS: From data of 1,333 NVAF patients with ischemic stroke or transient ischemic attack (TIA) in a prospective multicenter study, patients who started rivaroxaban after intravenous thrombolysis and/or mechanical thrombectomy were included. The clinical outcomes included the composite of ischemic events (recurrent ischemic stroke, TIA, or systemic embolism) and major bleeding at 3 months. RESULTS: Among the 424 patients, the median time from index stroke to starting rivaroxaban was 3.2 days. On multivariable logistic regression analysis, infarct size (odds ratio [OR], 0.99; 95%CI, 0.99-1.00) was inversely and successful reperfusion (OR, 2.13; 95%CI, 1.24-3.72) was positively associated with initiation of rivaroxaban within 72 hours. 205 patients were assigned to the early group (< 72 hours) and 219 patients (≥ 72 hours) to the late group. Multivariable Cox regression models showed comparable hazard ratios between the two groups at 3 months for ischemic events (hazard ratio [HR], 0.18; 95%CI, 0.03-1.32) and major bleeding (HR, 1.80; 95%CI, 0.24-13.54). CONCLUSIONS: Infarct size and results of reperfusion therapy were associated with the timing of starting rivaroxaban. There were no significant differences in the rates of ischemic events and major bleeding between patients after reperfusion therapy who started rivaroxaban < 72 hours and ≥ 72 hours after the index stroke. CLINICAL TRIAL REGISTRATION: Unique identifier: NCT02129920; URL: https://www.clinicaltrials.gov.

Pycnogenol® Supplementation Attenuates Memory Deficits and Protects Hippocampal CA1 Pyramidal Neurons via Antioxidative Role in a Gerbil Model of Transient Forebrain Ischemia.

Pycnogenol® (an extract of the bark of French maritime pine tree) is used for dietary supplement and known to have excellent antioxidative efficacy. However, there are few reports on neuroprotective effect of Pycnogenol® supplementation and its mechanisms against ischemic injury following transient forebrain ischemia (TFI) in gerbils. Now, we examined neuroprotective effect and its mechanisms of Pycnogenol® in the gerbils with 5-min TFI, which evokes a significant death (loss) of pyramidal cells located in the cornu ammonis (CA1) region of gerbil hippocampus from 4-5 days post-TFI. Gerbils were pretreated with 30, 40, and 50 mg/kg of Pycnogenol® once a day for 7 days before TFI surgery. Treatment with 50 mg/kg, not 30 or 40 mg/kg, of Pycnogenol® potently protected learning and memory, as well as CA1 pyramidal cells, from ischemic injury. Treatment with 50 mg/kg Pycnogenol® significantly enhanced immunoreactivity of antioxidant enzymes (superoxide dismutases and catalase) in the pyramidal cells before and after TFI induction. Furthermore, the treatment significantly reduced the generation of superoxide anion, ribonucleic acid oxidation and lipid peroxidation in the pyramidal cells. Moreover, interestingly, its neuroprotective effect was abolished by administration of sodium azide (a potent inhibitor of SODs and catalase activities). Taken together, current results clearly indicate that Pycnogenol® supplementation can prevent neurons from ischemic stroke through its potent antioxidative role.

Proteomics-Guided Study on Buyang Huanwu Decoction for Its Neuroprotective and Neurogenic Mechanisms for Transient Ischemic Stroke: Involvements of EGFR/PI3K/Akt/Bad/14-3-3 and Jak2/Stat3/Cyclin D1 Signaling Cascades.

Buyang Huanwu Decoction (BHD), a classic traditional Chinese medicine (TCM) formula, has been used for recovering neurological dysfunctions and treating post-stroke disability in China for 200 years. In the present study, we investigated the effects of BHD on inhibiting neuronal apoptosis, promoting proliferation and differentiation of neural stem cells (NSCs) and neurite formation and enhancing learning and memory functional recovery in an experimental rat ischemic stroke model. BHD significantly reduced infarct volume and decreased cell apoptosis in the ischemic brain. BHD enhanced neuronal cell viability in vitro. BHD dose-dependently promoted the proliferation of NSCs in ischemic rat brains in vivo. Moreover, BHD promoted neuronal and astrocyte differentiation in primary cultured NSCs in vitro. Water maze test revealed that BHD promoted the recovery of learning function but not memory functions in the transient ischemic rats. We then investigated the changes of the cellular signaling molecules by using two-dimension (2D) gel electrophoresis and focused on the PI3K/Akt/Bad and Jak2/Stat3/cyclin D1signaling pathway to uncover its underlying mechanisms for its neuroprotective and neurogenetic effects. BHD significantly upregulated the expression of p-PI3K, p-Akt, and p-Bad as well as the expression of p-Jak, p-Stat3, and cyclin D1 in vitro and in vivo. In addition, BHD upregulated Hes1 and downregulated cav-1 in vitro and in vivo. Taken together, these results suggest that BHD has neuroprotective effects and neurogenesis-promoting effects via activating PI3K/Akt/Bad and Jak2/Stat3/Cyclin D1 signaling pathways. Graphical Abstract Buyang Huanwu Decoction (BHD) activates the PI3K-AKT-BAD pathway in the ischemic brain for neuroprotection. BHD also activates JAK2/STAT3/Cyclin D1 signaling cascades for promoting neurogenesis in the hippocampus of post-ischemic brains. Moreover, BHD inhibits the expression of caveolin-1 and increases the expression of HES1 for promoting neuronal differentiation. The neuroprotective and neurogenesis-promoting effects in the hippocampus of post-ischemic brains promote learning ability.

Factors of post-stroke dementia: A nationwide cohort study in Taiwan.

AIM: We investigated the long-term risk of dementia for up to 10 years in patients with stroke and broadened the correlates. METHODS: We carried out a case-control study using the Taiwan National Health Insurance Research database in 2000 with a sampled population of 1 million. The study cohort comprised 8236 patients with stroke and no dementia history. We carried out a 1:1 case-control matched analysis on estimated propensity scores. Cox proportional hazards regressions were carried out to estimate the risk of dementia during the 5- and 10-year follow-up periods. The risk factors were also investigated. RESULTS: The stroke cohort was significantly at more risk of dementia during the 5- and 10-year follow-up periods, with adjusted hazard ratios 1.87 and 1.53, respectively. The patients with ischemic stroke, transient ischemic attack and intracerebral hemorrhage had a significantly higher risk of dementia after 5 and 10 years, with adjusted hazard ratios of 1.81 and 1.49, 1.92 and 1.61, and 2.14 and 1.61, respectively. The significant risk factors of dementia were age ≥60 years, resident in southern and eastern regions, having low insurance range, and antiplatelet use. CONCLUSIONS: Stroke and the subtypes, including ischemic stroke, transient ischemic attack and intracerebral hemorrhage, increase the long-term risk of dementia. The incidence of post-stroke dementia increases yearly, but the relative risk decreases gradually. Older adults, residents in southern and eastern regions, having low insurance range and antiplatelet use were prominent risk factors of post-stroke dementia in Taiwan. Careful management of stroke and risk factors of post-stroke dementia with long-term follow up of cognition should be reinforced. Geriatr Gerontol Int 2019; 19: 815-822.

Neuroprotection by chotosan, a Kampo formula, against glutamate excitotoxicity involves the inhibition of GluN2B-, but not GluN2A-containing NMDA receptor-mediated responses in primary cultured cortical neurons.

Chotosan (CTS), a traditional herbal formula called Kampo medicine, was shown to be effective in the treatment of vascular dementia in a clinical study, and exerted protective effects against transient cerebral ischemia-induced cognitive impairment in mice. In the present study, we investigated the neuroprotective effects of CTS using primary cultured rat cortical neurons. CTS (250-1000 µg/mL) inhibited neuronal death induced by 100 µM glutamate. This glutamate-induced neuronal death was blocked by a GluN2B-, but not GluN2A-containing NMDA receptor antagonist. Therefore, the neuroprotective effects of CTS were related to an inhibition of GluN2B-containing NMDA receptor-mediated responses.

Postischemic fish oil treatment confers task-dependent memory recovery.

A series of our previous studies demonstrated that fish oil (FO), equivalent to 300mg/kg docosahexahenoic acid (DHA), facilitates memory recovery after transient, global cerebral ischemia (TGCI) in the aversive radial maze (AvRM). The present study sought to address two main issues: (i) whether the memory-protective effect of FO that has been observed in the AvRM can be replicated in the passive avoidance test (PAT) and object location test (OLT) and (ii) whether FO at doses that are lower than those used previously can also prevent TGCI-induced memory loss. In Experiment 1, naive rats were trained in the PAT, subjected to TGCI (4-vessel occlusion model), and tested for retrograde memory performance 8 and 15days after ischemia. Fish oil (300mg/kg/day DHA) was given orally for 8days. The first dose was delivered 4h postischemia. In Experiment 2, the rats were subjected to TGCI, treated with the same FO regimen, and then trained and tested in the OLT. In Experiment 3, the rats were trained in the AvRM, subjected to TGCI, administered FO (100, 200, and 300mg/kg DHA), and tested for memory performance up to 3weeks after TGCI. At the end of the behavioral tests, the brains were examined for neurodegeneration and neuroblast proliferation. All of the behavioral tests (PAT, OLT, and AvRM) were sensitive to ischemia, but only the AvRM was able to detect the memory-protective effect of FO. Ischemia-induced neurodegeneration and neuroblast proliferation were unaffected by FO treatment. These results suggest that (i) the beneficial effect of FO on memory recovery after TGCI is task-dependent, (ii) doses of FO<300mg/kg DHA can protect memory function in the radial maze, and (iii) cognitive recovery occurs in the absence of neuronal rescue and/or hippocampal neurogenesis.

A Post-stroke Therapeutic Regimen with Omega-3 Polyunsaturated Fatty Acids that Promotes White Matter Integrity and Beneficial Microglial Responses after Cerebral Ischemia.

White matter injury induced by ischemic stroke elicits sensorimotor impairments, which can be further deteriorated by persistent proinflammatory responses. We previously reported that delayed and repeated treatments with omega-3 polyunsaturated fatty acids (n-3 PUFAs) improve spatial cognitive functions and hippocampal integrity after ischemic stroke. In the present study, we report a post-stroke n-3 PUFA therapeutic regimen that not only confers protection against neuronal loss in the gray matter but also promotes white matter integrity. Beginning 2 h after 60 min of middle cerebral artery occlusion (MCAO), mice were randomly assigned to receive intraperitoneal docosahexaenoic acid (DHA) injections (10 mg/kg, daily for 14 days), alone or in combination with dietary fish oil (FO) supplements starting 5 days after MCAO. Sensorimotor functions, gray and white matter injury, and microglial responses were examined up to 28 days after MCAO. Our results showed that DHA and FO combined treatment-facilitated long-term sensorimotor recovery and demonstrated greater beneficial effect than DHA injections alone. Mechanistically, n-3 PUFAs not only offered direct protection on white matter components, such as oligodendrocytes, but also potentiated microglial M2 polarization, which may be important for white matter repair. Notably, the improved white matter integrity and increased M2 microglia were strongly linked to the mitigation of sensorimotor deficits after stroke upon n-3 PUFA treatments. Together, our results suggest that post-stroke DHA injections in combination with FO dietary supplement benefit white matter restoration and microglial responses, thereby dictating long-term functional improvements.

A novel dual-glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptor agonist is neuroprotective in transient focal cerebral ischemia in the rat.

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists have been shown to be neuroprotective in previous studies in animal models of Alzheimer's or Parkinson's disease. Recently, novel dual-GLP-1/GIP receptor agonists that activate both receptors (DA) were developed to treat diabetes. We tested the protective effects of a novel potent DA against middle cerebral artery occlusion injury in rats and compared it with a potent GLP-1 analog, Val(8)-GLP-1(glu-PAL). Animals were evaluated for neurologic deficit score, infarct volume, and immunohistochemical analyses of the brain at several time points after ischemia. The Val(8)-GLP-1(glu-PAL)-treated and DA-treated groups showed significantly reduced scores of neurological dysfunction, cerebral infarction size, and percentage of TUNEL-positive apoptotic neurons. Furthermore, the expression of the apoptosis marker Bax, the inflammation marker iNOS, and the survival marker Bcl-2 was significantly increased. The DA-treated group was better protected against neurodegeneration than the Val(8)-GLP-1(glu-PAL) group, and the scores of neurological dysfunction, cerebral infarction size, and expression of Bcl-2 were higher, whereas the percentage of TUNEL-positive neurons and the levels of Bax and iNOS were lower in the DA group. DA treatment reduced the infarct volume and improved the functional deficit. It also suppressed the inflammatory response and cell apoptosis after reperfusion. In conclusion, the novel GIP and GLP-1 dual-receptor agonist is more neuroprotective than a GLP-1 receptor agonist in key biomarkers of neuronal degeneration.

Treating coronary artery disease in patients with a history of cerebrovascular disease.

Patients with coronary artery disease and a history of stroke account for as many as one in eight of all patients with coronary artery disease, and they are at higher risk of ischaemic events than patients with 'lone' coronary artery disease. It is therefore tempting to increase the potency of antithrombotic treatment in this patient subset. However, these patients are also at greater risk of intracranial haemorrhage. In recent trials of new antithrombotic agents in acute coronary syndromes, patients with a history of cerebrovascular disease derived no clinical benefit from (and were even harmed by) the potent novel antithrombotic agents, with an increased risk of intracranial haemorrhage. However, this risk did not appear to be uniform: it was higher in patients with a history of stroke than in those with a history of transient ischaemic attack, and appeared to be largely confined to the first year after stroke/transient ischaemic attack. Specific strategies to optimize the benefit/risk ratio of antithrombotic agents in this relatively common patient group should be developed and evaluated.

LC-MS/MS profiling and neuroprotective effects of Mentat® against transient global ischemia and reperfusion-induced brain injury in rats.

OBJECTIVE: The aim of this study was to evaluate the possible beneficial effects of Mentat against transient global ischemia and reperfusion-induced brain injury in rats. METHODS: The neuroprotective effects of Mentat were evaluated against transient global ischemia and reperfusion (I/R)-induced brain injury in rats. Various neurobehavioral and biochemical parameters were assessed, followed by morphologic and histopathologic evaluation of brain tissue to conclude the protective effect of Mentat. Additionally, in vitro antioxidant assays were performed to explore the antioxidant capacity of Mentat and detailed liquid chromatography-mass spectrometry (LC-MS/MS) profiling was carried out to identify the active phytoconstituents responsible for the protective effects of Mentat. RESULTS: Sixty minutes of transient global ischemia followed by 24 h reperfusion (I/R) caused significant alterations in the cognitive and neurologic functions in the ischemia control group (P < 0.01) compared with the sham control. Furthermore, 2,3,5-triphenyltetrazolium chloride staining of the ischemia control group showed 20.85% ± 0.39% of cerebral infarct area (P < 0.01), increased brain volume (% edema 17.81% ± 1.576%; P < 0.01), and increased lipid peroxidation (P < 0.01) in the brain homogenate. Additionally, the histopathology of the ischemia control group showed severe brain injury compared with the sham control group. Interestingly, pretreatment with Mentat (250 and 500 mg/kg, p.o.) and quercetin (20 mg/kg, p.o.) for 7 d has alleviated all pathological changes observed due to I/R injury. Mentat also showed very good antioxidant activity in in vitro assays (2,2-diphenyl-l-picrylhydrazyl, ferric-reducing antioxidant power, and oxygen radical absorbance capacity assays). Furthermore, the detailed LC-MS/MS analysis of Mentat was performed and enclosed for identifying the actives responsible for its protective effects. CONCLUSIONS: These findings suggest that Mentat is a neuroprotective agent that may be a useful adjunct in the management of ischemic stroke and its rehabilitation especially with respect to associated memory impairment and other related neurologic conditions.

Omega-3 polyunsaturated fatty acids enhance cerebral angiogenesis and provide long-term protection after stroke.

Stroke is a devastating neurological disorder and one of the leading causes of death and serious disability. After cerebral ischemia, revascularization in the ischemic boundary zone provides nutritive blood flow as well as various growth factors to promote the survival and activity of neurons and neural progenitor cells. Enhancement of angiogenesis and the resulting improvement of cerebral microcirculation are key restorative mechanisms and represent an important therapeutic strategy for ischemic stroke. In the present study, we tested the hypothesis that post-stroke angiogenesis would be enhanced by omega-3 polyunsaturated fatty acids (n-3 PUFAs), a major component of dietary fish oil. To this end, we found that transgenic fat-1 mice that overproduce n-3 PUFAs exhibited long-term behavioral and histological protection against transient focal cerebral ischemia (tFCI). Importantly, fat-1 transgenic mice also exhibited robust improvements in revascularization and angiogenesis compared to wild type littermates, suggesting a potential role for n-3 fatty acids in post-stroke cerebrovascular remodeling. Mechanistically, n-3 PUFAs induced upregulation of angiopoietin 2 (Ang 2) in astrocytes after tFCI and stimulated extracellular Ang 2 release from cultured astrocytes after oxygen and glucose deprivation. Ang 2 facilitated endothelial proliferation and barrier formation in vitro by potentiating the effects of VEGF on phospholipase Cγ1 and Src signaling. Consistent with these findings, blockade of Src activity in post-stroke fat-1 mice impaired n-3 PUFA-induced angiogenesis and exacerbated long-term neurological outcomes. Taken together, our findings strongly suggest that n-3 PUFA supplementation is a potential angiogenic treatment capable of augmenting brain repair and improving long-term functional recovery after cerebral ischemia.

Effects of delayed puerarin treatment in long-term neurological outcomes of focal ischemic stroke in rats.

OBJECTIVE: The present study aimed at investigate the therapeutic effects of delayed puerarin treatment in neurological outcomes after middle cerebral artery occlusion (MCAO) in rats. MATERIALS AND METHODS: Male Wistar rats were subjected to MCAO for 120 min followed by reperfusion for 14 days. Puerarin (0, 50, 100, 200 mg/kg, intra-peritoneally) was administered at 24 h after stroke onset and repeated daily for 14 days. Neurological deficits were evaluated at 1, 4, 7, 14 days after stroke. Brain infarct volume and peri-infarct context vessel density were examined at 14 days after stroke. RESULTS: Puerarin significantly improved neurological functions up to 14 days after stroke and decreased the infarct volume with doses of 50 mg/kg and 100 mg/kg compared with saline controls. Puerarin treatment also significantly increased peri-infarct context vessel density at 14 days after stroke. CONCLUSIONS: Delayed treatment of puerarin initiated at 24 h after stroke is beneficial with improved long-term neurological outcomes and reduced infarction volume in focal ischemic stroke in rats. Enhanced vascular remodeling by puerarin might at least partially contribute to its beneficial effects.

Asiaticoside attenuates memory impairment induced by transient cerebral ischemia-reperfusion in mice through anti-inflammatory mechanism.

Asiaticoside (AS) is isolated from Centella asiatica (L.) which has been using for a long time as a memory enhancing drug in India. This study was to investigate the effects of AS on memory impairment and inflammatory cytokines expression induced by transient cerebral ischemia and reperfusion in mice, as well as the potential signaling pathway. Transient bilateral common carotid artery occlusion (tBCCAO) induced severe memory deficits in mice according to the Morris water maze task and the step-down passive avoidance test. Meanwhile the microglial activation and the gene expression of inflammatory cytokines including interleukin (IL)-1ß, interleukin (IL)-6 and tumor necrosis factor (TNF)-α were increased in the hippocampus of the mice with cerebral ischemia and reperfusion. Oral administration of AS (40 and 60 mg/kg, once per day, started the day after surgery and lasted for 7 days) significantly ameliorated the memory impairment and the inflammation. Moreover, AS (20, 40 and 60 mg/kg) markedly reduced the microglial overactivation and the phosphorylation of p38 MAPK in hippocampus compared with the transient cerebral ischemia and reperfusion group. These results suggested that AS showed the neuroprotective effect against transient cerebral ischemia and reperfusion in mice, and this effect might be associated with the anti-inflammation effect of AS via inhibiting overactivation of p38 MAPK pathway.

Fish oil provides a sustained antiamnesic effect after acute, transient forebrain ischemia but not after chronic cerebral hypoperfusion in middle-aged rats.

We reported that fish oil (FO) abolishes retrograde amnesia consistently following transient global cerebral ischemia (TGCI) in young rats, provided it covered the first days prior to and after ischemia. Here, we further evaluated whether FO given post-ischemia in older rats (15-18 months old) is equally effective in facilitating memory recovery. We also tested whether the antiamnesic effect of FO observed after TGCI can be reproduced after chronic cerebral hypoperfusion (CCH). FO (300 mg/kg docosahexaenoic acid [DHA]) was delivered orally 4h after TGCI and continued once per day for 9 days. In the CCH group, FO treatment began soon after the first stage of 4-VO/ICA and continued daily for 43 days. Two weeks after surgery, the animals were tested for retrograde memory performance across 5 weeks. Both TGCI and CCH caused persistent memory impairment and hippocampal and cortical neurodegeneration. TGCI-induced retrograde amnesia was reversed by FO, an effect that was sustained for at least 5 weeks after discontinuing treatment. In contrast, the memory deficit caused by CCH remained unchanged after FO treatment. Both hippocampal and cortical damage was not alleviated by FO. We conclude that the FO-mediated antiamnesic effect following TGCI can be extended to older rats, even when the treatment begins 4h postischemia. Such efficacy was not reproduced after CCH. Therefore, the present results support the notion that FO may have therapeutic utility in treating learning/memory dysfunction after acute/transient cerebral ischemia and suggest that such benefits may not apply when a state of chronic cerebrovascular insufficiency is present.

Antithrombotic selection and risk factor management in ischemic stroke and transient ischemic attack.

In addition to appropriate antithrombotic therapy, the identification and treatment of modifiable ischemic stroke risk factors can reduce the likelihood of recurrent stroke. Neurosurgeons should be knowledgeable of the specific risk factors and general recommendations for ischemic stroke, as they may play a significant role in the management options for patients with intracranial and extracranial atherosclerotic disease. The authors of this article review the indications for and selection of antithrombotics in patients with cerebral ischemia. In addition, the identification and secondary prevention of select risk factors are discussed.

Effect of repeated allogeneic bone marrow mononuclear cell transplantation on brain injury following transient focal cerebral ischemia in rats.

AIMS: Transplantation of bone marrow mononuclear cells (BMMCs) exerts neuroprotection against cerebral ischemia. We examined the therapeutic timepoint of allogeneic BMMC transplantation in a rat model of focal cerebral ischemia, and determined the effects of repeated transplantation outside the therapeutic window. MAIN METHODS: Male Sprague-Dawley rats were subjected to 90 minute focal cerebral ischemia, followed by intravenous administration of 1 × 10(7) allogeneic BMMCs or vehicle at 0, 3 or 6 h after reperfusion or 2 × 10(7) BMMCs 6 h after reperfusion. Other rats administered 1 × 10(7) BMMCs at 6 h after reperfusion received additional BMMC transplantation or vehicle 9 h after reperfusion. Infarct volumes, neurological deficit scores and immunohistochemistry were evaluated 24 or 72 h after reperfusion. KEY FINDINGS: Infarct volumes at 24 h were significantly decreased in transplantation rats at 0 and 3 h, but not at 6 h, after reperfusion, compared to vehicle-treatment. Even high dose BMMC transplantation at 6h after reperfusion was ineffective. Repeated BMMC transplantation at 6 and 9h after reperfusion reduced infarct volumes and significantly improved neurological deficit scores at 24 and 72 h. Immunohistochemistry showed repeated BMMC transplantation reduced ionized calcium-binding adapter molecule 1, 4-hydroxy-2-nonenal and 8-hydroxydeoxyguanosine expression at 24 and 72 h after reperfusion. SIGNIFICANCE: Intravenous allogeneic BMMCs were neuroprotective following transient focal cerebral ischemia, and the therapeutic time window of BMMC transplantation was >3 h and <6 h after reperfusion in this model. Repeated transplantation at 6 and 9 h after reperfusion suppressed inflammation and oxidative stress in ischemic brains, resulting in improved neuroprotection.

Total bakkenolides protects neurons against cerebral ischemic injury through inhibition of nuclear factor-κB activation.

Total bakkenolides is the major component of the rhizome of Petasites trichinous Franch.. In this study, we investigated its neuroprotective effects in a rat transient focal cerebral ischemia-reperfusion model, and in an in vitro cerebral ischemia model, oxygen-glucose deprivation of cultured nerve cells. Oral administration of total bakkenolides immediately after reperfusion at doses of 5, 10 and 20 mg/kg markedly reduced brain infarct volume and neurological deficits. Total bakkenolides significantly attenuated cell death and apoptosis in primarily cultured neurons subject to 1-h hypoxia followed by 24-h reoxygenation. Morphologic observations directly confirmed its protective effect on neurons. We also demonstrated that total bakkenolides could inhibit nuclear factor-κB (NF-κB) activation by blocking the classic activation pathway through suppression of phosphorylation of IκB-kinase complex, NF-κB/p65 and inhibitor protein IκB, inducing nuclear translocation of NF-κB/p65 and degradation of IκB. Further, total bakkenolides inhibited the activation of Akt and the extracellular signal-regulated kinase 1/2, two important upstream activators of NF-κB. In conclusion, our results provide a strong pharmacological basis for further understanding the potential therapeutic role of total bakkenolides in cerebral ischemic disease and shed new light on its neuroprotective mechanism.

Danggui-Jakyak-San ameliorates memory impairment and increase neurogenesis induced by transient forebrain ischemia in mice.

BACKGROUND: Danggui-Jakyak-San (DJS), a traditional herbal prescription, has been used to treat insufficient blood supplies. Recently, regenerative medication for the treatment of cerebral ischemia has drawn the attention of many researchers. METHODS: In this study, we examined whether DJS exerts a neuronal regenerative effect in the hippocampus of a transient forebrain ischemia mice model. Transient forebrain ischemia was induced by bilateral common carotid artery occlusion (BCCAO). Animals were divided into three groups (sham, BCCAO + vehicle, and BCCAO + DJS). To test the effect of DJS on learning and memory, Morris water maze or passive avoidance test was conducted. To test neuroprotective and neurogenic effect, immunohistochemistry and Western blot analysis were used. Statistical significance was analyzed with Student t-test, one-way or two-way analysis of variance. RESULTS: We found that the administration of DJS ameliorated ischemia-induced spatial memory impairment in the Morris water maze task. Moreover, Akt/glycogen synthase kinase-3ß (GSK3ß)/ß-catenin signaling was increased by DJS, which would be one possible mechanism of DJS for neurogenesis in the hippocampal dentate gyrus region. CONCLUSIONS: These results suggest that DJS is a possible candidate for the treatment of ischemia-induced neuronal degeneration.