It is unanimously accepted that stroke is a highly heterogeneous disorder. Different subtypes of ischemic stroke may have different risk factors, clinical features, and prognoses. The aim of this study was to evaluate the risk factors, clinical characteristics, and prognoses of different subtypes of ischemic stroke defined by the Trial of ORG10172 in Acute Stroke Treatment (TOAST) criteria. We prospectively analyzed the data from 530 consecutive patients who were admitted to our hospital with acute ischemic stroke within 7 days of stroke onset during the study period. Standardized data assessment was used and the cause of ischemic stroke was classified according to the TOAST criteria. Patients were followed up till 30 and 90 days after stroke onset. It was found that large-artery atherosclerosis was the most frequent etiology of stroke (37.4%), and showed the highest male preponderance, the highest prevalence of previous transient ischemic attack, and the longest hospital stay among all subtypes. Small artery disease (36.4%) was associated with higher body mass index, higher plasma triglycerides, and lower plasma high-density lipoprotein cholesterol than cardioembolism. Cardioembolism (7.7%), which was particularly common in the elderly (i.e., individuals aged 65 years and older), showed the highest female preponderance, the highest prevalence of atrial fibrillation, the earliest presentation to hospital after stroke onset, the most severe symptoms on admission, the maximum complications associated with an adverse outcome, and the highest rate of stroke recurrence and mortality. Our results suggest that ischemic stroke should be regarded as a highly heterogeneous disorder. Studies involving risk factors, clinical features, and prognoses of ischemic stroke should differentiate between etiologic stroke subtypes.

Transient global cerebral ischemia (tGCI) causes excessive release of glutamate from neurons. Astrocytic glutamate transporter-1 (GLT-1) and glutamine synthetase (GS) together play a predominant role in maintaining glutamate at normal extracellular concentrations. Though our previous studies reported the alleviation of tGCI-induced neuronal death by hypoxic preconditioning (HPC) in hippocampal Cornu Ammonis 1 (CA1) of adult rats, the underlying mechanism has not yet been fully elaborated. In this study, we aimed to investigate the roles of GLT-1 and GS in the neuroprotection mediated by HPC against tGCI and to ascertain whether these roles can be regulated by connexin 43 (Cx43) and cellular-Src (c-Src) activity. We found that HPC decreased the level of extracellular glutamate in CA1 after tGCI via maintenance of GLT-1 expression and GS activity. Inhibition of GLT-1 expression with dihydrokainate (DHK) or inhibition of GS activity with methionine sulfoximine (MSO) abolished the neuroprotection induced by HPC. Also, HPC markedly upregulated Cx43 and inhibited p-c-Src expression in CA1 after tGCI, whereas inhibition of Cx43 with Gap26 dramatically reversed this effect. Furthermore, inhibition of p-c-Src with 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo (3, 4-d) pyrimidine (PP2) decreased c-Src activity, increased protein levels of GLT-1 and Cx43, enhanced GS activity, and thus reduced extracellular glutamate level in CA1 after tGCI. Collectively, our data demonstrated that reduced extracellular glutamate induced by HPC against tGCI through preventing the reduction of GLT-1 expression and maintaining GS activity in hippocampal CA1, which was mediated by upregulating Cx43 expression and inhibiting c-Src activity.