Background and Purpose-There are limited data on the causes and severity of subsequent stroke in patients presenting initially with TIA or stroke attributed to intracranial arterial stenosis. Methods-We evaluated the location, type (lacunar vs nonlacunar), cause, and severity of stroke in patients who had an ischemic stroke endpoint in the Warfarin Aspirin Symptomatic Intracranial Disease (WASID) trial. Results-Of the 569 patients enrolled in the WASID trial, 106 patients (18.6%) had an ischemic stroke during a mean follow-up of 1.8 years. Stroke occurred in the territory of the symptomatic artery in 77 (73%) of 106 patients. Among the 77 strokes in the territory, 70 (91%) were nonlacunar and 34 (44%) were disabling. Stroke out of the territory of the symptomatic artery occurred in 29 (27%) of 106 patients. Among these 29 strokes, 24 (83%) were nonlacunar, 14 (48%) were attributed to previously asymptomatic intracranial stenosis, and 9 (31%) were disabling. Conclusions-Most subsequent strokes in patients with symptomatic intracranial artery stenosis are in the same territory and nonlacunar, and nearly half of the strokes in the territory are disabling. The most commonly identified cause of stroke out of the territory was a previously asymptomatic intracranial stenosis. Penetrating artery disease was responsible for a low number of strokes.

In animal models of stroke, spinal cord injury, and subarachnoid hemorrhage, transient receptor potential melastatin 4 (Trpm4), a non-selective monovalent cation channel, is transcriptionally upregulated in neural and vascular cells. In these contexts, Trpm4 has been shown to co-associate with sulfonylurea receptor 1 (Sur1) to form Sur1-Trpm4 channels, which play a critical role in cytotoxic edema, accidental necrotic (oncotic) cell death, blood-brain barrier (BBB) breakdown and formation of vasogenic edema. To date, the expression and molecular interactions of Trpm4 within human cerebral infarcts have not been systematically evaluated. In this study, we examined Trpm4 expression in postmortem specimens obtained from 15 patients within the first 31 days after onset of focal cerebral ischemia. Significant upregulation of Trpm4 protein was found in all cases, relative to controls. De novo transcriptional upregulation of Trpm4 protein was confirmed using in situ hybridization for Trpm4 mRNA. Trpm4 co-localized and co-associated with Sur1 within ischemic endothelial cells and neurons which exhibited membrane thickening and irregularities characteristic of necrotic cell death. Sur1 and Trpm4 co-expression in abnormal endothelial cells also was associated with vasogenic edema, as evidenced by upregulated perivascular TNFα, perivascular extravasation of serum immunoglobulin G and associated inflammation. Upregulated Trpm4 protein persisted up to one month post onset of cerebral ischemia. Furthermore, pharmacological channel blockade by glibenclamide, a selective inhibitor of sulfonylurea receptor, was found to mitigate perivascular TNFα labeling in a rat middle cerebral artery occlusion (MCAo) stroke model. We conclude that the Sur1-Trpm4 channel is upregulated and associated with BBB disruption and cerebral edema formation in human cerebral infarcts. These data suggest that pharmacological targeting of this channel may represent a promising therapeutic strategy for clinical management of ischemic stroke.

It is currently well established that the immune system is activated in response to transient or focal cerebral ischemia. This acute immune activation occurs in response to damage, and injury, to components of the neurovascular unit and is mediated by the innate and adaptive arms of the immune response. The initial immune activation is rapid, occurs via the innate immune response and leads to inflammation. The inflammatory mediators produced during the innate immune response in turn lead to recruitment of inflammatory cells and the production of more inflammatory mediators that result in activation of the adaptive immune response. Under ideal conditions, this inflammation gives way to tissue repair and attempts at regeneration. However, for reasons that are just being understood, immunosuppression occurs following acute stroke leading to post-stroke immunodepression. This review focuses on the current state of knowledge regarding innate and adaptive immune activation in response to focal cerebral ischemia as well as the immunodepression that can occur following stroke. A better understanding of the intricate and complex events that take place following immune response activation, to acute cerebral ischemia, is imperative for the development of effective novel immunomodulatory therapies for the treatment of acute stroke.

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Toll-like receptor (TLR) signaling plays an important role in cerebral ischemia, but downstream signaling events, which can be organ-specific, are incompletely understood. We thereby investigated involvement of the MyD88-dependent (MyD88) and MyD88-independent (TRIF) TLR signaling pathways in 2 in vitro and 2 in vivo models of cerebral ischemia. For in vitro studies, we used a model of oxygen-glucose deprivation (OGD) followed by flow cytometric analysis to determine:1) viability of PC12 cells following knock-down with MyD88 siRNA compared to negative control siRNA and 2) viability, apoptosis and necrosis of cortical neurons from MyD88 null (-/-), TRIF mutant, and wild type (WT) mice. In addition, in vivo, 1) We examined CA1 neuronal survival 7 days after global forebrain ischemia and 2) infarct volumes 24h after Middle Cerebral Artery Occlusion (MCAO) in all 3 types of mice. OGD: 1) There were no differences in either percent viability of PC12 cells transfected with MyD88 compared to negative control siRNA or 2) in percent viability, apoptosis and necrosis of cortical neurons from MyD88-/-,TRIF mutant and WT mice. Global ischemia: neuronal survival was similar in all 3 groups of mice. Finally, MCAO: infarct volumes were not statistically different among all 3 groups of mice: MyD88 -/-, 23.9 ± 9.9 mm3, TRIF mutant, 26.7 ± 5.8mm3 and WT, 17.9 ± 8.4mm3. These findings show that disruption of MyD88 or TRIF signaling does not confer protection in brain ischemia and suggests the possibility of additional or alternate downstream adaptors during TLR signaling in cerebral ischemia.