Leukoaraiosis is associated with clinical symptom severity, poor neurological function prognosis and stroke recurrence in mild intracerebral hemorrhage: a prospective multi-center cohort study.

Leukoaraiosis (LA) results from ischemic injury in small cerebral vessels, which may be attributable to decreased vascular density, reduced cerebrovascular angiogenesis, decreased cerebral blood flow, or microcirculatory dysfunction in the brain. In this study, we enrolled 357 patients with mild intracerebral hemorrhage (ICH) from five hospitals in China and analyzed the relationships between LA and clinical symptom severity at admission, neurological function prognosis at 3 months, and 1-year stroke recurrence. Patients were divided into groups based on Fazekas scale scores: no LA (n = 83), mild LA (n = 64), moderate LA (n = 98) and severe LA (n = 112). More severe LA, larger hematoma volume, and higher blood glucose level at admission were associated with more severe neurological deficit. More severe LA, older age and larger hematoma volume were associated with worse neurological function prognosis at 3 months. In addition, moderate-to-severe LA, admission glucose and symptom-free cerebral infarction were associated with 1-year stroke recurrence. These findings suggest that LA severity may be a potential marker of individual ICH vulnerability, which can be characterized by poor tolerance to intracerebral attack or poor recovery ability after ICH. Evaluating LA severity in patients with mild ICH may help neurologists to optimize treatment protocols. This study was approved by the Ethics Committee of Ruijin Hospital Affiliated to Shanghai Jiao Tong University (approval No. 12) on March 10, 2011.

P2Y6 receptor inhibition aggravates ischemic brain injury by reducing microglial phagocytosis.

INTRODUCTION: Clearance of damaged cells and debris is beneficial for the functional recovery after ischemic brain injury. However, the specific phagocytic receptor that mediates microglial phagocytosis after ischemic stroke is unknown. AIM: To investigate whether P2Y6 receptor-mediated microglial phagocytosis is beneficial for the debris clearance and functional recovery after ischemic stroke. RESULTS: The expression of the P2Y6 receptor in microglia increased within 3 days after transient middle cerebral artery occlusion. Inhibition of microglial phagocytosis by the selective inhibitor MRS2578 enlarged the brain atrophy and edema volume after ischemic stroke, subsequently aggravated neurological function as measured by modified neurological severity scores and Grid walking test. MRS2578 treatment had no effect on the expression of IL-1α, IL-1ß, IL-6, IL-10, TNF-α, TGF-ß, and MPO after ischemic stroke. Finally, we found that the expression of myosin light chain kinase decreased after microglial phagocytosis inhibition in the ischemic mouse brain, which suggested that myosin light chain kinase was involved in P2Y6 receptor-mediated phagocytosis. CONCLUSION: Our results indicate that P2Y6 receptor-mediated microglial phagocytosis plays a beneficial role during the acute stage of ischemic stroke, which can be a therapeutic target for ischemic stroke.

DL-3n-Butylphthalide Improves Blood-Brain Barrier Integrity in Rat After Middle Cerebral Artery Occlusion.

Objective: DL-3n-butylphthalide (NBP) has beneficial effects in different stages of ischemic stroke. Our previous studies have demonstrated that NBP promoted angiogenesis in the perifocal region of the ischemic brain. However, the molecular mechanism of NBP for blood-brain barrier protection in acute ischemic stroke was unclear. Here, we explored the neuroprotective effects of NBP on blood-brain barrier integrity in the acute phase of ischemic stroke in a rat model. Methods: Adult male Sprague-Dawley rats (n = 82) underwent 2 h of transient middle cerebral artery occlusion and received 90 mg/kg of NBP for 3 days. Brain edema, infarct volume, surface blood flow, and neurological severity score were evaluated. Blood-brain barrier integrity was evaluated by Evans blue leakage and changes in tight junction proteins. We further examined AQP4 and eNOS expression, MMP-9 enzyme activity, and possible signaling pathways for the role of NBP after ischemic stroke. Results: NBP treatment significantly increased eNOS expression and surface blood flow in the brain, reduced brain edema and infarct volume, and improved neurological severity score compared to the control group (p < 0.05). Furthermore, NBP attenuated Evans blue and IgG leakage and increased tight junction protein expression compared to the control after 1 and 3 days of ischemic stroke (p < 0.05). Finally, NBP decreased AQP4 expression, MMP-9 enzyme activity, and increased MAPK expression during acute ischemic stroke. Conclusion: NBP protected blood-brain barrier integrity and attenuated brain injury in the acute phase of ischemic stroke by decreasing AQP4 expression and MMP-9 enzyme activity. The MAPK signaling pathway may be associated in this process.