| Background:Exercise is a clinically promising strategy for promoting neurological recovery in ischemic stroke patients. In animal studies, enforced delayed excises initiated after stroke appear to be able to enhance functional recovery without deteriorating ischemic brain lesions. However, recent clinical data suggest that early initiated exercise within48hour after stroke may offer beneficial effects in patients; whereas the evidence for a neuroprotective effect of early exercise in experimental stroke is scant and the underlying mechanism for early exercise-afforded neuroprotection is unknown. In the present study, we have investigated the effect of early exercise on brain damage, inflammation, the change of cerebral of brain blood flow in ischemia cortex, and neurobehavioral outcomes in a rat model of transient focal cerebral ischemia.Methods:Stroke was induced in adult male Sprague-Dawley rats by middle cerebral artery occlusion for60min, and the animals were then randomly assigned to early exercise or non-excise groups. Beginning at24hour after ischemia, exercise was induced by enforced treadmill training on a daily basis for a maximum of14days. The daily excises gradually reached the full amount (12meters/min for30min) at the3rd day. For outcome assessments, neurological scores and sensorimotor deficits (foot fault test and adhesive remove test) were determined at3-21days after ischemia, and the ability of feeling and balance were assessed by adhesive remove and beam balance at same time point, while spatial learning and memory were measured by Morris water maze at21-25days after ischemia. In additional rats, infarct volume, brain edema (wet and dry weight), and blood brain barrier integrity (Evans blue extravasations) were assessed at7th days after ischemia. The expression of pro-inflammatory cytokines (mRNAs) and cell adhesion proteins (ICAM and VCAM) was measured at3rd,5th and7th days after ischemia using real-time PCR, and the reactive astrocytes and microglia cells were determined by immunofluorescence staining. In order to detect the change of cerebral of brain blood flow in ischemia cortex after continued treadmill training of two weeks, the laser speckle flowmetry was used.Results:(1) Compared to non-excise stroke animals, animals received early exercise exhibited significantly improved neurological scores and performed significantly better in the foot fault tests (p<0.05vs. non-excise controls,), but not in the adhesive removal tests and beam balance tests. Animals under early exercise also showed significantly improved study and working memory in Morris water maze compared to non-excise animals (p<0.05).(2) In consistent with the early improvement of functional outcomes, animals under early exercise had significantly reduced infarct volume, brain water content, and blood brain barrier damage at7th days after ischemia compared to non-excise animals (p<0.05).(3) Moreover, the neuroprotection afforded by early exercise was associated with significantly reduced expression of proinflammatory cytokines (IL-lα, IL1-β, IL-6, iNOS, COX2, and TNFα) and cell adhesion molecules at3,5and7days after ischemia (p<0.05vs. non-excise controls), respectively.mean time, early exercise inhibited the activation of astrocytes and microglia cells at3and7days after ischemia.(4)Consisted with these, early exercise significantly improved the CBF in ischemic region compared with the non-exercise group.Conclusion:Our results provide novel evidence that early initiated exercise confers marked neuroprotection against focal ischemic brain injury in rats. This neuroprotection by early exercise is associated with the attenuation of pro-inflammatory reactions, brain edema, and blood brain barrier damage, and improved cerebral blood flow in the ischemia cortex after ischemia and reperfusion. Further work is required to elucidate the precise underlying mechanisms. |
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