Early exposure to enriched environment protects apoptosis and improves behavioral improvement by downregulating Fas/FasL signaling pathway after hypoxic-ischemic brain injury

Abstract Early rehabilitation presents favorable outcomes for stroke patients. However, the optimal strategy for early rehabilitation is unclear currently due to the current limitation in the data on the effects of early initiation of rehabilitation based on voluntary exercise. During the hyperacute phase of ischemic stroke, upregulation of Fas/FasL-mediated apoptosis is observed. Environmental enrichment (EE) is a therapeutic paradigm for laboratory animals that consists of complex combinations of physical, cognitive, social stimuli and voluntary exercise. Few studies delineated the effect of EE on apoptosis in an experimental model of hyperacute stroke. The aim of the study is to determine whether hyperacute exposure to EE can effectively regulate Fas/FasL-mediated apoptosis following hypoxic-ischemic brain injury and improve neurobehavioral function. C57Bl/6 mice were randomly assigned to either EE or standard cage (SC) within 3 hours or on day 3 after hypoxic-ischemic brain injury for 2 weeks. Neurobehavioral tests, transcriptome analysis, Western Blot, and immunohistochemistry were performed in the brain samples of cerebral cortex and hippocampus, and total infarct volume was calculated. Compared with SC, hyperacute exposure to EE was associated with greater improvement in anxiety, motor function, cognitive ability, reduced total infarct volume, and decreased neuronal death. It significantly downregulated Fas/FasL-mediated apoptosis, decreased expression of Fas, FADD, cleaved caspase-8/caspase-8, cleaved caspase-3/caspase-3, as well as Bax/Bcl-2 in both regions. Overall, the results of this study demonstrates that the early exposure to EE is a neuroprotective therapeutic translation for stroke rehabilitation through effective inhibition of extrinsic as well as intrinsic apoptotic pathways.