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Environmental enrichment combined with fasudil promotes motor function recovery and axonal regeneration after stroke.

ABSTRACT: Fasudil, a Rho-associated protein kinase (ROCK) inhibitor, has a protective effect on the central nervous system. In addition, environmental enrichment is a promising technique for inducing the recovery of motor impairments in ischemic stroke models. The present study aimed to explore whether environmental enrichment combined with fasudil can facilitate motor function recovery and induce cortical axonal regeneration after stroke. First, a mouse model of ischemic cerebral stroke was established by photochemical embolization of the left sensorimotor cortex. Fasudil solution (10 mg/kg per day) was injected intraperitoneally for 21 days after the photothrombotic stroke. An environmental enrichment intervention was performed on days 7-21 after the photothrombotic stroke. The results revealed that environmental enrichment combined with fasudil improved motor function, increased growth-associated protein 43 expression in the infarcted cerebral cortex, promoted axonal regeneration on the contralateral side, and downregulated ROCK, p-LIM domain kinase (LIMK)1, and p-cofilin expression. The combined intervention was superior to monotherapy. These findings suggest that environmental enrichment combined with fasudil treatment promotes motor recovery after stroke, at least partly by stimulating axonal regeneration. The underlying mechanism might involve ROCK/LIMK1/cofilin pathway regulation. This study was approved by the Institutional Animal Care and Use Committee of Fudan University, China (approval No. 20160858A232) on February 24, 2016.

SUBMITTER: Zhu YT

PROVIDER: S-EPMC8374579 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Environmental enrichment (EE) confers motor and cognitive recovery in pre-clinical models of traumatic brain injury (TBI), and neurogenesis has been attributed to mediating the benefits. Whether that ascription is correct has not been fully investigated. Hence, the goal of the current study is to further clarify the possible role of learning-induced hippocampal neurogenesis on functional recovery after cortical impact or sham injury by utilizing two EE paradigms (i.e., early + continuous, initiated immediately after TBI and presented 24?h/day; and delayed + abbreviated, initiated 4 days after TBI for 6?h/day) and comparing them to one another as well as to standard (STD) housed controls. Motor and cognitive performance was assessed on post-operative Days 1-5 and 14-19, respectively, for the STD and early + continuous EE groups and on Days 4-8 and 17-22, for the delayed + abbreviated EE groups. Rats were injected with bromodeoxyuridine (BrdU, 500?mg/ kg; intraperitoneally) for 3 days (12?h apart) before cognitive training and sacrificed 1 week later for quantification of BrdU+ and doublecortin (DCX+) labeled cells. Both early + continuous and delayed + abbreviated EE promoted motor and cognitive recovery after TBI, relative to STD (p?<?0.05), and did not differ from one another (p?>?0.05). However, only early + continuous EE increased DCX+ cells beyond the level of STD-housed controls (p?<?0.05). No effect of EE on non-injured controls was observed. Based on these data, two novel conclusions emerged. First, EE does not need to be provided early and continuously after TBI to confer benefits, which lends credence to the delayed + abbreviated EE paradigm as a relevant pre-clinical model of neurorehabilitation. Second, the functional recovery observed after TBI in the delayed + abbreviated EE paradigm is not contingent on increased hippocampal neurogenesis. Future studies will elucidate alternate viable mechanisms mediating the benefits induced by EE.

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Environmental enrichment combined with fasudil promotes motor function recovery and axonal regeneration after stroke.

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