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bioRxiv · 10.64898/2025.12.23.695091

Synergistic Effect of Valproate and Constraint Induced Movement Therapy on Functional Recovery Following Ischemic Stroke in Rats: Neuroplasticity and Corticosterone Associated Mechanisms

P G, R.·Doreswamy, Y.·T.R., L.
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Abstract

Most rehabilitation paradigms primarily rely on physical stimuli, but biological enhancers may play a complementary role in optimizing adaptive outcomes. The HDACi (Histone deacetylase inhibitor) drug valproate has shown neuroprotective properties following cerebral ischemia, but how it interacts with rehabilitative training is poorly understood. Therefore, we investigated the synergistic effect of Valproate (VPA) and constraint induced movement therapy (CIMT) on functional recovery following stroke. We induced cerebral ischemia by middle cerebral artery occlusion in adult male Sprague-Dawley rats. VPA (300 mg/kg, subcutaneously) was administered within 3 hours after reperfusion and continued for 7 days, followed by CIMT for another week (6 hours/day). The study revealed a significant increase in total infarction volume in the stroke rats compared to controls on day 7 post-stroke. The behavioral assessments revealed that combined treatment with VPA and CIMT restored the neurological and motor behavior deficits. VPA treatment reduced plasma corticosterone levels and modulated heart rate variability indices in stroke rats, suggesting involvement of neuroendocrine stress responses in post stroke recovery. The electrophysiological findings reveal improved functional connectivity between the penumbral (left) motor cortex and the uninjured motor cortex following combinational treatment. The present study also examined the effects of chronic CIMT and VPA monotherapies and delayed onset CIMT (one week after stroke) on functional recovery following stroke; however, these approaches showed limited efficacy. Thus, the study concludes that VPA, along with rehabilitative training, may represent a novel strategy to improve stroke induced persistent functional deficits. HighlightsO_LIValproate may act as an adjuvant biological enhancer for physical rehabilitation following ischemic stroke. C_LIO_LICombinational therapy, when administered for two weeks following ischemic stroke, resulted in significantly greater behavioral recovery than monotherapies. C_LIO_LIValproate did not reduce infarct volume, but modulated heart rate variability indices. C_LIO_LIValproate treatment attenuated the post stroke elevation of plasma corticosterone. C_LIO_LIAn increased power spectral density, along with increased waveform synchronization between the injured and the uninjured motor cortices, was observed during fine motor movements following two weeks of combinational treatment. C_LI

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P G, R., Doreswamy, Y., T.R., L.. 2025-12-25. Synergistic Effect of Valproate and Constraint Induced Movement Therapy on Functional Recovery Following Ischemic Stroke in Rats: Neuroplasticity and Corticosterone Associated Mechanisms. https://doi.org/10.64898/2025.12.23.695091

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