Optimizing functional recovery after acute ischemic stroke through intensity and frequency of rehabilitation: The critical role of HIF-1α/PLD2/mTOR signaling mechanisms

Abstract

Objectives: This study aims to identify the most optimal rehabilitation strategy for acute ischemic stroke recovery by examining the effects of different mobilization intensities and frequencies, and investigating the underlying mechanisms involving the HIF-1α/PLD2/mTOR signaling pathway.

Methods: A total of 152 adult male Sprague-Dawley rats were subjected to 2-h middle cerebral artery occlusion (MCAO) and divided into five groups to compare high-intensity exercise versus low-intensity exercise with interval (5 cycles of 5-min exercise and 5-min rest) versus continuous (30-min continuous exercise) sessions. The groups were as followed stroke-only, stroke with high-intensity-continuous (HC) exercise, stroke with high-intensity-interval (HI) exercise, stroke with low-intensity-continuous (LC) exercise, and stroke with low-intensity-interval (LI) exercise. Brain damage was assessed by measuring infarct volume, neurological deficits, and neuronal death. The long-term functional outcomes were evaluated using the adhesive tape touch, grid walk, Rota-rod, beam balance, and forelimb placing at days 7, 14, and 28. Neuroplasticity was measured by synaptogenesis [synaptophysin (SYN), post-synaptic density protein-95 (PSD-95)], and myelination [myelin-associated glycoprotein (MAG), myelin basic protein (MBP)]. The key role of regulatory molecules- hypoxia inducible factor 1α (HIF-1α), phospholipase D2 (PLD2), and the mechanistic target of rapamycin (mTOR) pathway- was also assessed.

Results: All exercise modalities significantly reduced infarct volumes, improved neurological deficits, and enhanced functional recovery (P < 0.05). In the low-intensity exercise groups, the LC rats showed a greater reduction in infarct volume and increased functional outcomes compared to the LI group (P < 0.05). Among the high-intensity exercise groups, long-term functional outcomes were significantly improved in the HI group compared to HC (P < 0.05). Both HI and LC significantly outperformed their counterparts in protecting hippocampal CA1 neurons, promoting synaptogenesis and myelination, and enhancing neuroplasticity signaling (P < 0.05). However, no major differences were observed between HI and LC in these outcomes. Activation of the HIF-1α/PLD2/mTOR pathway was identified as a key mechanism underlying the neuroplastic effects of rehabilitation, with HIF-1α inhibition further confirming its critical role.

Conclusion: Exercise rehabilitation, particularly the LC and HI protocols, significantly improves motor function post-stroke, likely through the HIF-1α/PLD2/mTOR pathway. These findings suggest that LC and HI exercise are promising clinical rehabilitation strategies for optimizing stroke recovery, warranting further clinical investigation.

Keywords: Early rehabilitation; Frequency; High-intensity-interval (HI) exercise; Intensity; Low-intensity-continuous (LC) exercise.