Intermittent hypoxia ameliorates behavioral deficits and exerts neurorestoration in a mouse photothrombotic stroke model.

BACKGROUND

Ischemic stroke disproportionately impacts the elderly with a higher risk and poor repair. Current therapeutic options are constrained by narrow time windows, strict contraindications, and suboptimal efficacy in older patients, leaving a critical unmet clinical need. Hypoxia-based interventions exert preclinical neuroprotective effects, yet the effects and underlying mechanisms of intermittent hypoxia (IH) in elderly patients with ischemic stroke remain unclear.

METHODS

This study tested IH in 25-month-old C57BL/6J mice with photothrombotic (PT) stroke, randomizing to Control, PT, or PT+IH groups. IH post-conditioning was administered a total of 7 sessions on days 3-16. One session consists of a 10-min phase with 8% oxygen, followed by a 10-min phase with room air. Behavioral changes were measured through the maximal grip strength test, beam balance test, cylinder test, adhesive removal test, grid-walking test, and open field test. Neuropathological changes and potential molecular mechanisms were analyzed via immunofluorescence staining and western blotting.

RESULTS

Our findings demonstrated that IH treatment significantly reduced cortical infarct volume and ameliorated PT-induced sensorimotor deficits in aged mice. Furthermore, IH alleviated neuronal damage and apoptosis, preserved cerebrovascular morphology, and attenuated excessive astrocyte-vasculature interactions. Mechanistically, IH upregulated astrocyte-specific hypoxia-inducible factor 1α (HIF-1α), mitigated mitochondrial fragmentation, and shifted the polarization of microglia and astrocytes from pro-inflammatory (M1/A1) to anti-inflammatory (M2/A2) phenotypes. Collectively, these effects contributed to enhanced neurogenesis and angiogenesis in the peri-infarct region.

CONCLUSION

In conclusion, these findings confirm IH's neurorestoration in aged stroke mice, potentially via HIF-1α-related regulation of mitochondrial function, glial polarization, and vascular integrity, supporting its translational potential.