Systemic irisin treatment modulates cognitive function through VEGF-associated hippocampal vascular signaling in chronic cerebral hypoperfusion

Abstract

Vascular dementia (VaD), primarily caused by chronic cerebral hypoperfusion (CCH), is characterized by pro gressive cognitive decline associated with neurovascular dysfunction. The present study aimed to investigate whether systemic administration of irisin, an exercise-induced myokine, modulates cognitive performance and VEGF-associated angiogenic signaling in the hippocampus under CCH conditions. Thirty-eight adult male Wistar albino rats were randomly assigned to five groups: control, sham, irisin, ischemia, and ischemia + irisin. CCH was induced via permanent bilateral common carotid artery occlusion. Irisin (100 ng/kg) was administered intraperitoneally three times per week for four weeks. Cognitive performance was assessed using the Morris Water Maze, and VEGF-positive vascular profiles were quantified within a standardized hippocampal area (1 mm2 per section). CCH resulted in significant impairments in spatial learning and memory, accompanied by a reduction in VEGF-positive vascular profiles in the hippocampus. In healthy rats, irisin administration was associated with improved memory performance and increased VEGF-positive vascular profiles. In ischemic rats, irisin treatment was linked to partial improvements in memory parameters and VEGF-associated vascular changes, although these effects did not reach statistical significance. Learning-phase outcomes were more var iable. Notably, the number of VEGF-positive vascular profiles positively correlated with spatial memory per formance. These findings suggest that beyond its known neuroprotective properties, irisin may contribute to cognitive support through modulation of angiogenesis-associated signaling under CCH. While further studies are required to clarify optimal dosing strategies and mechanistic pathways, irisin may represent a promising adjunctive candidate for vascular cognitive impairment, particularly in individuals unable to engage in regular physical exercise.