Recombinant Irisin Therapy Alters Brain Transcriptome and Protects Against Ischemic Damage in Middle-Aged Rats

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BACKGROUND: Irisin, a myokine cleaved from its precursor FNDC5 (fibronectin type III domain-containing protein 5) following exercise or low-frequency whole-body vibration, regulates energy metabolism and insulin sensitivity. This study examines irisin’s therapeutic potential in stroke in rats. METHODS: Adult Sprague-Dawley rats of both sexes underwent transient middle cerebral artery occlusion (90 minutes) or sham surgery. After 4.5 hours, they were randomized to receive saline or irisin treatment (0.1, 0.2, and 0.8 μg/g body weight). Infarct volume was quantified 1 day after transient middle cerebral artery occlusion using 2,3,5-triphenyltetrazolium chloride staining. In a subsequent study, reproductively senescent female rats received either saline or 0.2 μg/g body weight irisin at 4.5 hours post-transient middle cerebral artery occlusion, followed by weekly treatments for a month. Sensorimotor and cognitive functions were assessed using the cylinder test and Morris water maze. Ipsilateral cortical tissue was collected from a subset of the reproductive senescence rats following 2 weeks of treatment for RNA sequencing and real-time quantitative polymerase chain reaction analysis. RESULTS: Irisin (0.2 μg/g) significantly reduced infarct volume by 50% in females and 36% in males compared with their respective saline groups. In reproductive senescence females, irisin treatment for a month improved contralateral limb use by day 7 and enhanced spatial learning in the Morris water maze, reducing latency to find the hidden platform on the fourth day of testing (16.5 sec versus saline; P <0.05) and increasing time spent in the target quadrant during the probe trial (9.3 sec versus saline; P <0.05). Irisin therapy significantly altered cortical gene expression, with 332 genes upregulated and 136 downregulated. Gene ontology analysis revealed genes linked to the extracellular matrix were significantly upregulated, which was confirmed by increased expression of the cell-surface integrin αVβ5, known to interact with irisin. CONCLUSIONS: Post-transient middle cerebral artery occlusionirisin therapy modulates the transcriptome, enhancing motor and cognitive function while protecting against ischemic brain damage in middle-aged female rats.

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