Remote Ischemic Preconditioning Exerts Neuroprotective Effects Via the PGC-1α/FNDC5/BDNF Pathway in Focal Brain Ischemia of Rats.

[UNLABELLED] Remote ischemic preconditioning (RIpreC) is a strategy for remotely protecting target organs such as the brain by applying brief ischemia and reperfusion to the limb. However, the mechanisms underlying RIpreC-induced neuroprotection remain unclear. We aimed to investigate the neuroprotective effects of RIpreC on the peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α)/ fibronectin type III domain-containing protein 5 (FNDC5)/ brain-derived neurotrophic factor (BDNF) pathway in rat models of ischemic stroke. Rats were assigned to three groups: ischemia-reperfusion injury (IR,  = 11), RIpreC and IR (RIpreC,  = 11), and intact control (control,  = 5). RIpreC was performed approximately 24 h before IR injury. IR injury induced by middle cerebral artery occlusion (MCAO) for 60 min. At 2 days after MCAO, brain infarction, sensorimotor functions, and the expression of PGC-1α, FNDC5/irisin, BDNF, B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), caspase-3, terminal deoxynucleotidyl transferase-mediated biotinylated dUTP nick end labeling (TUNEL)-positive cells, and the p-Akt/Akt ratio were examined. In addition, SR-18,292, a PGC-1α inhibitor, was administered 1 h before MCAO. The RIpreC group had a significantly reduced infarct volume and ameliorated sensorimotor function compared with the IR group. RIpreC increased the expression of PGC-1α, FNDC5, BDNF, and the p-Akt/Akt ratio in the ischemic brain. Bax/Bcl-2 ratios, as well as perilesional caspase-3- and TUNEL-positive neuronal cells, decreased following RIpreC. Inhibition of PGC-1α blunted the RIpreC-induced neuroprotective and neurorestorative effects. This study suggests that RIpreC induced BDNF expression through a PGC-1α/FNDC5 pathway after ischemic stroke, thereby exerting neuroprotection and ameliorating post-stroke neurobehavioral dysfunctions.

[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1007/s12975-026-01422-z.