Irisin ameliorates neuroinflammation and neuronal apoptosis through integrin [alpha]V[beta]5/AMPK signaling pathway after intracerebral hemorrhage in mice

Background Neuroinflammation is a crucial factor in the development of secondary brain injury after intracerebral hemorrhage (ICH). Irisin is a newly identified myokine that confers strong neuroprotective effects in experimental ischemic stroke. However, whether this myokine can exert neuroprotection effects after ICH remains unknown. This study aimed to investigate the impact of irisin treatment on neuroinflammation and neuronal apoptosis and the underlying mechanism involving integrin [alpha]V[beta]5/AMPK pathway after ICH. Methods Two hundred and eighty-five adult (8-week-old) male C57BL/6 mice were randomly assigned to sham and ICH surgery groups. ICH was induced via intrastriatal injection of autologous blood. Irisin was administered intranasally at 30 min after ICH. To elucidate the underlying mechanism, cilengitide (a selective integrin [alpha]V[beta]5 inhibitor) and dorsomorphin (a selective phosphorylated AMPK inhibitor) were administered before irisin treatment. The short- and long-term neurobehavior tests, brain edema, quantitative-PCR, western blotting, Fluoro-Jade C, TUNEL, and immunofluorescence staining were performed to assess the neurofunctional outcome at the level of molecular, cell, histology, and function. Results Endogenous irisin and its receptor, integrin [alpha]V[beta]5, were increased, peaked at 24 h after ICH. irisin post-treatment improved both short- and long-term neurological functions, reduced brain edema after ICH. Interestingly, integrin [alpha]V[beta]5 was mainly located in the microglia after ICH, and irisin post-treatment inhibited microglia/macrophage pro-inflammatory polarization and promoted anti-inflammatory polarization. Moreover, irisin treatment inhibited neutrophil infiltration and suppressed neuronal apoptotic cell death in perihematomal areas after ICH. Mechanistically, irisin post-treatment significantly increased the expression of integrin [alpha]V[beta]5, p-AMPK and Bcl-2, and decreased the expression of IL-1[beta], TNF-[alpha], MPO, and Bax following ICH. The neuroprotective effects of irisin were abolished by both integrin [alpha]V[beta]5 inhibitor cilengitide and AMPK inhibitor dorsomorphin. Conclusions This study demonstrated that irisin post-treatment ameliorated neurological deficits, reduced brain edema, and ameliorated neuroinflammation and neuronal apoptosis, at least in part, through the integrin [alpha]V[beta]5/AMPK signaling pathway after ICH. Thus, irisin post-treatment may provide a promising t