The novel exercise-induced hormone irisin protects against neuronal injury via activation of the Akt and ERK1/2 signaling pathways and contributes to the neuroprotection of physical exercise in cerebral ischemia

Abstract

Background: Irisin is a novel exercise-induced myokine involved in the regulation of adipose browning and thermogenesis. In this study, we investigated the potential role of irisin in cerebral ischemia and determined whether irisin is involved in the neuroprotective effect of physical exercise in mice.

Materials and methods: The middle cerebral artery occlusion (MCAO) model was used to produce cerebral ischemia in mice. First, the plasma irisin levels and changes in expression of the irisin precursor protein FNDC5 in skeletal muscle were determined post ischemic stroke. Second, the association between plasma irisin levels and the neurological deficit score, brain infarct volume, or plasma concentrations of tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1β in mice with MCAO were evaluated. Third, the therapeutic effect of irisin on ischemic brain injury was evaluated in vivo and in vitro. Recombinant irisin was injected directly into the tail vein 30min after the MCAO operation, and then the effects of irisin treatment on brain infarct volume, neurological deficit, neuroinflammation, microglia activation, monocyte infiltration, oxidative stress and intracellular signaling pathway activation (Akt and ERK1/2) were measured. Irisin was also administered in cultured PC12 neuronal cells with oxygen and glucose deprivation (OGD). Finally, to assess the potential involvement of irisin in the neuroprotection of physical exercise, mice were exercised for 2weeks and an irisin neutralizing antibody was injected into these mice to block irisin 1h before the MCAO operation.

Results: The plasma irisin concentration and intramuscular FNDC5 protein expression decreased after ischemic stroke. Plasma irisin levels were negatively associated with brain infarct volume, the neurological deficit score, plasma TNF-α and plasma IL-6 concentrations. In OGD neuronal cells, irisin protected against cell injury. In mice with MCAO, irisin treatment reduced the brain infarct volume, neurological deficits, brain edema and the decline in body weight. Irisin treatment inhibited activation of Iba-1⁺ microglia, infiltration of MPO-1⁺ monocytes and expression of both TNF-α and IL-6 mRNA. Irisin significantly suppressed the levels of nitrotyrosine, superoxide anion and 4-hydroxynonenal (4-HNE) in peri-infarct brain tissues. Irisin treatment increased Akt and ERK1/2 phosphorylation, while blockade of Akt and ERK1/2 by specific inhibitors reduced the neuroprotective effects of irisin. Finally, the exercised mice injected with irisin neutralizing antibody displayed more severe neuronal injury than the exercised mice injected with control IgG.

Conclusion: Irisin reduces ischemia-induced neuronal injury via activation of the Akt and ERK1/2 signaling pathways and contributes to the neuroprotective effect of physical exercise against cerebral ischemia, suggesting that irisin may be a factor linking metabolism and cardio-cerebrovascular diseases.

Keywords: Cerebral ischemia; Irisin; Neuroinflammation; Neuroprotection; Physical exercise.