Intra-arterial human urinary kallidinogenase alleviates brain injury in rats with permanent middle cerebral artery occlusion through PI3K/AKT/FoxO1 signaling pathway

An urgent need exists to develop intra-arterial treatment for acute ischemic stroke in animal study. This study aimed to explore the beneficial effects of intra-arterial administration of human urinary kallidinogenase (HUK) on brain injury after permanent middle cerebral artery occlusion (pMCAO) in a rat model, and the potential underlying molecular mechanisms. Brain injury induced by pMCAO was evaluated through measuring neurological deficit scores, neuropathological changes, and inflammatory factors. Neurological deficits were observed 24 h after pMCAO and were alleviated by intra-arterial HUK treatment obviously. Inhibition of PI3K by LY294002 blocked the beneficial effect of HUK on neurological functions. In contrast to the pMCAO group, the intra-arterial HUK treatment group showed relatively more regularly arranged neurons and fewer pyknosis. Neurodegeneration, necrosis, infarct area and markers for brain injury were all ameliorated by intra-arterial HUK treatment. Moreover, a lower expression of inflammatory factors including interleukin (IL)-1 beta, IL-6, and tumor necrosis factor (TNF)-alpha, and a higher expression of IL-10 were observed in the intra-arterial HUK treatment group than that in the pMCAO group. Additionally, when comparing with pMCAO group, a lower level of caspase-3, bax, and apoptotic rate, and a higher level of bcl-2, p-PI3K, p-AKT and p-FoxO1 were observed in the pMCAO + HUK group. These results suggest that intra-arterial administration of HUK is a promising therapeutic strategy against pMCAO induced brain injury, and PI3K/AKT/FoxO1 signaling pathway may be involved in this process. (C) 2018 Elsevier B.V. All rights reserved.