Amifostine ameliorates cerebral ischaemia-reperfusion injury via p38-mediated oxidative stress and mitochondrial dysfunction.

Amifostine is a cytoprotective compound that is beneficial in ischaemic stroke cases. However, the neuroprotective effect of amifostine on ischaemia/reperfusion (I/R)-induced brain injury and its underlying mechanism are still poorly understood. Herein, we constructed an animal model of middle cerebral artery occlusion and reperfusion (MCAO/R) injury and an in vitro model of oxygen and glucose deprivation and reperfusion (OGD/R) injury. After administration of amifostine, we found significant improvements in neurological deficits, infarct size, and cerebral oedema. Moreover, amifostine alleviated histopathological alteration and increased the number of surviving neurons. Biochemical analysis showed that treatment with amifostine obviously improved the brain damage of MCAO/R mice, as manifested by a decrease in reactive oxygen species (ROS) and malondialdehyde (MDA) generation, and an increase in superoxide dismutase (SOD) activity. Moreover, amifostine decreased the mitochondrial membrane potential (m) loss, and cytochrome c escaping to cytoplasm, but increased the ATP level. In vitro, amifostine also showed an antioxidant effect, which was reflected by the reduced ROS generation, decreased mitochondrial superoxide generation, increased total SOD, SOD1 (Cu/Zn SOD, cytoplasmic SOD), and SOD2 (mitochondrial SOD) activities, and decreased m loss. Furthermore, amifostine suppressed neuronal apoptosis, accompanied by the reduction of Bax, cleaved caspase-9, cleaved caspase-3, and Bcl-2 upregulation. Amifostine also reduced the expression of p-p38 (Thr 180/Tyr 182) in vivo and in vitro. In short, amifostine exhibits a protective effect on cerebral I/R damage through modulating p38-related oxidative stress, mitochondrial dysfunction, and apoptosis.