Research articleRotenone decreases ischemia-induced injury by inhibiting mitochondrial permeability transition in mature brains

•Rotenone, an inhibitor of CI of the mitochondrial electron transport system, blocks mPTP in adult rat brain mitochondria.•Single intravenous dose of rotenone prevents ischemia-induced mPTP, ROS and cell death in rat cortex and cerebellum.•CI of mitochondrial electron transport system has a key role in mPTP regulation in rat brains.

The mitochondrial permeability transition pore (mPTP) is thought to be implicated in brain ischemia-induced cell death. Here we sought to determine whether complex I (CI) of the mitochondrial electron transfer system may be involved in regulation of mPTP opening during ischemia and whether a specific inhibitor of this complex - rotenone can protect against ischemia-induced cell death in an experimental model of total ischemia in adult rat brains. Anesthetized Wistar rats were administered a single injection of rotenone (0.01 mg/kg) to the tail vein and brains were removed and subjected to 120 min ischemia. We found that intravenous injection of rotenone 20 min before ischemia increased resistance to Ca2+-induced mPTP opening and decreased production of reactive oxygen species (ROS) in mitochondria isolated from ischemia-damaged cortex and cerebellum. Rotenone administration before ischemia decreased infarct size in both brain regions (cortex and cerebellum). Rotenone added directly to normal, non-ischemic cortical or cerebellar mitochondria increased their resistance to Ca2+-induced mPTP opening at concentration which fully inhibited NAD-dependent mitochondrial respiration. Our data demonstrate that rotenone used intravenously may be protective against acute brain ischemia-induced injuries by inhibition of mPTP opening and ROS production. These findings suggest that CI of mitochondrial electron transfer system plays a role in mPTP regulation during cerebral ischemia in mature brains and that agents acting on CI activity may be clinically useful for stroke therapy.