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.