Erythropoietin improves brain mitochondrial function in rats after traumatic brain injury

Mitochondria play a central role in cellular energetics, calcium homeostasis and apoptosis. Our previous study demonstrates traumatic brain injury induces brain mitochondrial dysfunction after injury. Preservation and/or restoration of mitochondrial function may be one of the strategies for neuroprotection. Erythropoietin, a hormone for erythropoiesis, also provides tissue protection against traumatic brain injury and stroke. The present study was undertaken to evaluate the effect of erythropoietin on traumatic brain injury-induced brain mitochondrial dysfunction. Traumatic brain injury decreased rates of respiration at the active state (state 3), increased that at the resting state (state 4) and consequently decreased respiratory control index (state 3/state 4 ratio) and the efficiency of ATP synthesis (the amount of ADP phosphorylated by inorganic phosphate divided by the amount of oxygen consumed during state 3 respiration). Erythropoietin administered intraperitoneally 30 minutes post-injury at 1000 U/kg partially improved mitochondrial function at day 1 post-injury. However, erythropoietin-induced improvement was not sustained at day 7 post-injury. Erythropoietin at 2000 or 5000 U/kg restored states 3 and 4 examined at day 1 post-injury to the sham levels. Consequently, the energy coupling capacities, such as respiratory control index and/or the efficiency of ATP synthesis, were also improved. The beneficial effect of erythropoietin at these doses persisted for at least 7 days post-injury. The beneficial effect of erythropoietin on brain mitochondrial function was observed with a wide therapeutic window from 5 minutes to 6 hours post-injury. Our data, for the first time, demonstrate that erythropoietin treatment restores brain mitochondrial function after traumatic brain injury, which will enhance cellular energy generation and reduce oxidative stress, strongly supporting erythropoietin as a promising agent for the therapeutic treatment of traumatic brain injury.