Effects of acety-l-carnitine treatment on mitochondrial function, tissue sparing and hind limb locomotor recovery following contusion spinal cord injury

This proposal focuses on directly targeting mitochondrial dysthnction as a therapeutic intervention for acute spinal cord injury (Sd). The fundamental concept underlying this proposal is that Sd-induced excitotoxicity increases mitochondrial Ca2~ cyclingloverload, ultimately leading to mitochondrial dysfunction, increased reactive oxygen species (ROS) production and concurrent glutathione depletion. This premise is based on our published work demonstrating a loss of mitochondrial bioenergetics, increased mitochondrial ROS production, and increased oxidative damage occur following acute contusion Sd in rats. We have also demonstrated that strategies which maintain mitochondrial homeostasis andlor reduce their oxidative damage are neuroprotective following acute contusion Sd, solidif~'ing the important roles of mitochondrial-derived excitotoxicity and elevated ROS production in SCI pathology. Consistent with this view, the only compounds which have shown modest efficacy in human Sd clinical trials are methylprednisolone (MP) and tirilazad, both of which are thought to act by inhibiting post-traumatic lipid peroxidation. Mitochondria are the major site of glutathionc production and utilization in cells. However, mitochondria are also the major source of ROS in cells, particularly following injury, thus they are also the major site of oxidative damage. This results in a cycle of mitochondrial ROS production begetting mitochondrial oxidative damage, which further increases ROS production. Our central hypothesis is that impaired mitochondrial bioenergetics, oxidative damage and mitochondrial calcium load capacity will be preserved with acetyl-L-carnitine (ALC) treatment following acute contusion SCI. Notably, ALC provides sufficient influx of reducing equivalent (NADH) and other compounds essential for energy production and homeostasis in mitochondria. Therefore, we will establish a therapeutic time window of ATJC administration post-SCI, using a dosage we have found effective in preliminary studies. Furthermore, we hypothesize that prolonged ALC treatment post-SCI will increase tissue sparing and hind limb functional recovery following chronic contusion SCI. Thus, our pharmacological approach is designed to provide neuroprotection and improve functional outcome following SCI by maintaining normal mitochondrial function. Consistent with these ideas, our preliminary results demonstrate that ALC administered acutely following contusion SCI indeed preserves mitochondrial respiration rates and increases tissue sparing compared to vehicle treated injured rats. Thus, results from the proposed studies have direct clinical implications regarding therapeutic strategies designed to foster neuroprotection by maintaining mitochondrial integrity post-injury.