An intrathecal bolus of cyclosporin A before injury preserves mitochondrial integrity and attenuates axonal disruption in traumatic brain injury

Traumatic brain injury evokes multiple axonal pathologies that contribute t o the ultimate disconnection of injured axons. In severe traumatic brain in jury, the axolemma is perturbed focally, presumably allowing for the influx of Ca2+ and initiation of Ca2+-sensitive, proaxotomy processes. Mitochondr ia in foci of axolemmal failure may act as Ca2+ sinks that sequester Ca2+ t o preserve low cytoplasmic calcium concentrations. This Ca2+ load within mi tochondria, however, may cause colloid osmotic swelling and loss of functio n by a Ca2+-induced opening of the permeability transition pore. Local fail ure of mitochondria, in turn, can decrease production of high-energy phosph ates necessary to maintain membrane pumps and restore ionic balance in foci of axolemmal permeability change. The authors evaluated the ability of the permeability transition pore inhibitor cyclosporin A (CsA) to prevent mito chondrial swelling in injured axonal segments demonstrating altered axolemm al permeability after impact acceleration injury in rat. At the electron mi croscopic level, statistically fewer abnormal mitochondria were seen in tra umatically injured axons from CsA-pretreated injured animals. Further, this mitochondrial protection translated into axonal protection in a second gro up of injured rats, whose brains were reacted with antibodies against amylo id precursor protein, a known marker of injured axons. Pretreatment with Cs A significantly reduced the number of axons undergoing delayed axotomy, as evidenced by a decrease in the density of amyloid precursor protein-immunor eactive axons. Collectively, these studies demonstrate that CsA protects bo th mitochondria and the related axonal shaft, suggesting that this agent ma y be of therapeutic use in traumatic brain injury.