Postinjury cyclosporin A administration limits axonal damage and disconnection in traumatic brain injury

Recent observations concerning presumed calcium-induced mitochondrial damag e and focal intraaxonal proteolysis in the pathogenesis of traumatic axonal injury (TAI) have opened new perspectives for therapeutic intervention. St udies from our laboratory demonstrated that cyclosporin A (CsA), a potent i nhibitor of Ca2+-induced mitochondrial damage, administered 30 min prior to traumatic brain injury preserved mitochondrial integrity in those axonal f oci destined to undergo delayed disconnection. We attributed this neuroprot ection to the inhibition by CsA of mitochondrial permeability transition (M PT). Additional experiments proved that CsA pretreatment also significantly reduced calcium-induced, calpain-mediated spectrin proteolysis (CMSP) and neurofilament compaction (NFC), pivotal events in the pathogenesis of axona l failure and disconnection. Given these provocative findings the goal of t he current study was to evaluate the potential of CsA to inhibit calcium-in duced axonal damage in a more clinically relevant postinjury treatment para digm. To this end, cyclosporin A was administered intrathecally to Sprague Dawley rats 30 min following impact acceleration traumatic brain injury. Th e first group of animals were sacrificed 120 min postinjury and the density of CMSP and NFC immunoreactive damaged axonal segments of CsA-treated and vehicle-treated injured animals were quantitatively analyzed. A second grou p of CsA- versus vehicle-treated rats was sacrificed at 24 h postinjury to compare the density of damaged axons displaying beta amyloid precursor prot ein (APP) immunoreactivity, a signature protein of axonal perturbation and disconnection. Postinjury CsA administration resulted in a significant decr ease (>60%) in CMSP/NFC immunoreactivity in corticospinal tracts and medial longitudinal fasciculi. A similar decrease was detected in the density of APP inmunoreactive damaged axons, indicating an attenuation of axonal disco nnection at 24 h postinjury in CsA-treated animals. These results once agai n suggest that the maintenance of the functional integrity of the mitochond ria can prevent TAI, presumably via the preservation of the local energy ho meostasis of the axon. Moreover and perhaps more importantly, these studies also demonstrate the efficacy of CsA administration when given in the earl y posttraumatic period. Collectively, our findings suggest that a therapeut ic window exists for the use of drugs targeting mitochondria and energy reg ulation in traumatic brain injury.