tacrolimus and Contusions

We report here that activation of the caspase-3 apoptotic cascade in spinal cord injury is regulated, in part, by calcineurin-mediated BAD dephosphorylation. BAD, a proapoptotic member of the bcl-2 gene family, is rapidly dephosphorylated after injury, dissociates from 14-3-3 in the cytosol, and translocates to the mitochondria of neurons where it binds to Bcl-x(L). Pretreatment of animals with FK506, a potent inhibitor of calcineurin activity, or MK801, an NMDA glutamate receptor antagonist, blocked BAD dephosphorylation and abolished activation of the caspase-3 apoptotic cascade. These findings extend previous in vitro observations and are the first to implicate the involvement of glutamate-mediated calcineurin activation and BAD dephosphorylation as upstream, premitochondrial signaling events leading to caspase-3 activation in traumatic spinal cord injury.

Topics: 14-3-3 Proteins; Animals; Apoptosis; bcl-Associated Death Protein; bcl-X Protein; Calcineurin; Calcineurin Inhibitors; Carrier Proteins; Caspase 3; Caspases; Contusions; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Fluorescent Antibody Technique; Immunoblotting; Immunosuppressive Agents; Mitochondria; Neurons; Neuroprotective Agents; Phosphorylation; Proto-Oncogene Proteins c-bcl-2; Rats; Signal Transduction; Spinal Cord Injuries; Tacrolimus; Tyrosine 3-Monooxygenase