NITRIC-OXIDE SYNTHASE, IMMUNOPHILINS AND POLY(ADP-RIBOSE) SYNTHETASE - NOVEL TARGETS FOR THE DEVELOPMENT OF NEUROPROTECTIVE DRUGS

During ischemic stroke, massive neural damage occurs due to excess rel ease of glutamate which acts mainly through N-methyl-D-aspartate (NMDA ) receptors. Activation of the NMDA receptor stimulates nitric oxide ( NO) production by NO synthase (NOS). NO mediates glutamate neurotoxici ty as inhibitors of NOS prevent neuronal death. FK506, an immunosuppre ssant drug, binds to FK506 binding protein (FKBP). One target of the F K506IFKBP complex is the calcium/calmodulin-dependent protein phosphat ase calcineurin, whose activity is inhibited upon interaction with FK5 06/FKBP. FK506 treatment increases phosphorylation level of calcinurin substrates including NOS. As a potent neuroprotective agent in vitro and in vivo, FK506 increases NOS phosphorylation and decreases NO prod uction. NO activates poly(ADP-ribose) synthetase (PARS), a nuclear enz yme that synthesizes poly(ADP-ribose) from NAD. Prolonged activation o f PARS depletes NAD and lowers cellular energy levels. Inhibition of P ARS also prevents NO toxicity. NOS inhibitors, immunosuppressants and PARS inhibitors may be useful agents to prevent neuronal damage during stroke.