Efficacy of a new neuroprotective agent, Gacyclidine, in a model of rat spinal cord injury

Prevention of the immediate excitotoxic phase occurring in response to spin al cord injury (SCI) is a major issue to reduce the neuronal damage respons ible for any ensuing motor deficits. The present study evaluated the neurop rotective efficacy of three noncompetitive NMDA receptor antagonists: Gacyc lidine (GK-11), a new compound, Dizocilpine (MK-801), and Cerestat (CNS-110 2) in a rat spinal cord contusion model. To mimic human SCI, a standardized model of rat spinal cord closed contusion in which animals spontaneously a nd progressively recover from the induced paraplegia was employed. Such mod el, characterized by a slow recovery of hindlimb locomotor function enables easy quantification of the neuroprotection at both the behavioral and cell ular level. The animals were treated intravenously with the respective drug s 10 min after the spinal contusion. The dose range study suggested that 1 mg/kg of Gacyclidine was the most effective dose to promote functional reco very in reducing by half the time needed to reach full locomotor recovery. Racemate and enantiomers of Gacyclidine showed similar neuroprotective effe cts, but treatment with the enantiomers were not as efficacious in promotin g full functional recovery. Similarly, a prolonged treatment with the racem ate was not as efficious as a single dose, suggesting that a prolonged bloc kade of the amino-excitatory neurotransmission may be deleterious. Finally, Dizocilpine and Cerestat treatments induced only a partial and delayed neu roprotective effect compared to Gacyclidine. Neuroprotection characterized by a reduction of the cystic cavity and of the astrogliosis was observed wi th all treatments. As Gacyclidine is already in clinical trials, the presen t findings suggest the premise that it is a promising agent for limiting th e initial neuronal damage induced by CNS trauma leading to better functiona l recovery.