Gacyclidine is a new
phencyclidine derivative with neuroprotective properties. Tritiated
gacyclidine and its enantiomers bind to
NMDA receptors with binding parameters similar to those of other non-competitive
NMDA receptor antagonists. The (-)enantiomer, (-)GK11, exhibits an affinity (2.5 nM) similar to that of
dizocilpine (MK-801), while the (+)enantiomer, (+)
GK11, has
a 10 times lower affinity. When its interaction with
NMDA receptors is prevented,
gacyclidine binds also to "non-
NMDA" binding sites which are mainly located in the molecular layer of the cerebellum on the dendritic tree of Purkinje cells. These binding sites do not appear to be related to any known
neurotransmitters. In primary cortical cultures,
gacyclidine and its enantiomers, at 0.1 to 5.0 microM, prevent
glutamate-induced neuronal death. In rats, in vivo neurotoxicity of
gacyclidine is far low than that of
MK-801. No necrotic neurons were detected in animals sacrificed at 18 or 96 h
after treatment with
gacyclidine (1, 5, 10 or 20 mg/kg i.v.). At the highest (20 mg/kg) but not the lower doses (1-100 mg/kg) electron microscopy revealed the presence of few cytoplasmic or intramitochondrial vacuoles. In
soman-treated monkeys
gacyclidine enhanced neuroprotective activity of "three drugs cocktail" (
atropine +
diazepam +
pralidoxime). Moreover, in rats,
gacyclidine exerts a dose- and time-dependent neuroprotection in three models of spinal cord lesion. Beneficial effects of
gacyclidine include reduction of lesion size and improvement of functional parameters after injury. In
traumatic brain injury models
gacyclidine improves also behavioral parameters and neuronal survival. Optimal protection is obtained when
gacyclidine is administered at 0 to 30 min after injury. It is, therefore, concluded that
gacyclidine exhibits
neuroprotective effects similar to those of other
NMDA receptor antagonists, with the advantage of being substantially less neurotoxic maybe due to its interaction with "non-
NMDA" binding sites.