Abstract

We have investigated the neuroprotective effects of ()-huprine Y on excitotoxic lesions in rat cerebellar granule cells (CGCs). (+/-)-Huprine Y prevented cell death induced by 100 muM glutamate, as well as, 10 muM MK-801, a NMDA receptor antagonist, in a significant manner. On the other hand, intracellular calcium increase induced by NMDA (200 muM), measured by fura-2 fluorescence, was prevented by (+/-)-huprine Y with an EC50 of 12.44 muM, which evidences the modulatory action of this compound on NMDA-induced calcium currents. In vivo, we have studied (+/-)-huprine Y neuroprotective effects on striatal lesions induced by the subacute administration of the mitochondrial toxin 3-nitropropionic acid (3-NP, 30 mg/kg, ip, for 10 days). We have assessed that both the behavioral and the morphological consequences of the lesion were prevented by pretreatment with (+/-)-huprine Y (2.5 mg/kg/twice a day, ip). Striatal gliosis induced by 3-NP treatment was prevented by (+/-)-huprine Y pretreatment, as demonstrated by the attenuation of both the increase in [H-3]PK 11195 specific binding indicative of microgliosis and the expression of hsp27 kDa, a chaperone expressed mainly in astrocytes. In conclusion, (+/-)-huprine Y attenuated excitotoxic-induced lesions, both in vitro and in vivo, and further evidence is provided for the potential use of this compound in the prevention of neurodegenerative disorders. (C) 2003 Elsevier Science (USA). All rights reserved.