Neuroprotective effects of (±)-huprine Y on in vitro and in vivo models of excitoxicity damage

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 μM glutamate, as well as, 10 μM MK-801, a NMDA receptor antagonist, in a significant manner. On the other hand, intracellular calcium increase induced by NMDA (200 μM), measured by fura-2 fluorescence, was prevented by (±)-huprine Y with an EC 50 of 12.44 μM, 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 [ 3H]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.