Neuroprotective effects of (+/-)-huprine Y on in vitro and in vivo models of excitoxicity damage.
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 microM glutamate, as well as, 10 microM MK-801, a NMDA receptor antagonist, in a significant manner. On the other hand, intracellular calcium increase induced by NMDA (200 microM), measured by fura-2 fluorescence, was prevented by (+/-)-huprine Y with an EC(50) of 12.44 microM, 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 [(3)H]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.
Canudas
Anna M
AM
Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Universitat de Barcelona, Barcelona, Spain.
Pubill
David
D
Sureda
Francesc X
FX
Verdaguer
Ester
E
Camps
Pelayo
P
Muñoz-Torrero
Diego
D
Jiménez
Andrés
A
Camins
Antoni
A
Pallàs
Mercè
M
D000634:Aminoquinolines / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005911:Gliosis / Q000139:chemically induced / Q000517:prevention & control; D018698:Glutamic Acid / Q000633:toxicity; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D007546:Isoquinolines / Q000493:pharmacokinetics; D051379:Mice; D018832:Molecular Chaperones; D009043:Motor Activity / Q000187:drug effects; D016202:N-Methylaspartate / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000096:biosynthesis; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000633:toxicity*; D009574:Nitro Compounds; D011422:Propionates; D051381:Rats
D000634:Aminoquinolines; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D006576:Heterocyclic Compounds, 4 or More Rings; C486113:Hsbp1 protein, mouse; C486114:Hspb1 protein, rat; D007546:Isoquinolines; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D018696:Neuroprotective Agents; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; C404519:huprine Y; D018698:Glutamic Acid; D016202:N-Methylaspartate; C015392:3-nitropropionic acid; D002118:Calcium; C037850:PK 11195