Chronic exposure to 2,5-hexanedione impairs the glutamate-nitric oxide-cyclic GMP pathway in cerebellar neurons in culture and in rat brain in vivo.
2,5-Hexanedione is a neurotoxic metabolite of hexane. The mechanisms of its neurotoxicity remain unclear. We assessed whether chronic exposure to 2,5-hexanedione affects the glutamate-nitric oxide-cGMP pathway in primary cultures of cerebellar neurons and/or in the cerebellum of rats. Chronic exposure of cultured cerebellar neurons to 2,5-hexanedione (200 microM) reduced by approximately 50% NMDA-induced formation of cGMP. Activation of soluble guanylate cyclase by nitric oxide was reduced by 46%. This treatment reduced the content of neuronal nitric oxide synthase and soluble guanylate cyclase in neurons by 23 and 20%, respectively. In the cerebellum of rats chronically exposed to 2,5-hexanedione (in the drinking water) NMDA-induced formation of cGMP was reduced by 55% as determined by in vivo brain microdialysis. Activation of soluble guanylate cyclase by nitric oxide was reduced by 65%. The content of neuronal nitric oxide synthase and of soluble guanylate cyclase was reduced by 25 and 21%, respectively, in the cerebellum of these rats. The effects are the same in both systems, indicating that cultured neurons are a good model to study the mechanisms of neurotoxicity of 2,5-hexanedione. These results indicate that chronic exposure to 2,5-hexanedione affects the glutamate-nitric oxide-cGMP pathway at different steps both in cultured neurons and in cerebellum of the animal in vivo. The alteration of this pathway may contribute to the neurotoxic effects of 2,5-hexanedione.
Hernandez-Viadel
M
M
Laboratory of Neurobiology, Instituto de Investigaciones Citológicas, FVIB, Amadeo de Saboya, 4, 46010 Valencia, Spain.
Montoliu
C
C
Monfort
P
P
Canales
J J
JJ
Erceg
S
S
Rowan
M
M
Ceccatelli
S
S
Felipo
V
V
D000818:Animals; D002478:Cells, Cultured; D002531:Cerebellum / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D006588:Hexanones / Q000494:pharmacology*; D017551:Microdialysis; D009474:Neurons / Q000378:metabolism*; D009498:Neurotoxins / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D006588:Hexanones; D009498:Neurotoxins; D009569:Nitric Oxide; D018698:Glutamic Acid; C011269:2,5-hexanedione; D006152:Cyclic GMP