Heme oxygenase-1 induction prevents neuronal damage triggered during mitochondrial inhibition: role of CO and bilirubin.
Heme oxygenase (HO) catalyzes the breakdown of heme to iron, carbon monoxide (CO), and biliverdin, the latter being further reduced to bilirubin (BR). A protective role of the inducible isoform, HO-1, has been described in pathological conditions associated with reactive oxygen species (ROS) and oxidative damage. The aim of this study was to investigate the role of HO-1 in the neurotoxicity induced by the mitochondrial toxin 3-nitropropionic acid (3-NP) in primary cultures of cerebellar granule neurons (CGNs). Toxicity of 3-NP is associated with ROS production, and this metabolic toxin has been used to mimic pathological conditions such as Huntington's disease. We found that cell death caused by 3-NP exposure was exacerbated by inhibition of HO with tin mesoporphyrin (SnMP). In addition, HO-1 up-regulation induced by the exposure to cobalt protoporphyrin (CoPP) before the incubation with 3-NP, prevented the cell death and the increase in ROS induced by 3-NP. Interestingly, addition of SnMP to CoPP-pretreated CGNs exposed to 3-NP, abolished the protective effect of CoPP suggesting that HO activity was responsible for this protective effect. This was additionally supported by the fact that CORM-2, a CO-releasing molecule, and BR, were able to protect against cell death and the increase in ROS induced by 3-NP. Our data clearly show that HO-1 elicits in CGNs a neuroprotective action against the neurotoxicity of 3-NP and that CO and BR may be involved, at least in part, in this protective effect. The present results increase our knowledge about the role of HO-1 in neuropathological conditions.
Orozco-Ibarra
Marisol
M
Facultad de Química, Departamento de Biología, Universidad Nacional Autónoma de México, Ciudad Universitaria, 04510 México DF, Mexico.
Estrada-Sánchez
Ana María
AM
Massieu
Lourdes
L
Pedraza-Chaverrí
José
J
D000818:Animals; D001663:Bilirubin / Q000378:metabolism / Q000494:pharmacology*; D002248:Carbon Monoxide / Q000378:metabolism / Q000494:pharmacology*; D002531:Cerebellum / Q000166:cytology; D004790:Enzyme Induction; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009574:Nitro Compounds / Q000633:toxicity; D011422:Propionates / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism
D009574:Nitro Compounds; D011422:Propionates; D017382:Reactive Oxygen Species; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1; C015392:3-nitropropionic acid; D001663:Bilirubin