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Nicotinic receptor activation by epibatidine induces heme oxygenase‐1 and protects chromaffin cells against oxidative stress
Author(s) -
Egea Javier,
Rosa Angelo O.,
Cuadrado Antonio,
García Antonio G.,
López Manuela G.
Publication year - 2007
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2007.04665.x
Subject(s) - epibatidine , heme oxygenase , chemistry , chelerythrine , pharmacology , oxidative stress , nicotinic acetylcholine receptor , biology , biochemistry , nicotinic agonist , protein kinase c , kinase , heme , receptor , enzyme
Activation of neuronal nicotinic acetylcholine receptors (nAChR) provides neuroprotection against different toxic stimuli that often lead to overproduction of reactive oxygen species (ROS) and cell death. ROS production has been related with disease progression in several neurodegenerative pathologies such as Alzheimer’s or Parkinson’s diseases. In this context, we investigated here if the exposure of bovine chromaffin cells to the potent nAChR agonist epibatidine protected against rotenone (30 μmol/L) plus oligomycin (10 μmol/L) (rot/oligo) toxicity, an in vitro model of mitochondrial ROS production. Epibatidine induced a concentration‐ and time‐dependent protection, which was maximal at 3 μmol/L after 24 h. Pre‐incubation with dantrolene (100 μmol/L) (a blocker of the ryanodine receptor channel), chelerythrine (1 μmol/L) (a protein kinase C inhibitor), or PD98059 (50 μmol/L) (a MEK inhibitor), aborted epibatidine‐elicited cytoprotection. Mitochondrial depolarization, ROS, and caspase 3 active produced by rot/oligo were also prevented by epibatidine. Epibatidine doubled the amount of heme oxygenase‐1 (HO‐1), a critical cell defence enzyme against oxidative stress. Furthermore, the HO‐1 inhibitor Sn(IV) protoporphyrin IX dichloride reversed the epibatidine protecting effects and HO‐1 inducer Co (III) protoporphyrin IX dichloride exhibited neuroprotective effects by itself. The results of this study point to HO‐1 as the cytoprotective target of nAChR activation through the following pathway: endoplasmic reticulum Ca 2+ ‐induced Ca 2+ ‐release activates the protein kinase C/extracellular regulated kinase/HO‐1 axis to mitigate mitochondrial depolarization and ROS production. This study provides a mechanistic insight on how nAChR activation translates into an antioxidant and antiapoptotic signal through up‐regulation of HO‐1.