Nicotinic receptor activation by epibatidine induces heme oxygenase-1 and protects chromaffin cells against oxidative stress
Article first published online: 20 APR 2007
Journal of Neurochemistry
Volume 102, Issue 6, pages 1842–1852, September 2007
How to Cite
Egea, J., Rosa, A. O., Cuadrado, A., García, A. G. and López, M. G. (2007), Nicotinic receptor activation by epibatidine induces heme oxygenase-1 and protects chromaffin cells against oxidative stress. Journal of Neurochemistry, 102: 1842–1852. doi: 10.1111/j.1471-4159.2007.04665.x
- Issue published online: 1 MAY 2007
- Article first published online: 20 APR 2007
- Received November 24, 2006; revised manuscript received March 28, 2007; accepted April 4, 2007.
- extracellular regulated kinase 1/2;
- heme oxygenase-1;
- neuronal nicotinic acetylcholine receptors;
- reactive oxygen species
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 Ca2+-induced Ca2+-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.