Alpha7 nicotinic receptor activation protects against oxidative stress via heme-oxygenase I induction

作者：Navarro Elisa; Buendia Izaskun; Parada Esther; Leon Rafael; Jansen Duerr Pidder; Pircher Haymo; Egea Javier; Lopez Manuela G^*

来源：Biochemical Pharmacology, 2015, 97(4): 473-481.

DOI：10.1016/j.bcp.2015.07.022

• Oxidative stress
• Organotypic cultures
• alpha 7 nicotinic receptor
• Neuroprotection
• Protein aggregation
• Heme-oxygenase I

Subchronic oxidative stress and inflammation are being increasingly implicated in the pathogenesis of numerous diseases, such as Alzheimer's or Parkinson's disease. This study was designed to evaluate the potential protective role of alpha 7 nicotinic receptor activation in an in vitro model of neurodegeneration based on subchronic oxidative stress. Rat organotypic hippocampal cultures (OHCs) were exposed for 4 days to low concentration of lipopolysaccharide (LPS) and the complex III mitochondrial blocker, antimycin-A. Antimycin-A (0.1 mu M) and lipopolysaccharide (1 ng/ml) caused low neurotoxicity on their own, measured as propidium iodide fluorescence in CA1 and CA3 regions. However, their combination (LPS/AA) caused a greater detrimental effect, in addition to mitochondrial depolarization, overproduction of reactive oxygen species (ROS) and Nox4 overexpression. Antimycin-A per se increased ROS and mitochondrial depolarization, although these effects were significantly higher when combined with LPS. More interesting was the finding that exposure of OHCs to the combination of LPS/AA triggered aberrant protein aggregation, measured as thioflavin S immunofluorescence. The alpha 7 nicotinic receptor agonist, PNU282987, prevented the neurotoxicity and the pathological hallmarks observed in the LPS/AA subchronic toxicity model (oxidative stress and protein aggregates); these effects were blocked by alpha-bungarotoxin and tin protoporphyrin, indicating the participation of alpha 7 nAChRs and heme-oxygenase I induction. In conclusion, subchronic exposure of OHCs to low concentration of antimycin-A plus LPS reproduced pathological features of neurodegenerative disorders. alpha 7 nAChR activation ameliorated these alterations by a mechanism involving heme-oxygenase I induction.

• 出版日期2015-10-15