title: Activation of α7 nicotinic acetylcholine receptors protects astrocytes against oxidative stress-induced apoptosis: implications for Parkinson's disease.
abstract: Astrocytes have been implicated in the immune responses associated with Parkinson's disease (PD). Inhibition of astrocyte apoptosis is a novel strategy for the treatment of PD. Recent studies suggest that α7 nicotinic acetylcholine receptors (α7-nAChRs) expressed in glial cells are critical links between inflammation and neurodegeneration in PD. However, little is known about their contribution to astrocyte apoptosis during the development of this disorder. In the present study, we showed that nicotine exerts a protective effect on H2O2-induced astrocyte apoptosis and glial cell-derived neurotrophic factor (GDNF) downregulation, and this effect was abolished by an α7-nAChR-selective antagonist. The underlying mechanisms might involve alleviation of mitochondrial membrane potential loss, stabilization of the Bax/Bcl-2 balance, and inhibition of cleaved caspase-9 activity through α7-nAChR activation. Systemic administration of nicotine dramatically alleviated MPTP-induced symptoms, protected dopaminergic neurons against degeneration, inhibited astrocytes and microglia activation in the substantia nigra pars compacta (SNpc) and blocked the decrease of GDNF in the striatum by activating α7-nAChRs. Taken together these findings demonstrate, for the first time, that nicotine suppresses H2O2-induced astrocyte apoptosis via the mitochondrial pathway through the stimulation of α7-nAChRs. Targeting α7-nAChRs expressed in astrocytes may be a novel therapeutic strategy for the treatment of neurodegenerative disorders.
authors.affiliation: Department of Infectious Diseases, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Respiratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Zeng
authors.affiliation: Department of Orthopedics, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Yujian
authors.initials: Y
authors.lastname: Hui
authors.affiliation: Department of Orthopedics, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Chenlei
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Division of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Wu
authors.affiliation: Division of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.
authors.forename: Devin H
authors.initials: DH
authors.lastname: Taylor
authors.affiliation: Department of Respiratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Ji
authors.affiliation: Department of Orthopedics, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Weimin
authors.initials: W
authors.lastname: Fan
authors.affiliation: Department of Infectious Diseases, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Zuhu
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department of Orthopedics, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China. Electronic address: junhu89@vip.sina.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Hu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D002478:Cells, Cultured; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D020734:Parkinsonian Disorders / Q000378:metabolism*; D065842:Pars Compacta / Q000187:drug effects / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists / Q000378:metabolism* / Q000502:physiology
chemical_list: D018696:Neuroprotective Agents; D018722:Nicotinic Agonists; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine
keywords: Apoptosis; Astrocyte; Mitochondria; Nicotinic acetylcholine receptors; Parkinson's disease