Elsevier

Neuropharmacology

Volume 91, April 2015, Pages 87-96
Neuropharmacology

Activation of α7 nicotinic acetylcholine receptors protects astrocytes against oxidative stress-induced apoptosis: Implications for Parkinson's disease

https://doi.org/10.1016/j.neuropharm.2014.11.028Get rights and content

Highlights

  • Nicotine exerted a protective effect on astrocytic apoptosis via α7-nAChRs.

  • The anti-apoptotic mechanisms might involve the mitochondrial apoptotic pathway.

  • Nicotine inhibited GDNF reduction in vitro and in vivo via α7-nAChRs.

  • Nicotine alleviated chronic MPTP-induced symptoms in vivo via α7-nAChRs.

  • Targeting α7-nAChRs expressed in astrocytes provides a therapeutic strategy in PD.

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.

Introduction

Astrocytes are the most abundant glial cell population in the brain. They are derived from the neuroectoderm and are essential for brain function and homeostasis. Impaired astrocyte function can severely influence neuronal survival (Wang and Bordey, 2008). Increasing evidence suggests that astrocyte apoptosis may contribute to the pathogenesis of many acute and chronic neurodegenerative disorders including cerebral ischemia, Alzheimer's disease and Parkinson's disease (PD) (Takuma et al., 2004). Recent studies show that inhibition of astrocyte apoptosis is an essential neuroprotective strategy (Chen et al., 2008, Ebrahimi et al., 2012, Zhang et al., 2007b). Therefore, a better understanding of astrocyte apoptosis may provide insight into the responses of the central nervous system (CNS) to pathogenic challenges and help identify appropriate molecular targets for therapeutic intervention in a variety of neurodegenerative diseases (Farina et al., 2007).

Epidemiologic studies have shown that there is a negative correlation between smoking and the prevalence of PD (Chen et al., 2010, Morens et al., 1995, Ritz et al., 2007). Nicotine, a potent agonist of nicotinic acetylcholine receptors (nAChRs), may have anti-Parkinsonian effects (Janson et al., 1988, Parain et al., 2003, Parain et al., 2001, Quik et al., 2006, Quik et al., 2012). In previous studies, we showed that pretreatment of primary cultured mouse astrocytes with nicotine suppressed 1-methyl-4-phenylpyridinium ion (MPP+)-mediated or lipopolysaccharide (LPS)-induced astrocyte activation. This suppression was evidenced by decreased production of tumor necrosis factor (TNF)-α, suppression of extracellular regulated kinase 1/2 (Erk1/2) and p38 activation in astrocytes. These effects were reversed by an α7-nAChR-selective antagonist (Liu et al., 2012). Numerous studies have confirmed the therapeutic potential of targeting α7-nAChR-mediated anti-inflammatory effects through the modulation of proinflammatory cytokines, which are associated with some neurodegenerative diseases (Bencherif et al., 2011, Marrero et al., 2011, Quik et al., 2009). Anti-inflammatory treatments can have both short term and long-term effects on necrotic and apoptotic cell death, respectively (Beattie, 2004, Marrero and Bencherif, 2009). In addition, Erk1/2 and p38 are not only involved in the inflammation pathway, but also play a critical role in the apoptosis pathway (Gong et al., 2014, Harper and Wilkie, 2003). However, little is known about the role of α7-nAChRs in the regulation of astrocyte apoptosis.

Our previous data suggested that systemic treatment with nicotine attenuates acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced behavioral symptoms and protects against dopaminergic neuron loss in the substantia nigra pars compacta (SNpc) (Liu et al., 2012). Some studies assert that a different primary cascade is activated by MPTP neurotoxicity in mice that received either acute or chronic MPTP treatment (Petroske et al., 2001). Chronic MPTP treatment induces apoptotic cell death in mice. This chronically induced cell death is the main apoptotic cascade involved in the associated neuronal injury (Furuya et al., 2004, Novikova et al., 2006), whereas, little is known about the role of α7-nAChRs in chronic MPTP neurotoxicity in mice.

In the present study, we investigated whether nicotine has protective effects on oxidative stress-induced astrocyte apoptosis by acting on α7-nAChRs and evaluated the α7-nAChR-mediated anti-apoptosis mechanisms in vitro. In addition, we examined whether nicotine plays a protective role against the effects of chronic MPTP treatment in vivo.

Section snippets

Astrocyte cell cultures

Primary cultures of mouse astrocytes were prepared from the midbrain of C57BL/6 black newborn mice 1–2 days after birth as previously described (Liu et al., 2012). In brief, the midbrain was dissected under sterile conditions and the meninges were carefully removed. Brain tissues were dissociated in 0.25% trypsin for 10 min at 37 °C. The cell suspension was separated by centrifugation at 240 g for 5 min, and the cells were transferred to poly-d-lysine pre-coated cell culture flasks. The

Nicotine inhibits H2O2-induced astrocyte apoptosis via α7-nAChRs

The effect of nicotine on H2O2-induced astrocyte apoptosis was examined by flow cytometry coupled with Annexin V-FITC and PI cell staining. Cells in the lower right quadrant indicate Annexin-positive, early apoptotic cells, whereas those in the upper right quadrant indicate Annexin-positive/PI-positive, late apoptotic cells. The percentage of apoptotic cells includes both early and late apoptotic cells. Incubation of cultured mouse astrocytes with 500 μM H2O2 for 24 h significantly increased

Discussion

As major components of the neural network, astrocytes play an important role in the neuropathogenesis of PD and contribute to the neuroprotection and survival of neurons during the progression of this disorder. Any significant impairment of astrocyte function is sufficient to induce neuronal dysfunction. The study of astrocytes is particularly important considering the co-existence of the apoptotic death of neurons and astrocytes in the damaged brains of patients with neurodegenerative

Acknowledgments

This study was supported by grants from the National Natural Science Foundation of China (No. 81373397 and 81341017), the Jiangsu Department of Science and Technology Basic Research Program (No. BK20131443), the Priority Academic Program Development of Jiangsu Higher Education Institutions (No. JX10231801), and the State Scholarship Fund (No. 201208320286).

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      Studies have shown that the number of GFAP+ cells were decreased in the hippocampus and medial prefrontal cortex MDD patients and chronic mild stress-induced rodent models[127–129]. However, the changes of astrocytes in other neurological diseases such as Parkinson's disease, Alzheimer's disease and stroke are different from those in MDD patients, which may be due to the fact that in addition to astrocytes, there are other factors involved in the pathogenesis of these diseases[130–134]. In consistent with previous studies[118,135–137], we found that CRS downregulated the number of GFAP+ cells, which indicated the apoptosis of astrocytes.

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    These two authors contributed equally to this work.

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