α7 nicotinic acetylcholine receptor-mediated neuroprotection against dopaminergic neuron loss in an MPTP mouse model via inhibition of astrocyte activation

Abstract

BackgroundAlthough evidence suggests that the prevalence of Parkinson’s disease (PD) is lower in smokers than in non-smokers, the mechanisms of nicotine-induced neuroprotection remain unclear. Stimulation of the α7 nicotinic acetylcholine receptor (α7-nAChR) seems to be a crucial mechanism underlying the anti-inflammatory potential of cholinergic agonists in immune cells, including astrocytes, and inhibition of astrocyte activation has been proposed as a novel strategy for the treatment of neurodegenerative disorders such as PD. The objective of the present study was to determine whether nicotine-induced neuroprotection in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model occurs via α7-nAChR-mediated inhibition of astrocytes.MethodsBoth in vivo (MPTP) and in vitro (1-methyl-4-phenylpyridinium ion (MPP+) and lipopolysaccharide (LPS)) models of PD were used to investigate the role(s) of and possible mechanism(s) by which α7-nAChRs protect against dopaminergic neuron loss. Multiple experimental approaches, including behavioral tests, immunochemistry, and stereology experiments, astrocyte cell cultures, reverse transcriptase PCR, laser scanning confocal microscopy, tumor necrosis factor (TNF)-α assays, and western blotting, were used to elucidate the mechanisms of the α7-nAChR-mediated neuroprotection.ResultsSystemic administration of nicotine alleviated MPTP-induced behavioral symptoms, improved motor coordination, and protected against dopaminergic neuron loss and the activation of astrocytes and microglia in the substantia nigra. The protective effects of nicotine were abolished by administration of the α7-nAChR-selective antagonist methyllycaconitine (MLA). In primary cultured mouse astrocytes, pretreatment with nicotine suppressed MPP+-induced or LPS-induced astrocyte activation, as evidenced by both decreased production of TNF-α and inhibition of extracellular regulated kinase1/2 (Erk1/2) and p38 activation in astrocytes, and these effects were also reversed by MLA.ConclusionTaken together, our results suggest that α7-nAChR-mediated inhibition of astrocyte activation is an important mechanism underlying the protective effects of nicotine.

Tanshinone IIA attenuates the cerebral ischemic injury-induced increase in levels of GFAP and of caspases-3 and -8

“…Astrocytes, the most abundant population of glial cells that constitute the microenvironment of the central nervous system (Liu et al, 2012), are intimately associated with the brain homeostasis and maintenance of brain function. While astrocytes are significant in effects repair processes in the CNS, excessive prolongation of their activation is known to lead to undesirable inflammatory outcomes (Sun et al, 2012).…”

Activation of a7 Nicotinic Acetylcholine Receptors Prevents Monosodium Iodoacetate-Induced Osteoarthritis in Rats

“…All experiments were carried out in accordance with the guidelines of the National Institutes of Health for the Care and Use of Laboratory Animals (publication number 85-23, revised 1985) and the Society for Neuroscience Guidelines for the Care and Use of Animals in Neuroscience Research, and were approved by the Institutional Animal Care and Use Committee of Nanjing Medical University [18]. …”

RIC-3, a potential target for regulating cholinergic signaling and inflammation

“…But, the mechanisms of action of nicotine and nAChRs in reducing PD are, as yet, unknown. Suggested mechanisms include neuroprotection 46,47 , effects on dopamine release 48 , and reduced neuro-inflammation resulting from activation of astrocytes or microglia 49 . Thus, the mechanisms of action of PD-associated RIC-3 mutations in this disease need to be identified.…”