Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2012

Open Access 01-12-2012 | Research

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

Authors: Yuan Liu, Jun Hu, Jie Wu, Chenlei Zhu, Yujian Hui, Yaping Han, Zuhu Huang, Kevin Ellsworth, Weimin Fan

Published in: Journal of Neuroinflammation | Issue 1/2012

Login to get access

Abstract

Background

Although 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.

Methods

Both 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.

Results

Systemic 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.

Conclusion

Taken together, our results suggest that α7-nAChR-mediated inhibition of astrocyte activation is an important mechanism underlying the protective effects of nicotine.
Literature
1.
Jakowec MW, Petzinger GM: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned model of parkinson’s disease, with emphasis on mice and nonhuman primates. Comp Med 2004, 54:497–513.PubMed
2.
Farina C, Aloisi F, Meinl E: Astrocytes are active players in cerebral innate immunity. Trends Immunol 2007, 28:138–145.CrossRefPubMed
3.
Hu J, Zhu C, Liu Y, Wang F, Huang Z, Fan W, Wu J: Dynamic alterations of gene expression of nicotinic acetylcholine receptor alpha7, alpha4 and beta2 subunits in an acute MPTP-lesioned mouse model. Neurosci Lett 2011, 494:232–236.CrossRefPubMed
4.
Liberatore GT, Jackson-Lewis V, Vukosavic S, Mandir AS, Vila M, McAuliffe WG, Dawson VL, Dawson TM, Przedborski S: Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease. Nat Med 1999, 5:1403–1409.CrossRefPubMed
5.
Fan Y, Kong H, Shi X, Sun X, Ding J, Wu J, Hu G: Hypersensitivity of aquaporin 4-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine and astrocytic modulation. Neurobiol Aging 2008, 29:1226–1236.CrossRefPubMed
6.
Yang YJ, Zhang S, Ding JH, Zhou F, Hu G: Iptakalim protects against MPP+-induced degeneration of dopaminergic neurons in association with astrocyte activation. Int J Neuropsychopharmacol 2009, 12:317–327.CrossRefPubMed
7.
8.
9.
Dutta G, Zhang P, Liu B: The lipopolysaccharide Parkinson’s disease animal model: mechanistic studies and drug discovery. Fundam Clin Pharmacol 2008, 22:453–464.CrossRefPubMedPubMedCentral
10.
Gao M, Jin Y, Yang K, Zhang D, Lukas RJ, Wu J: Mechanisms involved in systemic nicotine-induced glutamatergic synaptic plasticity on dopamine neurons in the ventral tegmental area. J Neurosci 2010, 30:13814–13825.CrossRefPubMedPubMedCentral
11.
Turek JW, Kang CH, Campbell JE, Arneric SP, Sullivan JP: A sensitive technique for the detection of the alpha 7 neuronal nicotinic acetylcholine receptor antagonist, methyllycaconitine, in rat plasma and brain. J Neurosci Methods 1995, 61:113–118.CrossRefPubMed
12.
Zhou F, Wu JY, Sun XL, Yao HH, Ding JH, Hu G: Iptakalim alleviates rotenone-induced degeneration of dopaminergic neurons through inhibiting microglia-mediated neuroinflammation. Neuropsychopharmacology 2007, 32:2570–2580.CrossRefPubMed
13.
14.
Shytle RD, Mori T, Townsend K, Vendrame M, Sun N, Zeng J, Ehrhart J, Silver AA, Sanberg PR, Tan J: Cholinergic modulation of microglial activation by alpha 7 nicotinic receptors. J Neurochem 2004, 89:337–343.CrossRefPubMed
15.
Clark AR, Dean JL, Saklatvala J: Post-transcriptional regulation of gene expression by mitogen-activated protein kinase p38. FEBS Lett 2003, 546:37–44.CrossRefPubMed
16.
Choi SH, Joe EH, Kim SU, Jin BK: Thrombin-induced microglial activation produces degeneration of nigral dopaminergic neuronsin vivo. J Neurosci 2003, 23:5877–5886.
17.
Zhang S, Zhou F, Ding JH, Zhou XQ, Sun XL, Hu G: ATP-sensitive potassium channel opener iptakalim protects against MPP-induced astrocytic apoptosis via mitochondria and mitogen-activated protein kinase signal pathways. J Neurochem 2007, 103:569–579.CrossRefPubMed
18.
Takuma K, Baba A, Matsuda T: Astrocyte apoptosis: implications for neuroprotection. Prog Neurobiol 2004, 72:111–127.CrossRefPubMed
19.
Allam MF, Del CAS, Navajas RF: Parkinson’s disease, smoking, and gender. Mov Disord 2007, 22:1829–1830.CrossRefPubMed
20.
Quik M, O’Neill M, Perez XA: Nicotine neuroprotection against nigrostriatal damage: importance of the animal model. Trends Pharmacol Sci 2007, 28:229–235.CrossRefPubMed
21.
Park HJ, Lee PH, Ahn YW, Choi YJ, Lee G, Lee DY, Chung ES, Jin BK: Neuroprotective effect of nicotine on dopaminergic neurons by anti-inflammatory action. Eur J Neurosci 2007, 26:79–89.CrossRefPubMed
22.
Takeuchi H, Yanagida T, Inden M, Takata K, Kitamura Y, Yamakawa K, Sawada H, Izumi Y, Yamamoto N, Kihara T, Uemura K, Inoue H, Taniguchi T, Akaike A, Takahashi R, Shimohama S: Nicotinic receptor stimulation protects nigral dopaminergic neurons in rotenone-induced Parkinson’s disease models. J Neurosci Res 2009, 87:576–585.CrossRefPubMed
23.
Perez XA, Bordia T, McIntosh JM, Grady SR, Quik M: Long-term nicotine treatment differentially regulates striatal alpha6alpha4beta2* and alpha6(nonalpha4)beta2* nAChR expression and function. Mol Pharmacol 2008, 74:844–853.CrossRefPubMedPubMedCentral
24.
25.
Parain K, Hapdey C, Rousselet E, Marchand V, Dumery B, Hirsch EC: Cigarette smoke and nicotine protect dopaminergic neurons against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Parkinsonian toxin. Brain Res 2003, 984:224–232.CrossRefPubMed
26.
27.
28.
Cui WY, Li MD: Nicotinic modulation of innate immune pathways via alpha7 nicotinic acetylcholine receptor. J Neuroimmune Pharmacol 2010, 5:479–488.CrossRefPubMed
29.
Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, Li JH, Wang H, Yang H, Ulloa L, Al-Abed Y, Czura CJ, Tracey KJ: Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 2003, 421:384–388.CrossRefPubMed
30.
Yoshikawa H, Kurokawa M, Ozaki N, Nara K, Atou K, Takada E, Kamochi H, Suzuki N: Nicotine inhibits the production of proinflammatory mediators in human monocytes by suppression of I-kappaB phosphorylation and nuclear factor-kappaB transcriptional activity through nicotinic acetylcholine receptor alpha7. Clin Exp Immunol 2006, 146:116–123.CrossRefPubMedPubMedCentral
31.
Sedelis M, Schwarting RK, Huston JP: Behavioral phenotyping of the MPTP mouse model of Parkinson’s disease. Behav Brain Res 2001, 125:109–125.CrossRefPubMed
32.
Furuya T, Hayakawa H, Yamada M, Yoshimi K, Hisahara S, Miura M, Mizuno Y, Mochizuki H: Caspase-11 mediates inflammatory dopaminergic cell death in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. J Neurosci 2004, 24:1865–1872.CrossRefPubMed
33.
Petroske E, Meredith GE, Callen S, Totterdell S, Lau YS: Mouse model of Parkinsonism: a comparison between subacute MPTP and chronic MPTP/probenecid treatment. Neuroscience 2001, 106:589–601.CrossRefPubMed
Metadata
Title
α7 nicotinic acetylcholine receptor-mediated neuroprotection against dopaminergic neuron loss in an MPTP mouse model via inhibition of astrocyte activation
Authors
Yuan Liu
Jun Hu
Jie Wu
Chenlei Zhu
Yujian Hui
Yaping Han
Zuhu Huang
Kevin Ellsworth
Weimin Fan
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2012
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/1742-2094-9-98

Other articles of this Issue 1/2012

Journal of Neuroinflammation 1/2012 Go to the issue

Review

Complement activation in the injured central nervous system: another dual-edged sword?

Research

Brain leukocyte infiltration initiated by peripheral inflammation or experimental autoimmune encephalomyelitis occurs through pathways connected to the CSF-filled compartments of the forebrain and midbrain

Research

A possible role for inflammation in mediating apoptosis of oligodendrocytes as induced by the Lyme disease spirochete Borrelia burgdorferi

Research

Macrophage imbalance (M1 vs. M2) and upregulation of mast cells in wall of ruptured human cerebral aneurysms: preliminary results

Research

Inhibition of Src kinase activity attenuates amyloid associated microgliosis in a murine model of Alzheimer’s disease

Short report

Elevated levels of circulating IL-18BP and perturbed regulation of IL-18 in schizophrenia