Neuroprotective mechanism of nicotine in a mouse model of rotenone-induced Parkinson’s disease

doi:10.12307/2024.821

Abstract

Abstract: BACKGROUND: Studies have found that nicotine can activate the dopamine system, slowing the progression of Parkinson’s disease, but the specific mechanism is still unclear. Research on the neuroprotective mechanism of nicotine in animal models of Parkinson’s disease is lacking.
OBJECTIVE: To investigate the neuroprotective effect of nicotine on rotenone-induced Parkinson’s disease in mice.
METHODS: Twenty-eight C57BL/6 mice were randomly divided into vehicle group, rotenone group, autophagy agonist group and nicotine group, with seven mice in each group. Dopaminergic nerve damage was induced by rotenone in C57BL/6 mice, and the autophagy agonist (rapamycin) or nicotine was given before modeling. The spatial exploration function of the mice was observed by open field test. Western blot and Q-PCR were used to detect the expression of α-synuclein, autophagy related factors Beclin-1 and P62, and apoptosis-related factors Bax, Bcl-2 and Cleaved-caspase3 in the nigra of each group. The deposition of mitochondria, autophagosomes and lipofuscin in nigra cells were observed by transmission electron microscopy. The survival of neurons was observed by Nissl staining. The expression of tyrosine hydroxylase was observed by immunofluorescence and immunohistochemical staining.
RESULTS AND CONCLUSION: The open field test showed that the distance, average speed and time of movement were reduced in the rotenone group compared with the solvent group. Compared with the rotenone group, the exercise distance, average speed and exercise time of mice were increased in the nicotine group and autophagy agonist group (P < 0.05). The results of immunofluorescence and immunohistochemistry showed that the mean fluorescence intensity and mean absorbance value of tyrosine hydroxylase in the rotenone group decreased compared with that in the solvent group. Compared with the rotenone group, the mean fluorescence intensity and mean absorbance value of tyrosine hydroxylase were increased in the nicotine group and autophagy agonist group. Western blot and Q-PCR results showed that compared with the solvent group, the expressions of α-synuclein and P62 in the rotenone group were increased, while Beclin-1 expression was decreased (P < 0.05); compared with the rotenone group, the expression of α-synuclein and P62 decreased in the nicotine group and autophagy agonist group, and the expression of Beclin-1 increased (P < 0.05). Compared with the solvent group, the expressions of Bax and Cleaved caspase3 were increased and Bcl-2 expression was decreased in the rotenone group (P < 0.05); compared with the rothenone group, the expressions of Bax and Cleaved-caspase3 were decreased and the expression of Bcl-2 was increased in the nicotine and autophagy agonist groups (P < 0.05). To conclude, nicotine may have a dopaminergic neuroprotective effect on rotenone-induced Parkinson’s disease mouse models by improving autophagy dysfunction and reducing apoptosis.

Key words: nicotine, autophagy, apoptosis, rotenone, Parkinson’s disease, neuroprotection, alpha-synuclein, tyrosine hydroxylase

CLC Number:

Zhang Xinyue, Zhu Liuhui, He Yu, Guan Ying, Zhu Zhouhai, Ren Hui, Yang Xinglong. Neuroprotective mechanism of nicotine in a mouse model of rotenone-induced Parkinson’s disease[J]. Chinese Journal of Tissue Engineering Research, 2024, 28(35): 5612-5617.

Figures/Tables 7

References

[1] SCHAPIRA AH, JENNER P. Etiology and pathogenesis of Parkinson’s disease. Mov Disord. 2011;26(6):1049-1055.
[2] DICKSON DW. Neuropathology of Parkinson disease. Parkinsonism Relat Disord. 2018;46 Suppl 1(Suppl 1):S30-S33.
[3] WIRDEFELDT K, ADAMI HO, COLE P, et al. Epidemiology and etiology of Parkinson’s disease: a review of the evidence. Eur J Epidemiol. 2011;26 Suppl 1:S1-58.
[4] QUIK M. Smoking, nicotine and Parkinson’s disease. Trends Neurosci. 2004; 27(9):561-568.
[5] DOMÍNGUEZ-BALEÓN C, ONG JS, SCHERZER CR, et al. Understanding the effect of smoking and drinking behavior on Parkinson’s disease risk: a Mendelian randomization study. Sci Rep. 2021;11(1):13980.
[6] BRENNER DE, KUKULL WA, VAN BELLE G, et al. Relationship between cigarette smoking and Alzheimer’s disease in a population-based case-control study. Neurology. 1993;43(2):293-300.
[7] DOLL R, PETO R, BOREHAM J, et al. Smoking and dementia in male British doctors: prospective study. BMJ. 2000;320(7242):1097-1102.
[8] BENEDETTI MD, BOWER JH, MARAGANORE DM, et al. Smoking, alcohol, and coffee consumption preceding Parkinson’s disease: a case-control study. Neurology. 2000;55(9):1350-1358.
[9] ADACHI A, KOIZUMI M, OHSUMI Y. Autophagy induction under carbon starvation conditions is negatively regulated by carbon catabolite repression. J Biol Chem. 2017;292(48):19905-19918.
[10] KLIONSKY DJ, ABDEL-AZIZ AK, ABDELFATAH S, et al. Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition). Autophagy. 2021;17(1):1-382.
[11] ZOU CG, MA YC, DAI LL, et al. Autophagy protects C. elegans against necrosis during Pseudomonas aeruginosa infection. Proc Natl Acad Sci U S A. 2014;111(34):12480-12485.
[12] TYSNES OB, STORSTEIN A. Epidemiology of Parkinson’s disease. J Neural Transm (Vienna). 2017;124(8):901-905.
[13] TALPADE DJ, GREENE JG, HIGGINS DS JR, et al. In vivo labeling of mitochondrial complex I (NADH:ubiquinone oxidoreductase) in rat brain using [(3)H]dihydrorotenone. J Neurochem. 2000;75(6):2611-2621.
[14] NEFZGER MD, QUADFASEL FA, KARL VC. A retrospective study of smoking in Parkinson’s disease. Am J Epidemiol. 1968;88(2):149-158.
[15] TANNER CM, GOLDMAN SM, ASTON DA, et al. Smoking and Parkinson’s disease in twins. Neurology. 2002;58(4):581-588.
[16] GETACHEW B, CSOKA AB, ASCHNER M, et al. Nicotine protects against manganese and iron-induced toxicity in SH-SY5Y cells: Implication for Parkinson’s disease. Neurochem Int. 2019;124:19-24.
[17] MIHAILESCU S, DRUCKER-COLÍN R. Nicotine, brain nicotinic receptors, and neuropsychiatric disorders. Arch Med Res. 2000;31(2):131-144.
[18] TOULORGE D, GUERREIRO S, HILD A, et al. Neuroprotection of midbrain dopamine neurons by nicotine is gated by cytoplasmic Ca2+. FASEB J. 2011; 25(8):2563-2573.
[19] YANAGIDA T, TAKEUCHI H, KITAMURA Y, et al. Synergistic effect of galantamine on nicotine-induced neuroprotection in hemiparkinsonian rat model. Neurosci Res. 2008;62(4):254-261.
[20] QUIK M, WONNACOTT S. α6β2* and α4β2* nicotinic acetylcholine receptors as drug targets for Parkinson’s disease. Pharmacol Rev. 2011;63(4):938-966.
[21] JURADO-CORONEL JC, AVILA-RODRIGUEZ M, CAPANI F, et al. Targeting the Nicotinic Acetylcholine Receptors (nAChRs) in Astrocytes as a Potential Therapeutic Target in Parkinson’s Disease. Curr Pharm Des. 2016;22(10): 1305-1311.
[22] MONSALVE-MERCADO MM, ROUDI Y. Hippocampal spike-time correlations and place field overlaps during open field foraging. Hippocampus. 2020;30(4):354-366.
[23] SEO JH, RAH JC, CHOI SH, et al. Alpha-synuclein regulates neuronal survival via Bcl-2 family expression and PI3/Akt kinase pathway. FASEB J. 2002;16(13): 1826-1828.
[24] BRETAUD S, ALLEN C, INGHAM PW, et al. p53-dependent neuronal cell death in a DJ-1-deficient zebrafish model of Parkinson’s disease. J Neurochem. 2007;100(6):1626-1635.
[25] HARTMANN A, MICHEL PP, TROADEC JD, et al. Is Bax a mitochondrial mediator in apoptotic death of dopaminergic neurons in Parkinson’s disease? J Neurochem. 2001;76(6):1785-1793.
[26] OFFEN D, BEART PM, CHEUNG NS, et al. Transgenic mice expressing human Bcl-2 in their neurons are resistant to 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine neurotoxicity. Proc Natl Acad Sci U S A. 1998;95(10):5789-5794.
[27] MAJESKI AE, DICE JF. Mechanisms of chaperone-mediated autophagy. Int J Biochem Cell Biol. 2004;36(12):2435-2444.
[28] WANG YT, LU JH. Targeting chaperone-mediated autophagy for Parkinson’s disease therapy. Neural Regen Res. 2023;18(8):1723-1724.
[29] HIRSCH L, JETTE N, FROLKIS A, et al. The Incidence of Parkinson’s Disease: A Systematic Review and Meta-Analysis. Neuroepidemiology. 2016;46(4):292-300.
[30] WEBB JL, RAVIKUMAR B, ATKINS J, et al. Alpha-Synuclein is degraded by both autophagy and the proteasome. J Biol Chem. 2003;278(27):25009-25013.
[31] CUERVO AM, STEFANIS L, FREDENBURG R, et al. Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science. 2004;305(5688):1292-1295.