Summary
The repeated finding of an apparent protective effect of cigarette smoking on the risk of Parkinson's disease is one of the few consistent results in the epidemiology of this disorder. Among the innumerous substances that originate from tobacco smoke, nicotine is by far the most widely studied, and the most likely candidate for a protective effect against neuronal degeneration in Parkinson's disease. Nicotine is a natural alkaloid that has considerable stimulatory effects on the central nervous system (CNS). Its effects on the CNS are mediated by the activation of neuronal heteromeric acetylcholine-gated ion channel receptors (nAChR, also termed nicotinic acetylcholine receptors). In the present study, we describe the neuroprotective effects of (−)nicotine in two animal models of parkinsonism: the diethyldithiocarbamate (DDC)-induced enhancement of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity in mice, and the methamphetamine-induced neurotoxicity in rats and mice. In parallel experiments, we found that (−)nicotine induces the basic fibroblast growth factor (FGF-2) and the brain-derived neurotrophic factor (BDNF) in rat striatum. As FGF-2 and BDNF have been reported to be neuroprotective for dopaminergic cells, our data indicate that the increase in neurotrophic factors is a possible mechanism by which (−)nicotine protects from experimental parkinsonisms. Moreover, they suggest that nAChR agonists could be of potential benefit in the progression of Parkinson's disease.
References
Aizenman E, Lian-Hong T, Reynolds IJ (1991) Effects of nicotinic agonists on the NMDA receptor. Brain Res 551: 355–357
Asai T, Wanaka A, Kato H, Masana Y, Seo M, Tohyama M (1993) Differential expression of two members of FGF receptor gene family, FGFR-1 and FGFR-2 mRNA, in the adult rat central nervous system. Mol Brain Res 17: 174–178
Baron JA (1986) Cigarette smoking and Parkinson's disease. Neurology 36: 1490–1495
Bean AJ, Elde R, Cao Y, Oellig C, Tamminga C, Goldstein M, Pettersson RF, Hoxfelt T (1991) Expression of acidic and basic fibroblast growth factors in the substantia nigra of rat, monkey and human. Proc Natl Acad Sci USA 88: 10237–10241
Burns RS, Chiueh CC, Markey SP, Ebert MH, Jacobowitz DM, Kopin IJ (1983) A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Proc Natl Acad Sci USA 80: 4546–4550
Cintra A, Cao Y, Oellig C, Tinner B, Bortolotti R, Pettersson RF, Fuxe K (1991) Basic FGF is present in dopaminergic neurons of the ventral midbrain of the rat. NeuroReport 2: 597–600
Conti-Tronconi BM, McLane KE, Raftery MA, Grando SA, Protti MP (1994) The nicotinic acetylcholine receptor: structure and autoimmune pathology. Crit Rev Biochem Mol Biol 29: 69–123
Corsini GU, Pintus S, Chiueh CC, Weiss JF, Kopin IJ (1985) 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in mice is enhanced by pretreatment with diethyldithiocarbamate. Eur J Pharmacol 119: 127–128
Fornai F, Vaglini F, Maggio R, Bonuccelli U, Corsini GU (1996) Excitatory amino acids and MPTP toxicity. Adv Neurol 69: 167–176
Fowler JS, Volkow ND, Wang G-J, Pappas N, Logan J, MacGregor R, Alexoff D, Shea C, Schlyer D, Wolf AP, Warner D, Zezulkova I, Cliento R (1996) Inhibition of monoamine oxidase B in the brains of smokers. Nature 379: 733–736
Hefti FJ (1994) Neurotrophic factor therapy for nervous system degenerative diseases. Neurobiology 25: 1418–1435
Hotchkiss AJ, Gibb JW (1980) Long-term effects of multiple doses of methamphetamine on tryptophan hydroxylase and tyrosine hydroxylase activity in rat brain. J Pharmacol Exp Ther 214: 257–262
Jackson DM, Westind-Danielsson A (1994) Pharmacol Ther 64: 291–369
Langston JW, Ballard PA, Tetrud JW, Irwin I (1983) Chronic parkinsonism in human due to a product of meperidine-analog synthesis. Science 219: 979–980
Lees AJ on behalf of the Parkinson's Disease Research Group of the United Kingdom (1995) Comparison of therapeutic effects and mortality data of levodopa and levodopa combined with selegiline in patients with early, mild Parkinson's disease. Br Med J 311: 1602–1607
Marin P, Maus M, Desagher S, Glowinski J, Prémont J (1994) Nicotine protects cultured striatal neurons against N-methyl-D-aspartate receptor-mediated neurotoxicity. NeuroReport 5: 1977–1980
McGeer EG, Singh EA, McGeer PL (1992) Apparent anterograde transport of basic fibroblast growth factor in the rat nigrostriatal dopamine system. Neurosci Lett 148: 31–33
Morens DM, Grandinetti A, Reed D, White LR, Ross GW (1995) Cigarette smoking and protection from Parkinson's disease: false association or etiologic clue? Neurology 45: 1041–1051
Muraki A, Koyama T, Nakayama M, Ohmori T, Yamashita I (1992) MK-801, a non-competitive antagonist of NMDA receptor prevents methamphetamine-induced decrease of striatal dopamine uptake sites in the rat striatum. Neurosci Lett 136: 39–42
Otto D, Unsicker K (1990) Basic FGF reverses chemical and morphological deficits in the nigrostriatal system of MPTP-treated mice. J Neurosci 10: 1912–1921
Parkinson's Study Group (1989) Effects of deprenyl on the progression of disability in early Parkinson's disease. N Engl J Med 321: 1364–1371
Sidman RL, Angevine Jr JB, Taber Pierce E (1971) Atlas of the mouse brain and spinal cord. Harvard University Press
Sonsalla PK, Nicklas WJ, Heikkila RE (1989) Role for excitatory amino acids in methamphetamine induced nigrostriatal dopaminergic toxicity. Science 243: 398–400
Sonsalla PK, Riordan DE, Heikkila RE (1991) Competitive and noncompetitive antagonist at N-methyl-D-aspartate receptors protect against methamphetamine-induced dopaminergic damage in mice. J Pharmacol Exp Ther 256: 506–512
Tetrud JW, Langston JW (1989) The effect of deprenyl (selegiline) on the natural history of Parkinson's disease. Science 245: 519–522
Tooyama I, Kawamata T, Walker D, Yamada T, Hanai K, Kimura H, Iwane M, Igarashi K, McGeer EG, McGeer PL (1993) High molecular weight basic fibroblast growth factor-like protein is localized to a subpopulation of mesencephalic dopaminergic neurons in the rat brain. Neurology 43: 372–376
Vaglini F, Fascetti F, Fornai F, Maggio R, Corsini GU (1994) (+)MK-801 prevents the DDC-induced enhancement of MPTP toxicity in mice. Brain Res 668: 194–203
Vaglini F, Pardini C, Cavalletti M, Maggio R, Corsini GU (1995) L-Deprenyl fails to protect mesencephalic dopamine neurons and PC12 cells from the neurotoxic effect of 1-methyl-4-phenylpyridinium ion. Brain Res 674: 127–132
Wagner GC, Ricarute GA, Seiden LS, Schuster CR, Miller JM, Westly J (1980) Long-lasting depletion of striatal dopamine and loss of dopamine uptake sites following repeated administration of methamphetamine. Brain Res 171: 151–160
Wanaka A, Johnson EM, Milbrandt J (1990) Localization of FGF receptor mRNA in the adult rat central nervous system by in situ hybridization. Neuron 5: 267–281
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Maggio, R., Riva, M., Vaglini, F. et al. Striatal increase of neurotrophic factors as a mechanism of nicotine protection in experimental parkinsonism. J. Neural Transmission 104, 1113–1123 (1997). https://doi.org/10.1007/BF01273324
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01273324