Abstract
Lithium has been used for the treatment of bipolar mood disorder and is shown to have neuroprotective properties. Since lithium inhibits the activity of glycogen synthase kinase 3 (GSK3) which is implicated in various human diseases, particularly neurodegenerative diseases, the therapeutic potential of lithium receives great attention. Parkinson’s disease (PD) is the second most common neurodegenerative disease, characterized by the pathological loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Intranigral injection of the catecholaminergic neurotoxin 6-hydroxydopamine (6-OHDA) causes selective and progressive degeneration of dopaminergic neurons in SNpc, and is a commonly used animal model of PD. The current study was designated to determine whether lithium is effective in alleviating 6-OHDA-induced neurodegeneration in the SNpc of rats. We demonstrated that chronic subcutaneous administration of lithium inhibited GSK3 activity in the SNpc, which was evident by an increase in phosphorylation of GSK3β at serine 9, cyclin D1 expression, and a decrease in tau phosphorylation. 6-OHDA did not affect GSK3 activity in the SNpc. Moreover, lithium was unable to alleviate 6-OHDA-induced degeneration of SNpc dopaminergic neurons. The results suggest that GSK3 is minimally involved in the neurodegeneration in the rat 6-OHDA model of PD.
Similar content being viewed by others
Abbreviations
- 6-OHDA:
-
6-hydroxydopamine
- GSK3:
-
Glycogen synthase kinase 3
- MPP+ :
-
S1-methyl-4-phenyl-pyridinium
- PD:
-
Parkinson’s disease
- SNpc:
-
Substantia nigra pars compacta
- TH:
-
Tyrosine hydroxylase
References
Schapira AH, Olanow CW (2008) Drug selection and timing of initiation of treatment in early Parkinson’s disease. Ann Neurol 64:S47–S55
Marmol F (2008) Lithium: bipolar disorder and neurodegenerative diseases Possible cellular mechanisms of the therapeutic effects of lithium. Prog Neuropsychopharmacol Biol Psychiatry 32:1761–1771
Wada A (2009) Lithium and neuropsychiatric therapeutics: neuroplasticity via glycogen synthase kinase-3beta, beta-catenin, and neurotrophin cascades. J Pharmacol Sci 110:14–28
Chuang DM (2004) Neuroprotective and neurotrophic actions of the mood stabilizer lithium: can it be used to treat neurodegenerative diseases? Crit Rev Neurobiol 16:83–90
Dill J, Wang H, Zhou F et al (2008) Inactivation of glycogen synthase kinase 3 promotes axonal growth and recovery in the CNS. J Neurosci 28:8914–8928
Fornai F, Longone P, Cafaro L et al (2008) Lithium delays progression of amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 105:2052–2057
Martinez A, Perez DI (2008) GSK-3 inhibitors: a ray of hope for the treatment of Alzheimer’s disease? J Alzheimers Dis 15:181–191
Sarkar S, Krishna G, Imarisio S et al (2008) A rational mechanism for combination treatment of Huntington’s disease using lithium and rapamycin. Hum Mol Genet 17:170–178
Wei H, Leeds PR, Qian Y et al (2000) beta-amyloid peptide-induced death of PC 12 cells and cerebellar granule cell neurons is inhibited by long-term lithium treatment. Eur J Pharmacol 392:117–123
Wei H, Qin ZH, Senatorov VV et al (2001) Lithium suppresses excitotoxicity-induced striatal lesions in a rat model of Huntington’s disease. Neuroscience 106:603–612
Bhat RV, Budd Haeberlein SL, Avila J (2004) Glycogen synthase kinase 3: a drug target for CNS therapies. J Neurochem 89:1313–1317
Grimes CA, Jope RS (2001) The multifaceted roles of glycogen synthase kinase 3beta in cellular signaling. Prog Neurobiol 65:391–426
Luo J (2009) GSK3beta in Ethanol Neurotoxicity. Mol Neurobiol 40:108–121
Chen G, Bower KA, Ma C et al (2004) Glycogen synthase kinase 3beta (GSK3beta) mediates 6-hydroxydopamine-induced neuronal death. FASEB J 18:1162–1164
Chen YY, Chen G, Fan Z et al (2008) GSK3beta and endoplasmic reticulum stress mediate rotenone-induced death of SK-N-MC neuroblastoma cells. Biochem Pharmacol 76:128–138
Wang W, Yang Y, Ying C et al (2007) Inhibition of glycogen synthase kinase-3 beta protects dopaminergic neurons from MPTP toxicity. Neuropharmacology 52:1678–1684
Youdim MB, Arraf Z (2004) Prevention of MPTP (N-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine) dopaminergic neurotoxicity in mice by chronic lithium: involvements of Bcl-2 and Bax. Neuropharmacology 46:1130–1140
Simola N, Morelli M, Carta AR (2007) The 6-hydroxydopamine model of Parkinson’s disease. Neurotox Res 11:151–167
DauerW PrzedborskiS (2003) Parkinson’s disease: mechanisms and models. Neuron 39:889–909
Franlin KBJ, Paxinos G (1997) The mouse brain in stereotaxic coordinates. Academic Press, San Diego
Nonaka S, Chuang DM (1998) Neuroprotective effects of chronic lithium on focal cerebral ischemia in rats. Neuroreport 9:2081–2084
Wang X, Fan Z, Wang B et al (2007) Activation of double-stranded RNA-activated protein kinase by mild impairment of oxidative metabolism in neurons. J Neurochem 103:2380–2390
Ke ZJ, DeGiorgio LA, Volpe BT et al (2003) Reversal of thiamine deficiency-induced neurodegeneration. J Neuropathol Exp Neurol 62:195–207
Truong L, Allbutt H, Kassiou M et al (2006) Developing a preclinical model of Parkinson’s disease: a study of behaviour in rats with graded 6-OHDA lesions. Behav Brain Res 169:1–9
Zuch CL, Nordstroem VK, Briedrick LA et al (2000) Time course of degenerative alterations in nigral dopaminergic neurons following a 6-hydroxydopamine lesion. J Comp Neurol 427:440–454
Liu Y, Chen G, Ma C et al (2009) Overexpression of glycogen synthase kinase 3beta sensitizes neuronal cells to ethanol toxicity. J Neurosci Res 87:2793–2802
Rowe MK, Chuang DM (2004) Lithium neuroprotection: molecular mechanisms and clinical implications. Expert Rev Mol Med 6:1–18
Jope RS (2003) Lithium and GSK-3: one inhibitor, two inhibitory actions, multiple outcomes. Trends Pharmacol Sci 24:441–443
Petit-Paitel A, Brau F, Cazareth J et al (2009) Involvment of cytosolic and mitochondrial GSK-3beta in mitochondrial dysfunction and neuronal cell death of MPTP/MPP-treated neurons. PLoS One 4:e5491
Olanow CW, Kordower JH (2009) Modeling Parkinson’s disease. Ann Neurol 66:432–436
Acknowledgments
We would like to thank Kimberly A. Bower for reading this manuscript. This research was supported by grants from the Ministry of Science and Technology of China (2010CB912000; 2007CB947100), the National Natural Science Foundation of China (30870812 and 30570580), the Knowledge Innovation Program of the Chinese Academy of Sciences (KSCX2-YW-R-115), the Chief Scientist Program of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences (SIBS2008006), and Science and Technology Commission of Shanghai Municipality (Grant No. 07DJ14005). Dr Z. J. Ke was also supported by the One Hundred Talents Program of the Chinese Academy of Sciences, and Shanghai Pujiang Program. Dr J. Luo was also supported by a grant from NIH/NIAAA (AA015407).
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Yong, Y., Ding, H., Fan, Z. et al. Lithium Fails to Protect Dopaminergic Neurons in the 6-OHDA Model of Parkinson’s Disease. Neurochem Res 36, 367–374 (2011). https://doi.org/10.1007/s11064-010-0368-z
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11064-010-0368-z