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Lithium Fails to Protect Dopaminergic Neurons in the 6-OHDA Model of Parkinson’s Disease

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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.

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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

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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).

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Correspondence to Jia Luo or Zun-Ji Ke.

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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

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