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Lithium’s Gene Expression Profile, Relevance to Neuroprotection A cDNA Microarray Study

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A Correction to this article was published on 22 August 2022

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Abstract

Lithium can prevent 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) dopaminergic neurotoxicity in mice. This is attributed to induced antioxidant and antiapoptotic state, which among other factors results from induction of Bcl-2 and reduction of Bax, however, cDNA microarray reveals that this represents only one cascade of lithium targets. From analyzing the gene expression profile of lithium, we are able to point out candidate genes that might be involved in the antioxidant and neuroprotective properties of lithium. Among these are, the cAMP response element binding (CREB) protein, extracellular signal-regulated kinase (ERK), both CREB and ERK—part of the mitogen-activated kinase pathway—were upregulated by lithium, downregulated by MPTP, and maintained in mice fed with lithium chloride (LiCl) supplemented diet and treated with MPTP. Our positive control included tyrosine hydroxylase which both its mRNA and protein levels were independently measured, in addition to Bcl-2 protein levels. Other important genes which were similarly regulated are plasma glutathione peroxidase precursor (GSHPX-P), protein kinase C alpha type, insulin-like growth factor binding protein 4 precursor, and interferon regulatory factor. In addition, some genes were oppositely regulated, i.e., downregulated by lithium, upregulated by MPTP, and maintained in mice fed with LiCl supplemented diet and treated with MPTP, among these genes were basic fibroblast growth factor receptor 1 precursor, inhibin alpha subunit, glutamate receptor subunit zeta 1 precursor (NMD-R1), postsynaptic density protein-95 which together with NMD-R1 can form an apoptotic promoting complex. The discussed targets represent part of genes altered by chronic lithium. In fact lithium affected the expressions of more than 50 genes among these were basic transcription factors, transcription activators, cell signaling proteins, cell adhesion proteins, oncogenes and tumor suppressors, intracellular transducers, survival and death genes, and cyclins, here we discuss the relevance of these changes to lithium’s reported neuroprotective properties.

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Abbreviations

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

TH:

Tyrosine hydroxylase

PD:

Parkinson’s disease

SNpc:

Substantia nigra pars compact

ERK:

Extracellular-regulated kinase

CREB:

cAMP responsive element binding

MAPK:

Mitogen-activated protein kinase

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Authors and Affiliations

  1. Department of Internal Medicine B, Ziv Medical Center, Safed, Israel

    Raymond Farah

  2. Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel

    Raymond Farah

  3. Clalit Health Service, Western Galilee, Israel

    Rola Khamisy-Farah

  4. Department of Pharmacology, the Bruce Rappaport Family Faculty of Medicine, Technion, Haifa, Israel

    Zaher Arraf, Zaher Arraf, Tamar Amit & Moussa B. H. Youdim

Authors
  1. Zaher Arraf
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  2. Rola Khamisy-Farah
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  3. Tamar Amit
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  4. Moussa B. H. Youdim
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  5. Raymond Farah
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Correspondence to Zaher Arraf or Raymond Farah.

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The original online version of this article was revised: the order of author names has been corrected and included Zaher Arraf as co-corresponding author.

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Arraf, Z., Khamisy-Farah, R., Amit, T. et al. Lithium’s Gene Expression Profile, Relevance to Neuroprotection A cDNA Microarray Study. Cell Mol Neurobiol 33, 411–420 (2013). https://doi.org/10.1007/s10571-013-9907-x

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