Cellular and Molecular Neurobiology

, Volume 33, Issue 3, pp 411–420 | Cite as

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

  • Raymond Farah
  • Rola Khamisy-Farah
  • Tamar Amit
  • Moussa B. H. Youdim
  • Zaher Arraf
Original Research


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.


cDNA microarray Lithium Gene expression profile MPTP CREB MAP kinase ERK1 PKC Reverse transcription 





Tyrosine hydroxylase


Parkinson’s disease


Substantia nigra pars compact


Extracellular-regulated kinase


cAMP responsive element binding


Mitogen-activated protein kinase


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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Raymond Farah
    • 1
    • 2
  • Rola Khamisy-Farah
    • 3
  • Tamar Amit
    • 4
  • Moussa B. H. Youdim
    • 4
  • Zaher Arraf
    • 4
  1. 1.Department of Internal Medicine BZiv Medical CenterSafedIsrael
  2. 2.Faculty of Medicine in the GalileeBar-Ilan UniversitySafedIsrael
  3. 3.Clalit Health ServiceWestern GalileeIsrael
  4. 4.Department of Pharmacologythe Bruce Rappaport Family Faculty of Medicine, TechnionHaifaIsrael

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