Neuropharmacology

Biography

Biography: Galila Agam

Abstract

Compromised neuroplasticity and neuroprotection, mitochondrial and autophagy-dysfunction and neuroinflamation are implicated in the pathophysiology of bipolar-disorder, neurodevelopmental disorders and neurodegenerative disorders including ALS. Lithium, the prototype drug for bipolar-disorder, is neuroprotective. Among molecular effects the drug modulates the phosphatidylinositol system. It causes build-up of brain inositol-phosphates and depletion of free-inositol due to inhibition of the brain-abundant inositol-monophosphatase (IMPase)-1, and reduces mRNA levels of the sodium-myo-inositol transporter (SMIT1). IMPase-1 is encoded by IMPA1. Knockout of each of IMPA1 and SMIT1 in mice results in behavioral alterations found in lithium-treated mice. We carried out a DNA microarrays study, MS-MS proteomics accompanied by Westernblot analysis and multiplex cytokines protein levels analysis in the frontal-cortex of chronic lithium-treated mice [food supplementation, mean blood-levels 0.89 mEq/L±0.43 (S.D.)] and in IMPA1- and SMIT1-knockout mice. Pathway analysis of the microarrays results indicated transcriptional effects common to lithium-treatment and to each of the knockouts culminating in increased mitochondrial-function. The proteomic study indicated that enhanced autophagy is common to lithium-treatment and IMPA1-knockout. Both lithium-treatment and IMPA1-knockout reduced the levels of seven hippocampal pro-inflammatory cytokines by 56-73%. The results strongly suggest that unlike some of the previous ALS studies in rodents and humans an appropriate regime of chronic lithium-treatment, reaching blood-levels that are therapeutically-relevant in bipolar-disorder, induces augmentation of mitochondrial-function and autophagy and modulates neuroinflammation. Therefore, the potential beneficial effect of lithium for neurodegenerative disorders, in general, and ALS, in particular, deserves serious attention.