How does Lithium work? : Therapeu Advan in Psychopharm June 2013

27.06.2013

Lithium’s therapeutic role in manic illness was shown in 1949. The mechanisms of its action still remains not completely understood.

Kayleigh M. Brown and Derek K. Tracy review the current understanding regarding the mechanisms of action in this article.

Lithium does not bind to cellular receptors. Lithium act by modify the intracellular second messenger systems and downstream of metabotropic neurotransmitter receptors, via enzyme inhibition. Two such pathways are  phosphatidylinositol (PI) signalling pathway  and the protein kinase glycogen synthase kinase 3β (GSK-3β).

Lithium deplete free myo-inositol ( an essential component of the PI intracellular signalling pathway). concentrations and this can alter cell signalling. The enzyme  IMPase  regenerates myo-inositol  and lithium inhibits this enzyme.Magnetic resonance spectroscopy (MRS) have shown abnormal PI-cycle activity and elevated myo-inositol concentrations in patients with bipolar disorders. We do not have any blood–brain barrier penetrant IMPase inhibitors  to evaluate the precise biochemical and therapeutic effects of lithium-induced inositol depletion. This depletion seems to start a cascade which probably ends in changes in gene expression.

Glycogen synthase kinase 3 (GSK3 ) is regulator of various signalling pathways.GSK3 displays high activity in cells under resting conditions. Phosphorylation at different sites of GSK can either increase or decrease the activity. Activation of protein Kinase b   provide the most prevalent negative regulation of GSK3   by phosphorylatin the threonine residue of GSK 3. Lithium directly and indirectly inhibit GSK3  and part of this is via Protein Kinase B.

The inhibitory effects of lithium on enzymatic targets such as GSK3 and IMPase might be through the competition between lithium and the native enzymatic cofactor magnesium for metal-binding sites. Lithium and magnesium  have similar ionic radii and  physical/chemical properties.

Downstream effects of enzyme inhibition results in various changes that include:  1.  cytoskeletal growth stabilisation and plasticity.GSK3 inhibition can disrupt microtubule assembly, with effects on cytoskeletal protein association dynamics which might mediate neuroplastic changes. 2.Inhibition of glutamatergic excitotoxicity via NMDA receptor-mediated calcium influx 3. inhibition of autophagy 4.Increasing neuronal growth cones 5. Induction and upregulation of the cortical  (BDNF) and vascular endothelial growth factor.6. Reduction of IP3 levels inhibit calcium release from the Endoplasmic Reticulum with effects on neuronal functioning.

Conclusion:  The PI and GSK3 enzymatic pathways are altered by lithium. Magnesium displacement might be a common mechanism of action. Precise contribution of each to clinical effects is uncertain. 

Summary of the article: Lithium: the pharmacodynamic actions of the amazing ion: Kayleigh M. Brown and Derek K. Tracy.Ther Adv Psychopharmacol.(2013) 3(3) 163–176

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