2005], thus it follows that lithium potentially exerts a therapeutic effect by affecting cell signalling as a result of IMPase inhibition, and subsequent reduction
of elevated inositol and phosphatidylinositol levels [Haimovich et al. 2012]. This notion is further supported by the fact that lithium is an uncompetitive inhibitor of IMPase [Berridge and Irvine, 1989], thus the level of inhibition increases at high substrate concentrations; since myo-inositol levels are higher in bipolar patients [Silverstone et al. 2005], the level of inhibition Inhibitors,research,lifescience,medical is increased in these individuals, potentially explaining why lithium treatment is effective in bipolar disorders Inhibitors,research,lifescience,medical but not in comparative normal subjects [Berridge and Irvine, 1989]. Despite the extensive evidence in support of inositol depletion as a viable explanation of lithium’s pharmacodynamic actions, other click here observations have been inconsistent and often contradictory [Marmol, 2008]. Shaltiel and colleagues, for example, found reduced IMPase activity in lymphocyte-derived Inhibitors,research,lifescience,medical cell lines of bipolar patients [Shaltiel et al. 2001]. A lack of novel blood–brain barrier penetrant
IMPase inhibitors currently limits evaluating the precise biochemical and therapeutic effects of lithium-induced inositol depletion [Gould and Manji, 2005]. The mechanism by which lithium exerts its effects on the PI signalling pathway is still unclear, and it remains possible, for example, that a decrease in intracellular myo-inositol is only the first
stage of Inhibitors,research,lifescience,medical action, initiating a cascade of secondary changes in the PKC signalling pathway and gene expression [Agam et al. 2002; Manji and Chen, 2002], that are ultimately associated with lithium’s Inhibitors,research,lifescience,medical therapeutic efficacy. Further research, and the development of appropriate pharmacological agents, are therefore still required, to enable results of greater consistency, and to determine the exact mechanism by which lithium-induced inositol depletion has a therapeutic effect in patients with mood disorders. Glycogen synthase kinase 3 The ubiquitous serine/threonine protein kinase glycogen synthase kinase 3 (GSK3), offers another potential target for lithium. GSK3 is a critical CYTH4 downstream regulator of diverse signalling pathways [Zhang et al. 2003; Chiu and Chuang, 2010], and has a key role in the regulation of a number of cell functions, including insulin receptor signalling, the specification of cell fates during embryonic development, immunity and inflammation responses and neurotransmission [Cohen and Frame, 2001; Kaidanovich-Beilin and Woodgett, 2011].