Implication of cyclin-dependnet kinase 5 in the neuroprotective properties of Lithium

Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Universitat de Barcelona, Nucli Universitari de Pedralbes, E-08028 Barcelona, Spain.
Neuroscience (Impact Factor: 3.36). 02/2005; 134(3):1001-11. DOI: 10.1016/j.neuroscience.2005.04.061
Source: PubMed


Although numerous studies have demonstrated a neuroprotective and anti-apoptotic role of lithium in neuronal cell cultures, the precise mechanism by which this occurs, remains to be elucidated. In this study, we evaluated the lithium-mediated neuroprotection against colchicine-induced apoptosis in cultured cerebellar granule neurons. Previously, it has been demonstrated that colchicine mediates apoptosis in cerebellar granule neurons through cytoskeletal alteration and activation of an intrinsic pro-apoptotic pathway. Recently we also demonstrated a potential role of cyclin-dependent kinase 5 (cdk5) in this pathway. Here we report that colchicine induces dephosphorylation in Ser-9 and phosphorylation in Tyr-216, and thus activation, of glycogen synthase kinase-3beta in cerebellar granule neurons, and that this modification is inhibited by the presence of 5 mM lithium. However, the selective glycogen synthase kinase-3beta inhibitors SB-415286 and SB-216763 were unable to prevent colchicine-induced apoptosis in these cells, suggesting that the anti-apoptotic activity of lithium is not mediated by glycogen synthase kinase-3beta under these conditions. On the other hand, 5 mM lithium prevented the colchicine-induced increase in cdk5 expression and breakdown of cdk5/p35 to cdk5/p25. In addition, we show that up-regulation of cdk5/p25 is unrelated to inhibition of the activity of myocyte enhancer factor 2, a pro-survival transcription factor. These data suggest a previously undescribed neuroprotective mechanism of lithium associated with the modulation of cdk5/p35 or cdk5/p25 expression.

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    • "Lithium inhibits GSK3-β directly by competing with Mg 2+ and, indirectly, through phosphatase inhibition, PP2A, then increasing phosphorylation at S 9 (Tajes et al., 2009). In addition, lithium reduces intracellular Ca 2+ that promotes calpain-mediated proteolysis of p35 into p25, thus reducing CDK5 hyperactivation (Jorda et al., 2005; Crespo- Biel et al., 2009; Crews et al., 2009; Tajes et al., 2009). While studying the effect of gp120 from HIV on SH-SY5Y cells, Crews et al. (2009) observed a lower CDK5 activity in cells preincubated with LiCl in the absence of the neurotoxic agent. "
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