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
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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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Available from: Mercè Pallàs, Oct 09, 2015
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    • "Consequently, J in was decreased in wildtype and HIV-1 Tg rats under Lithium's ability to attenuate increases in k* and J in for AA could have been due to downregulation of cPLA 2 and cyclooxygenase-2 expression, and brain PGE 2 concentration, which are all increased in the HIV-1 Tg rat brain (Chang and Jones 1998; Bosetti et al. 2002a; Rao et al. 2005; Rintala et al. 1999; Rao et al. 2011), or to attenuation of brain Nmethyl-D-aspartate receptor-initiated signaling via AA (Basselin et al. 2006; Ma and Zhang 2003) (Fig. 3). Lithium also may have inhibited glycogen synthetase kinase-3 beta (Dou et al. 2005; O'Brien et al. 2011; Maggirwar et al. 1999) or interfered with the cyclin-dependent kinase 5 (Wang et al. 2007; Jorda et al. 2005). Lithium's blocking of intracellular events is consistent with evidence that it has neuroprotective properties (see Introduction). "
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    ABSTRACT: HIV-1 transgenic (Tg) rats, a model for human HIV-1 associated neurocognitive disorder (HAND), show upregulated markers of brain arachidonic acid (AA) metabolism with neuroinflammation after 7 months of age. Since lithium decreases AA metabolism in a rat lipopolysaccharide model of neuroinflammation, and may be useful in HAND, we hypothesized that lithium would dampen upregulated brain AA metabolism in HIV-1 Tg rats. Regional brain AA incorporation coefficients k* and rates J ( in ), markers of AA signaling and metabolism, were measured in 81 brain regions using quantitative autoradiography, after intravenous [1-(14) C]AA infusion in unanesthetized 10-month-old HIV-1 Tg and age-matched wildtype rats that had been fed a control or LiCl diet for 6 weeks. k* and J ( in ) for AA were significantly higher in HIV-1 Tg than wildtype rats fed the control diet. Lithium feeding reduced plasma unesterified AA concentration in both groups and J ( in ) in wildtype rats, and blocked increments in k* (19 of 54 regions) and J ( in ) (77 of 81 regions) in HIV-1 Tg rats. These in vivo neuroimaging data indicate that lithium treatment dampened upregulated brain AA metabolism in HIV-1 Tg rats. Lithium may improve cognitive dysfunction and be neuroprotective in HIV-1 patients with HAND through a comparable effect.
    Journal of Neuroimmune Pharmacology 07/2012; 7(3):701-13. DOI:10.1007/s11481-012-9381-0 · 4.11 Impact Factor
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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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    ABSTRACT: Human T-cell leukemia virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurodegenerative disease characterized by selective loss of axons and myelin in the corticospinal tracts. This central axonopathy may originate from the impairment of anterograde axoplasmic transport. Previous work showed tau hyperphosphorylation at T(181) in cerebrospinal fluid of HAM/TSP patients. Similar hyperphosphorylation occurs in SH-SY5Y cells incubated with supernatant from MT-2 cells (HTLV-I-infected lymphocytes secreting viral proteins, including Tax) that produce neurite shortening. Tau phosphorylation at T(181) is attributable to glycogen synthase kinase 3-β (GSK3-β) and cyclin-dependent kinase 5 (CDK5) activation. Here we investigate whether neurite retraction in the SH-SY5Y model associates with concurrent changes in other tau hyperphosphorylable residues. Threonine 181 turned out to be the only tau hyperphosphorylated residue. We also evaluate the role of GSK3-β and CDK5 in this process by using specific kinase inhibitors (LiCl, TDZD-8, and roscovitine). Changes in both GSK3-β active and inactive forms were followed by measuring the regulatory phosphorylable sites (S(9) and Y(216) , inactivating and activating phosphorylation, respectively) together with changes in β-catenin protein levels. Our results showed that LiCl and TDZD-8 were unable to prevent MT-2 supernatant-mediated neurite retraction and also that neither Y(216) nor S(9) phosphorylations were changed in GSK3-β. Thus, GSK3-β seems not to play a role in T(181) hyperphosphorylation. On the other hand, the CDK5 involvement in tau phosphorylation was confirmed by both the increase in its enzymatic activity and the absence of MT-2 neurite retraction in the presence of roscovitine or CDK5 siRNA transfection.
    Journal of Neuroscience Research 09/2011; 89(9):1489-98. DOI:10.1002/jnr.22678 · 2.59 Impact Factor
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    • "Sustained activation of Cdk5 in neurons has been implicated in many neurodegenerative diseases (Cruz and Tsai, 2004; Dhariwala and Rajadhyaksha, 2008). In cultured rat CGCs, lithium pretreatment prevented colchicine-induced apoptosis and associated increase in Cdk5 expression and fragmentation of p35 into p25 (Jorda et al., 2005). Additionally, pretreatment with lithium also attenuated intracellular calcium increase, calpain activity, Cdk5 activation, and cellular death in primary cultured hippocampal neurons and rat striatum following the treatment of 3-nitropropionic acid (Crespo-Biel et al., 2009), a succinate dehydrogenase inhibitor (for review, Brouillet et al., 1999). "
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    ABSTRACT: The mood stabilizer lithium inhibits glycogen synthase kinase-3 (GSK-3) directly or indirectly by enhancing serine phosphorylation of both α and β isoforms. Lithium robustly protected primary brain neurons from glutamate-induced excitotoxicity; these actions were mimicked by other GSK-3 inhibitors or silencing/inhibiting GSK-3α and/or β isoforms. Lithium rapidly activated Akt to enhance GSK-3 serine phosphorylation and to block glutamate-induced Akt inactivation. Lithium also up-regulated Bcl-2 and suppressed glutamate-induced p53 and Bax. Induction of brain-derived neurotrophic factor (BDNF) was required for lithium's neuroprotection to occur. BDNF promoter IV was activated by GSK-3 inhibition using lithium or other drugs, or through gene silencing/inactivation of either isoform. Further, lithium's neuroprotective effects were associated with inhibition of NMDA receptor-mediated calcium influx and down-stream signaling. In rodent ischemic models, post-insult treatment with lithium decreased infarct volume, ameliorated neurological deficits, and improved functional recovery. Up-regulation of heat-shock protein 70 and Bcl-2 as well as down-regulation of p53 likely contributed to lithium's protective effects. Delayed treatment with lithium improved functional MRI responses, which was accompanied by enhanced angiogenesis. Two GSK-3-regulated pro-angiogenic factors, matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor were induced by lithium. Finally, lithium promoted migration of mesenchymal stem cells (MSCs) by up-regulation of MMP-9 through GSK-3β inhibition. Notably, transplantation of lithium-primed MSCs into ischemic rats enhanced MSC migration to the injured brain regions and improved the neurological performance. Several other GSK-3 inhibitors have also been reported to be beneficial in rodent ischemic models. Together, GSK-3 inhibition is a rational strategy to combat ischemic stroke and other excitotoxicity-related brain disorders.
    Frontiers in Molecular Neuroscience 08/2011; 4:15. DOI:10.3389/fnmol.2011.00015 · 4.08 Impact Factor
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