Opposed effects of lithium on the MEK‐ERK pathway in neural cells: inhibition in astrocytes and stimulation in neurons by GSK3 independent mechanisms

Abstract

SummaryLithium is widely used in the treatment of bipolar disorder, but despite its proven therapeutic efficacy, the molecular mechanisms of action are not fully understood. The present study was undertaken to explore lithium effects of the MEK/ERK cascade of protein kinases in astrocytes and neurons. In asynchronously proliferating rat cortical astrocytes, lithium decreased time-and dose-dependently the phosphorylation of MEK and ERK, with 1 mM concentrations achieving 60 and 50% inhibition of ERK and MEK, respectively, after a 7-day exposure. Lithium also inhibited [ 3 H]thymidine incorporation into DNA and induced a G2/M cell cycle arrest. In serumdeprived, quiescent astrocytes, pre-exposure to lithium resulted in the inhibition of cell cycle re-entry as stimulated by the mitogen endothelin-1: under this experimental setting, lithium did not affect the rapid, peak phosphorylation of MEK taking place after 3-5 min, but was effective in inhibiting the long-term, sustained phosphorylation of MEK. Lithium inhibition of the astrocyte MEK/ERK pathway was independent of inositol depletion. Further, compound SB216763 inhibited Tau phosphorylation at Ser396 and stabilized cytosolic b-catenin, consistent with the inhibition of glycogen synthase kinase-3b (GSK-3b), but failed to reproduce lithium effects on MEK and ERK phosphorylation and cell cycle arrest. In cerebellar granule neurons, millimolar concentrations of lithium enhanced MEK and ERK phosphorylation in a concentrationdependent manner, again through an inositol and GSK-3b independent mechanism. These opposing effects in astrocytes and neurons make lithium treatment a promising strategy to favour neural repair and reduce reactive gliosis after traumatic injury. Lithium has been used in the treatment of bipolar mood disorder for decades, but despite its therapeutic efficacy, the molecular mechanisms underlying its actions remain unclear (Jope 1999;Phiel and Klein 2001). In this regard, based on the observation that lithium inhibits inositol monophosphatase and inositol polyphosphate 1-phosphatase, thereby blocking inositol 1,4,5-trisphosphate recycling to inositol, the inositol depletion hypothesis considered that persistent activation of phosphoinositide phospholipase C in the presence of lithium would lower the cellular inositol concentration, leading eventually to the depletion of phosphatidylinositol 4,5-bisphosphate and the impairment of calcium signalling (Berridge et al. 1989;Atack 1996). This hypothesis has received some support after the finding that lithium, carbamazepine, and valproic acid, all three drugs used in the treatment of bipolar disorder, increase growth cone area in sensory neurons, in a manner that was counteracted by inositol addition, and mediated probably by inhibition of prolyl oligopeptidase by an as yet unknown mechanism (Williams et al. 2002).In the past few years, however, lithium has emerged as a remarkable neuroprotective agent: it was first shown to protect cerebellar granule neurons from undergoing apoptotic cell death when cul...

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Pharmacologic Activation of Wnt Signaling by Lithium Normalizes Retinal Vasculature in a Murine Model of Familial Exudative Vitreoretinopathy

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