elevated levels during neurite growth during development or regeneration, and a >3-fold increase in GAP-43 levels was observed after 5 days’ VPA exposure.127,142 Follow-up studies have recently shown that, similar to the effects

observed in neuroblastoma cells in vitro, chronic lithium or VPA also robustly increases the levels of activated ERK in areas of brain that, have been implicated in the pathophysiology and treatment, of BD: the FC and hippocampus.142 Interestingly, neurotrophic factors are now known Inhibitors,research,lifescience,medical to promote cell survival by activating MAP kinases to suppress intrinsic, cellular apoptotic machinery, not by inducing cell survival pathways (see above).129,131-134,144-146 Thus, a downstream target of the MAP kinase cascade, ribosomal S -6 kinase (Rsk) phosphorylat.es

CREB and this leads to induction of bcl-2 gene expression (Figure 1). Recent studies have therefore undertaken to determine if lithium or VPA regulates the expression of bcl-2. Chronic treatment of rats with “therapeutic” doses of lithium and Inhibitors,research,lifescience,medical VPA produced a doubling of bcl-2 levels in FC, effects that were primarily due to a marked increase in the number of bcl-2 immunoreactive cells in layers II and III of FC.147-149 Interestingly, the importance of neurons in layers II to IV of the Inhibitors,research,lifescience,medical FC in mood disorders has recently been emphasized, since primate studies indicate that these areas are important for providing connections with other cortical regions,

and that, they are targets for subcortical input.150 Chronic lithium also markedly increased the number of bcl-2 immunoreactive cells in the dentate Inhibitors,research,lifescience,medical gyrus and striatum144; and detailed immunohistochcmical studies following chronic Inhibitors,research,lifescience,medical VPA treatment are currently underway. Subsequent to these findings, it has been demonstrated that lithium also increases bcl-2 levels in C57BL/6 mice,146 in neuroblastoma SH-SY5Y cells (human neuronal origin) in vitro,151 and in rat VX-689 in vitro cerebellar granule cells in vitro.152 The latter study was undertaken as part of investigations into the molecular and cellular before mechanisms underlying the neuroprotective actions of lithium against glutamate excitotoxicity (see below). These investigators found that lithium produced a remarkable increase in bcl-2 protein and mRNA levels. Moreover, lithium has recently been demonstrated to reduce the levels of the proapoptotic protein p53 both in cerebellar granule cells152 and in neuroblastoma SH-SY5Y cells.153 Thus, overall, the data clearly show that chronic lithium robustly increases the levels of the neuroprotective protein bcl-2 in areas of rodent FC, hippocampus, and striatum in vivo, and in cultured cells of both rodent and human neuronal origin in vitro. Furthermore, at least in cultured cell systems, lithium has also been demonstrated to reduce the levels of the proapoptotic protein p53.