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. Author manuscript; available in PMC: 2012 Jun 1.
Published in final edited form as: Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2011 Jun;36(6):461–476. doi: 10.3969/j.issn.1672-7347.2011.06.001

Fig. 1. A schematic iilustration of proposed mechanisms underlying lithium's neuroprotective effects.

Fig. 1

Lithium can directly and indirectly inhibit constitutively activated glycogen synthase kinase-3 (GSK-3) by multiple mechanisms, leading to disinhibition of several transcription factors, including cyclic AMP-response element binding protein (CREB), heat-shock factor-1 (HSF-1), and β-catenin, and subsequent induction of major cytoprotective proteins such as brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), heat shock protein (HSP)70, and B-cell lymphoma/leukemia-2 protein (Bcl-2). Lithium-induced neurotrophic factors such as BDNF, in turn, activate its cell surface receptor and the downstream phosphoinositide 3-kinase (PI3K)/Akt and MAP kinase kinase (MEK)/extracellular-signal regulated kinase (ERK) pathways. BDNF induction is an early and essential step for neuroprotection against glutamate excitotoxicity and may contribute to lithium-induced neurogenesis. Lithium also indirectly inhibits GSK-3 activity via PI3K-dependent activation of protein kinase C (PKC) and cAMP-dependent activation of protein kinase A (PKA). The ability of lithium to decrease inositol 1,4,5-trisphosphate (IP3) levels is a novel route for inducing autophagy. Furthermore, lithium inhibits N-methyl-D-aspartate (NMDA) receptor-mediated calcium influx, which in turn decreases subsequent activation of c-Jun N-terminal kinase (JNK), p38 kinase, and transcription factor activator protein-1 (AP-1). Inhibition of intracellular calcium increase not only suppreses cellular stress, but also reduces the activity of calpain and calpain-mediated activation of pro-apoptotic cyclin-dependent kinase 5 (Cdk5)/p25 kinase. Lines with solid arrows represent stimulatory connections; lines with flattened ends represent inhibitory connections. Dashed lines represent pathways with reduced activity as a result of lithium treatment.