[Neuroprotective actions of lithium]

Area of Science:

• Neuroscience
• Pharmacology
• Cell Biology

Context:

• Lithium is a primary treatment for bipolar disorder, but its mechanisms are unclear.
• Clinical evidence suggests lithium possesses neurotrophic and neuroprotective properties.
• Understanding lithium's molecular actions is crucial for its therapeutic applications.

Purpose:

• To elucidate the molecular mechanisms underlying lithium's neuroprotective and neurotrophic effects.
• To investigate lithium's impact on neuronal survival, progenitor cell proliferation, and neuroplasticity.
• To explore lithium's therapeutic potential in animal models of neurological disorders.

Summary:

• Lithium (0.2-1.2 mM) protects cultured cortical neurons from glutamate excitotoxicity by reducing NMDA receptor-mediated calcium influx, decreasing NR2B subunit tyrosine phosphorylation, and inhibiting Src kinase activity.
• Lithium-induced neuroprotection is dependent on brain-derived neurotrophic factor (BDNF) and its receptor TrkB, as lithium increases intracellular BDNF levels and activates TrkB.
• Long-term lithium treatment stimulates cortical progenitor cell proliferation and protects against glutamate-, glucocorticoid-, and haloperidol-induced decreases in proliferation, suggesting a role in central nervous system (CNS) neuroplasticity.
• In vivo, lithium post-treatment reduced infarct volume and neurological deficits in a stroke model (MCAO/reperfusion) by activating heat-shock factor-1 and inducing heat-shock protein-70.
• Lithium mitigated excitotoxin-induced neuronal loss in a Huntington's disease model by up-regulating Bcl-2 and down-regulating p53 and Bax, reducing DNA damage and caspase-3 activation.

Impact:

• Provides novel insights into the molecular mechanisms of lithium neuroprotection against excitotoxicity.
• Suggests that lithium's neurotrophic and neuroprotective actions may contribute to its efficacy in bipolar disorder patients.
• Highlights the potential expanded use of mood stabilizers like lithium for treating excitotoxin-related neurodegenerative diseases.