Potential mechanisms involved in the prevention of neurodegenerative diseases by lithium.
Lithium is a monovalent cation that was introduced in 1949 by John Cade for the treatment of bipolar disorder. Clinical reports and subsequent studies confirmed this application and the beneficial effects of this compound. However, over the last 15 years, various authors have also demonstrated the neuroprotective effects of lithium against several neurotoxic paradigms. Thus, experimental studies in neuronal cell cultures and animal models of Alzheimer disease and others pathologies have provided strong evidence for the potential benefits of lithium. The main mechanism underlying its neuroprotective effects is thought to be inhibition of glycogen synthase kinase-3 (GSK-3), although other biochemical pathways in the brain could also be affected. In this review, the main mechanisms of lithium action are summarized, including the modulation of glutamate receptors, effects on arachidonic acid metabolism, its role with respect to AKT, and other potential mechanisms. In addition, its effects on neuroprotective proteins such as Bcl-2 and p53 are also discussed. Although the cellular and molecular biological effects of lithium may constitute an effective therapeutic strategy for Alzheimer disease, further clinical and experimental studies with this drug and specific GSK-3 inhibitors are necessary to confirm the use of lithium in therapeutic approaches to neurodegenerative diseases.
Camins
Antoni
A
Unitat de Farmacologia i Farmacognòsia Facultat de Farmàcia, Centros de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Institut de Biomedicina (IBUB). Universitat de Barcelona, Barcelona, Spain. camins@ub.edu
Verdaguer
Ester
E
Junyent
Felix
F
Yeste-Velasco
Marc
M
Pelegrí
Carme
C
Vilaplana
Jordi
J
Pallás
Mercé
M
D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D018020:Lithium Compounds / Q000494:pharmacology*; D008954:Models, Biological; D020932:Nerve Growth Factor / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*
D018020:Lithium Compounds; D018696:Neuroprotective Agents; D020932:Nerve Growth Factor; D038362:Glycogen Synthase Kinase 3