Neuroprotective effects of lithium in cultured cells and animal models of diseases.
Lithium, the major drug used to treat manic depressive illness, robustly protects cultured rat brain neurons from glutamate excitotoxicity mediated by N-methyl-D-aspartate (NMDA) receptors. The lithium neuroprotection against glutamate excitotoxiciy is long-lasting, requires long-term pretreatment and occurs at therapeutic concentrations of this drug. The neuroprotective mcchanisms involve inactivation of NMDA receptors, decreased expression of pro-apoptotic proteins, p53 and Bax, enhanced expression of the cytoprotective protein, Bcl-2, and activation of the cell survival kinase, Akt. In addition, lithium pretreatment suppresses glutamate-induced loss of the activities of Akt, cyclic AMP-response element binding protein (CREB), c-Jun - N-terminal kinase (JNK) and p38 kinase. Lithium also reduces brain damage in animal models of neurodegenerative diseases in which excitotoxicity has been implicated. In the rat model of stroke using middle cerebral artery occlusion, lithium markedly reduces neurologic deficits and decreases brain infarct volume even when administered after the onset of ischemia. In a rat Huntington's disease model, lithium significantly reduces brain lesions resulting from intrastriatal infusion of quinolinic acid, an excitotoxin. Our results suggest that lithium might have utility in the treatment of neurodegenerative disorders in addition to its common use for the treatment of bipolar depressive patients.
Chuang
De-Maw
DM
Section on Molecular Neurobiology, Mood and Anxiety Disorder Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-1363, USA. chuang@helix.nih.gov
Chen
Ren-Wu
RW
Chalecka-Franaszek
Elzbieta
E
Ren
Ming
M
Hashimoto
Ryota
R
Senatorov
Vladimir
V
Kanai
Hirohiko
H
Hough
Christopher
C
Hiroi
Toyoko
T
Leeds
Peter
P
D000818:Animals; D001714:Bipolar Disorder / Q000188:drug therapy; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000187:drug effects; D004195:Disease Models, Animal; D018698:Glutamic Acid / Q000378:metabolism; D016651:Lithium Carbonate / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D020521:Stroke / Q000188:drug therapy
D017362:Cyclic AMP Response Element-Binding Protein; D016194:Receptors, N-Methyl-D-Aspartate; D016651:Lithium Carbonate; D018698:Glutamic Acid