Lithium induces brain-derived neurotrophic factor and activates TrkB in rodent cortical neurons: an essential step for neuroprotection against glutamate excitotoxicity.
Mechanisms underlying the therapeutic effects of lithium for bipolar mood disorder remain poorly understood. Recent studies demonstrate that lithium has neuroprotective actions against a variety of insults in vitro and in vivo. This study was undertaken to investigate the role of the brain-derived neurotrophic factor (BDNF)/TrkB signaling pathway in mediating neuroprotection of lithium against glutamate excitotoxicity in cortical neurons. Pretreatment with either lithium or BDNF protected rat cerebral cortical neurons from glutamate excitotoxicity. The duration of treatment required to elicit maximal neuroprotection by BDNF (1 day) was much shorter than that by lithium (6 days). K252a, an inhibitor of Trk tyrosine kinases, and a BDNF neutralizing antibody suppressed the neuroprotective effect of lithium. Treatment of cortical neurons with lithium increased the cellular BDNF content in 3 days and the phosphorylation of TrkB at Tyr490 in 5 days, suggesting that long-term lithium administration enhances BDNF expression/secretion, leading to the activation of TrkB receptor. Lithium failed to protect against glutamate excitotoxicity in cortical neurons derived from homozygous and heterozygous BDNF knockout mice, although lithium fully protected cortical neurons prepared from wild type mice littermates. Taken together, these data suggest that the BDNF/TrkB pathway plays an essential role in mediating the neuroprotective effect of lithium.
Hashimoto
Ryota
R
Molecular Neurobiology Section, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-1363, USA.
Takei
Nobuyuki
N
Shimazu
Kazuhiro
K
Christ
Lori
L
Lu
Bai
B
Chuang
De-Maw
DM
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D018698:Glutamic Acid / Q000633:toxicity*; D018021:Lithium Chloride / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D020813:Receptor, trkB / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D019208:Brain-Derived Neurotrophic Factor; D018690:Excitatory Amino Acid Agonists; D018696:Neuroprotective Agents; D018698:Glutamic Acid; D020813:Receptor, trkB; D018021:Lithium Chloride