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Lithium protection against glutamate excitotoxicity in rat cerebral cortical neurons: involvement of NMDA receptor inhibition possibly by decreasing NR2B tyrosine phosphorylation
Author(s) -
Hashimoto Ryota,
Hough Christopher,
Nakazawa Takanobu,
Yamamoto Tadashi,
Chuang DeMaw
Publication year - 2002
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.0022-3042.2001.00728.x
Subject(s) - excitotoxicity , nmda receptor , glutamate receptor , chemistry , neuroscience , lithium (medication) , phosphorylation , metabotropic glutamate receptor 5 , tyrosine phosphorylation , receptor , pharmacology , endocrinology , metabotropic glutamate receptor , biology , biochemistry
Abstract The therapeutic mechanisms of lithium for treating bipolar mood disorder remain poorly understood. Recent studies demonstrate that lithium has neuroprotective actions against a variety of insults. Here, we studied neuroprotective effects of lithium against excitotoxicity in cultured cerebral cortical neurons. Glutamate‐induced excitotoxicity in cortical neurons was exclusively mediated by NMDA receptors. Pre‐treatment of cortical neurons with LiCl time‐dependently suppressed excitotoxicity with maximal protection after 6 days of pre‐treatment. Significant protection was observed at the therapeutic and subtherapeutic concentration of 0.2–1.6 m m LiCl with almost complete protection at 1 m m . Neuroprotection was␣also elicited by valproate, another major mood‐stabilizer. The neuroprotective effects of lithium coincided with inhibition␣of␣NMDA receptor‐mediated calcium influx. Lithium pre‐treatment did not alter total protein levels of NR1, NR2A and NR2B subunits of NMDA receptors. However, it did markedly reduce the level of NR2B phosphorylation at Tyr1472 and this was temporally associated with its neuroprotective effect. Because NR2B tyrosine phosphorylation has been positively correlated with NMDA receptor‐mediated synaptic activity and excitotoxicity, the suppression of NR2B phosphorylation by lithium is likely to result in the inactivation of NMDA receptors and contributes to neuroprotection against excitotoxicity. This action could also be relevant to its clinical efficacy for bipolar patients.