Chronic lithium treatment robustly protects neurons in the central nervous system against excitotoxicity by inhibiting N -methyl- d -aspartate receptor-mediated calcium influx

Abstract

Lithium is the most commonly used drug for the treatment of manic depressive illness. The precise mechanisms underlying its clinical efficacy remain unknown. We found that long-term exposure to lithium chloride dramatically protects cultured rat cerebellar, cerebral cortical, and hippocampal neurons against glutamate-induced excitotoxicity, which involves apoptosis mediated by N-methyl-Daspartate (NMDA) receptors. This neuroprotection is longlasting, occurs at therapeutically relevant concentrations of lithium with an EC 50 of approximately 1.3 mM, and requires treatment for 6-7 days for complete protection to occur. In contrast, a 24-h treatment with lithium is ineffective. The protection in cerebellar neurons is specific for glutamateinduced excitotoxicity and can be attributed to inhibition of NMDA receptor-mediated calcium inf lux measured by 45 Ca 2؉ uptake studies and fura-2 f luorescence microphotometry. The long-term effects of lithium are not caused by down-regulation of NMDA receptor subunit proteins and are unlikely related to its known ability to block inositol monophosphatase activity. Our results suggest that modulation of glutamate receptor hyperactivity represents at least part of the molecular mechanisms by which lithium alters brain function and exerts its clinical efficacy in the treatment for manic depressive illness. These actions of lithium also suggest that abnormality of glutamatergic neurotransmission as a pathogenic mechanism underlying bipolar illness warrants future investigation.

Valproic acid inhibits histone deacetylase activity and suppresses excitotoxicity-induced GAPDH nuclear accumulation and apoptotic death in neurons

“…SYM-induced excitotoxicity in CGC was completely blocked by an NMDA receptor antagonist, MK-801, reminiscent with the finding that glutamate or domoic acid-induced Ca 2 þ influx and toxicity in CGC is preferentially blocked by NMDA receptor blockers. 21,22 Our results suggest that SYM-induced apoptosis is due to the accumulation of glutamate resulting from inhibition of EAATs 14 or enhanced glutamate release due to the activation of kainate receptors, 15,22 thus in turn Figure 5 VPA delays the accumulation of GAPDH in the nuclei of CGC following SYM treatment. (A) Immunohistochemistry of GAPDH.…”

No association of three GRIN2B polymorphisms with lithium response in bipolar patients

“…This has been confirmed in animal models where radio-ligand binding of [3H]-MK801 or other NMDA receptor antagonists was decreased in the cerebral cortex of mice after the chronic administration of antidepressant drugs [8,14]. Moreover, it has been found that lithium indirectly reduces pro-apoptotic function in neurons by inhibiting N-methyl-D-aspartate (NMDA)-receptor-mediated calcium influx [12], and this action appears to be associated with changes in NMDA receptor subunit levels [4,12]. In cortical neurons, such calcium influx inhibition is correlated with a decrease in GRIN2B phosphorylation [4].…”

“…In recent years, it has been indicated that lithium may affect the biophysical properties of ionotropic glutamate receptors [6,7]. It was also established that lithium exerts its neuroprotective effect through the reduction of NMDA receptor-induced excitotoxicity [5,12]. This has been confirmed in animal models where radio-ligand binding of [3H]-MK801 or other NMDA receptor antagonists was decreased in the cerebral cortex of mice after the chronic administration of antidepressant drugs [8,14].…”

Chronic lithium treatment of B lymphoblasts from bipolar disorder patients reduces transient receptor potential channel 3 levels

“…For example, chronic Li treatment attenuated NMDA receptormediated Ca 2 þ influx in neuronal preparations. 11 As well, Li treatment decreased both [Ca 2 þ ] B and stimulated Ca 2 þ responses in a variety of cell lines including cultured astrocytes, 12 C6 glioma cells 13 and rat GH 3 pituitary cells. 14 In a more direct clinical paradigm, therapeutic levels of Li significantly lowered [Ca 2 þ ] B and [Ca 2 þ ] S in platelets from BD patients but not in control subjects.…”