The NMDA receptor as a therapeutic target in major depressive disorder.
ABSTRACT Ample evidence indicates that glutamate homeostasis and neurotransmission are disrupted in major depressive disorder; but the nature of this disruption and the mechanisms by which it contributes to the syndrome are unclear. Likewise, the effect of existing antidepressants on glutamate is unclear, as is the potential of drugs directly targeting glutamatergic neurotransmission to act as novel antidepressant medications. These are areas of active research. Here we review current knowledge of the contribution of the NMDA receptor, one of the several types of glutamate receptor, to depression and its treatment. Several lines of evidence, in humans and in animal models, support the contention that neurotransmission via the NMDA receptor is dysregulated in depression. Drugs that target the NMDA receptor have shown antidepressant properties in both clinical and preclinical studies. Nevertheless, other effects of such medications, including both cognitive side effects and their psychotomimetic properties, complicate such an application and represent a challenge to the development of clinically useful agents.
SourceAvailable from: Jeroen H.F. de Baaij[Show abstract] [Hide abstract]
ABSTRACT: Magnesium (Mg2+) is an essential ion to the human body, playing an instrumental role in supporting and sustaining health and life. As the second most abundant intracellular cation after potassium, it is involved in over 600 enzymatic reactions including energy metabolism and protein synthesis. Although Mg2+ availability has been proven to be disturbed during several clinical situations, serum Mg2+ values are not generally determined in patients. This review aims to provide an overview of the function of Mg2+ in human health and disease. In short, Mg2+ plays an important physiological role particularly in the brain, heart, and skeletal muscles. Moreover, Mg2+ supplementation has been shown to be beneficial in treatment of, among others, preeclampsia, migraine, depression, coronary artery disease, and asthma. Over the last decade, several hereditary forms of hypomagnesemia have been deciphered, including mutations in transient receptor potential melastatin type 6 (TRPM6), claudin 16, and cyclin M2 (CNNM2). Recently, mutations in Mg2+ transporter 1 (MagT1) were linked to T-cell deficiency underlining the important role of Mg2+ in cell viability. Moreover, hypomagnesemia can be the consequence of the use of certain types of drugs, such as diuretics, epidermal growth factor receptor inhibitors, calcineurin inhibitors, and proton pump inhibitors. This review provides an extensive and comprehensive overview of Mg2+ research over the last few decades, focusing on the regulation of Mg2+ homeostasis in the intestine, kidney, and bone and disturbances which may result in hypomagnesemia.Physiological Reviews 01/2015; 95(1):1-46. DOI:10.1152/physrev.00012.2014 · 29.04 Impact Factor
Bulletin of Clinical Psychopharmacology 03/2011; DOI:10.5350/KPB-BCP201121101 · 0.37 Impact Factor
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ABSTRACT: Imipramine, a major antidepressant, is known to inhibit reuptake of serotonin and norepinephrine, which contributes to recovery from major depressive disorder. It has recently been reported that acute imipramine treatment inhibits N-methyl-D-aspartate (NMDA) receptor activity. However, the mechanisms underlying long-term effects of imipramine have not been identified. We tested these distinct effects in mouse cortical neurons and found that acute (30s) imipramine treatment decreased Ca(2+) influx through NMDA receptors, whereas long-term treatment (48h) increased Ca(2+) influx via the same receptors. Furthermore, long-term treatment increased NMDA receptor 2B (NR2B) subunit expression via epigenetic changes, including increased acetylation of histones H3K9 and H3K27 in the NR2B promoter and decreased activity of histone deacetylase 3 (HDAC3) and HDAC4. These results suggest that the long-term effects of imipramine on NMDA receptors are quite different from its acute effects. Furthermore, increased NR2B expression via epigenetic alterations might be a part of the mechanism responsible for this long-term effect. Copyright © 2015 Elsevier B.V. All rights reserved.European Journal of Pharmacology 02/2015; 752. DOI:10.1016/j.ejphar.2015.02.010 · 2.68 Impact Factor