N-Methyl D-Aspartic Acid (NMDA) Receptors and Depression

Yıl 2009, Cilt: 1 Sayı: 1, 22 - 35, 01.03.2009

Vahap Ozan Kotan Salih Saygın Eker Enver Yusuf Sivrioglu Cengiz Akkaya

Öz

The monoaminergic hypothesis of depression has provided the basis for extensive research into the pathophysiology of mood disorders and has been of great significance for the development of effective antidepressants. Current antidepressant treatments not only increase serotonin and/or noradrenaline bioavailability but also originate adaptive changes increasing synaptic plasticity. Novel approaches to depression and to antidepressant therapy are now focused on intracellular targets that regulate neuroplasticity and cell survival. Accumulating evidence indicates that there is an anatomical substrate for such a devastating neuropsychiatric disease as major depression. Loss of synaptic plasticity and hippocampal atrophy appear to be prominent features of this highly prevalent disorder. A combination of genetic susceptibility and environmental factors make hippocampal neurons more vulnerable to stress. Abundant experimental evidence indicates that stress causes neuronal damage in brain regions, notably in hippocampal subfields. Stress-induced activation of glutamatergic transmission may induce neuronal cell death through excessive stimulation of N-methyl-D-aspartic acid (NMDA) receptors. Recent studies mention that the increase of nitric oxide synthesis and inflammation in major depression may contribute to neurotoxicity through NMDA receptor. Both standard antidepressants and NMDA receptor antagonists are able to prevent stress-induced neuronal damage. NMDA antagonists are effective in widely used animal models of depression and some of them appear to be effective also in the few clinical trials performed to date. We are still far from understanding the complex cellular and molecular events involved in mood disorders. There appears to be an emerging role for glutamate neurotransmission in the search for the pathogenesis of major depression. Attenuation of NMDA receptor function mechanism appears to be a promising target in the search for a more effective antidepressant therapy.

Anahtar Kelimeler

Depression, glutamate, NMDA

Depresyon ve N-Metil D-Aspartik Asit (NMDA) Reseptör İlişkisi

Öz

Depresyonun monoaminerjik hipotezi, duygu durum bozukluklarının patofizyolojisini araştırma ve önemli etkinliğe sahip antidepresanların geliştirilmesinde bir temel oluşturmuştur. Günümüzün antidepresan tedavileri yalnızca serotonin ve/veya noradrenalin biyoyararlanımını arttırmayıp, aynı zamanda sinaptik plastisiteyi artırarak adaptif değişiklikler ortaya çıkarmaktadır. Major depresif bozukluk (MDB) patogenezi ve antidepresan tedavilere yeni yaklaşımlar hücresel hayatta kalım ve nöroplastisiteyi düzenleyen hücreiçi hedeflere yöneliktir. Sinaptik plastisitenin kaybı ve hipokampal atrofi bu yaygın hastalığın belirgin özellikleri gibi görünmektedir. Genetik duyarlılık ve çevresel faktörlerin bir araya gelmesi ile hipokampal nöronlar strese daha duyarlı hale gelmektedir. Stresin hipokampal alanlar başta olmak üzere beyinde nöronal hasara sebep olduğu deneysel kanıtlarla gösterilmiştir. Glutamaterjik transmisyon aktivasyonunun stresle indüksiyonu aşırı N-metil-D-aspartik asit (NMDA) reseptör stimülasyonu aracılığıyla nöronal hücre ölümünü tetikleyebilmektedir. Son yıllarda MDB'de arttığı ileri sürülen inflamasyon ve nitrik oksit (NO) düzeylerinin de, NMDA reseptörü üzerinden nörotoksisiteyi arttırdığı düşünülmektedir. Hem standart antidepresanlar hem de NMDA reseptör antagonistleri stresle indüklenen nöronal hasarı önleyebilmektedir. NMDA antagonistleri depresyonun hayvan modellerinde belirgin şekilde, klinik denemelerde de kısmen etkin bulunmuştur. Bugün hala duygu durum bozukluklarında yeri olan kompleks hücresel ve moleküler olayları anlamaya uzak olunsa da, MDB patogenezinin araştırılmasında glutamat nörotransmisyonunun önemli bir yere sahip olduğu söylenebilir. Daha etkin antidepresan tedavi araştırmasında, NMDA reseptör fonksiyonunun azaltılması umut vaad eden bir mekanizmadır.

Anahtar Kelimeler

Depresyon, glutamat, NMDA

Kaynakça

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