The activation of Nod-like receptor protein 3 (NLRP3) has lately been implicated in stress and depression as an initiator mechanism required for the production of interleukin (IL)-1b and IL-18. Agmatine, an endogenous polyamine widely distributed in mammalian brain, is a novel neurotransmitter/neuromodulator, with antistress, anxiolytic and antidepressant-like effects. In this study, we examined the effect of exogenously administered agmatine on NLRP3 inflammasome pathway/cytokine responses in rats exposed to restraint stress for 7 days. The rats were divided into three groups: stress, stress+agmatine (40 mg/kg; i.p.) and control groups. Agmatine significantly down-regulated the gene expressions of all stress-induced NLRP3 inflammasome components (NLRP3, NF-jB, PYCARD, caspase-1, IL-1b and IL-18) in the hippocampus and prefrontal cortex (PFC) and reduced pro-inflammatory cytokine levels not only in both brain regions, but also in serum. Stress-reduced levels of IL-4 and IL-10, two major anti-inflammatory cytokines, were restored back to normal by agmatine treatment in the PFC. The findings of the present study suggest that stress-activated NLRP3 inflammasome and cytokine responses are reversed by an acute administration of agmatine. Whether antidepressant-like effect of agmatine can somehow, at least partially, be mediated by the inhibition of NLRP3 inflammasome cascade and relevant inflammatory responses requires further studies in animal models of depression.

The neuroinflammation perspective of depression: reuniting the outstanding mechanisms of the pathophysiology Major Depressive Disorder (MDD) is a serious mental health problem that leads to patients' disability and has huge impact on social and economic burden to society. The current available medications for the treatment of depression are mainly targeted on enhancing monoamine neurotransmission. However, antidepressant treatments are still lacking high efficacy in many cases which is associated with low treatment response and remission rates. However, the latest knowledge regarding the pathophysiology of depression indicates that depression is developed by highly complex and integrated mechanisms in which monoaminergic deficiency could only be part of. The paradigm is now shifting from monoaminergic hypothesis to significance of other novel mechanisms that could possibly play substantial role for the development of depression in a highly interrelated manner. In fact, neuroinflammation, amongst other mechanisms does seem to be a key pathological component by having impact on certain pathway pathologies including glutamatergic neurotransmission, oxidative processes, neurotropic factors, neurotransmitter metabolism, and glucocorticoid functions in the central nervous system (CNS) and in the periphery, thereby triggers the pathological alterations that is thought to contribute to the development of depression. The neuroinflammation comprehends the processes exampled from excessive pro-inflammatory cytokine release to activation of microglia and indolamine 2,3-dioxygenase (IDO) pathway, excessive glutamatergic neurotransmission, hyperactive hypothalamus-pituitary-adrenal (HPA) axis, decreased neurogenesis and synaptic plasticity. In fact, the antidepressant effect of ketamine as a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist might be at least partially linked to inflammatory modulations. The significance of inflammation in depression is not only mentioned by the literature of basic researches from a mechanistic aspect but also by the possible clinical implications suggested by the clinical reports. Although the exact role of inflammation in depression and its clinical translation have not been determined yet, the inflammationmediated point of view might provide novel insights for improving the diagnosis at clinic (e.g., inflammatory biomarkers), predicting antidepressant treatment response and thereby re-evaluating the treatment strategy. Moreover, with all that, the inflammation aspect raises the question for the possible significance of utilizing anti-inflammatory approaches in the treatment of depression.

Negative symptoms in schizophrenia remain an unmet clinical need. There is no licensed treatment specifically for this debilitating aspect of the disorder and effect sizes of new therapies are too small to make an impact on quality of life and function. Negative symptoms are multifactorial but often considered in terms of two domains, expressive deficit incorporating blunted affect and poverty of speech and avolition incorporating asociality and lack of drive. There is a clear need for improved understanding of the neurobiology of negative symptoms which can be enabled through the use of carefully validated animal models. While there are several tests for assessing sociability in animals, tests for blunted affect in schizophrenia are currently lacking. Two paradigms have recently been developed for assessing negative affect of relevance to depression in rats. Here we assess their utility for studying negative symptoms in schizophrenia using our well validated model for schizophrenia of sub-chronic (sc) treatment with Phencyclidine (PCP) in adult female rats. Results demonstrate that sc PCP treatment produces a significant negative affect bias in response to a high value reward in the optimistic and affective bias tests. Our results are not easily explained by the known cognitive deficits induced by sc PCP and support the hypothesis of a negative affective bias in this model. We suggest that further refinement of these two tests will provide a means to investigate the neurobiological basis of negative affect in schizophrenia, thus supporting the assessment of efficacy of new targets for this currently untreated symptom domain.

ÖZET:Depresyon ve sitokin hipotezinde yeni ufuklar: 'NLRP3 inflamazomu' Depresyon prevalansının tip II diyabet, kardiyovasküler hastalıklar, otoimmün kaynaklı romatoid artrit, sistemik lupus eritamatozus gibi kronik inflamatuvar hastalıklar eşliğinde arttığı bilinmektedir. Geçtiğimiz on yıllık süreç içerisinde periferde oluşan inflamatuvar yanıtların santral sinir sistemini etkileyebileceği gösterilmiştir. İnflamatuvar bir uyaran beyine ulaştığında, mikroglia hücreleri sensör görevi görerek nöroinflamasyon sürecinin başlatırlar. Nöroinflamasyon normal şartlarda beynin gelişimi için gerekli bir süreç olmasına karşın kronik stres ya da depresyon tablosunda olduğu gibi uzun süreli veya şiddetli bir tetikleyici inflamatuvar faktör varlığında patolojik bir tabloya dönüşerek hastalık etkeni haline gelebilmektedir. Günümüzde klinik ve deneysel çok sayıda çalışma depresyon tablosu ile artmış proinflamatuvar sitokin seviyeleri arasındaki ilişkiye dikkat çekmektedir. Mevcut antidepresan tedaviler ile depresyon hastalarında yüksek seyreden söz konusu sitokin seviyelerinin azaldığı ve sitokin aracılı immün yanıtları baskılayan ajanlarla antidepresan benzeri etkiler elde edildiği gösterilmiştir. Diğer taraftan inflamatuvar sitokinlerin depresyon hastalarında arttığı bilinen hipotalamus-hipofiz-adrenal (HPA) ekseninin aktivasyonunda rol oynayarak inflamasyon tablosunun daha da güçlenmesine yol açtıkları düşünülmektedir. Depresyon hastalarının yaklaşık %30'unun mevcut antidepresan tedavilere yanıt vermediğinin bilinmesi, günümüzde depresyonda yeni mekanizmal hedefler ve tedavi yaklaşımlarına yönelik çalışmaları beraberinde getirmektedir. Bu noktada sitokin-aracılı inflamatuvar yanıtları başlatan moleküler mekanizmaların araştırılması, sürece sitokinlerin üretim ve salınım aşamalarının öncesinde müdahale getirilebilmesi yönünden ilgi çekici bir konu niteliği taşımaktadır. Bu gözden geçirme çalışmasında, depresyonda sitokin hipotezine yeni bir bakış açısı kazandırabilmesi ve olası yeni tedavi hedeflerini gündeme getirebilmesi bakımından; IL-1β ve IL-18 aracılı inflamatuvar yanıtların başlamasında görev alan; makrofaj ve mikroglia hücrelerinde oluşum gösteren multiprotein kompleks yapısındaki NLRP3 inflamazomu ve ilişkili yolakların ele alınması amaçlanmıştır.

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