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Port Glasgow, United Kingdom

Stress, in its many forms, is long associated with the etiology and course of schizophrenia. The mechanisms mediating the impacts of stress are not fully elucidated. Here it is proposed that stress induced cortisol alters kynurenic acid (KA) and quinolinic acid (QA) in the cortex and amygdala/striatum, respectively. These effects are significantly modulated by BAG-1 (bcl-2 associated anthanogene) and involve ROS, IL-18, and the induction of IDO (indoleamine 2,3-dioxygenase). The kynurenine pathway (KP) products response to stress seems to mediate both prenatal etiology and symptom course in adulthood. It is suggested that the effects of cortisol and quinolinic acid in the amygdala, coupled to an increase in dopamine efflux, mediate amygdala driven developmental changes in the cortex and VTA/N.Accumbens junction. This change in patterned brain activity co-ordinates alterations in motivated behaviour and thought outputs. Such developmental alterations determine changes in sensory-amygdala interactions, readily allowing developmental links to changes in lateral inhibition and pre-pulse inhibition. Decreases in vitamin D3 and melatonin further potentiate such stress induced changes. The likely involvement of glia in mediating increases in the KP products suggests that adaptation to stress is driven by neuronal activity as a form of glia to glia communication. © 2010 Elsevier Ltd.

Anderson G.,CRC | Maes M.,Chulalongkorn University
Current Pharmaceutical Design | Year: 2014

This paper reviews recent work on the biological underpinnings of clinical depression emphasizing the crucial role of immunoinflammatory and oxidative and nitrosative stress (O&NS) pathways in driving changes in neuronal regulating tryptophan catabolites (TRYCATs). The essence of the association of O&NS pathways with autoimmune responses in depression is via damage to lipid membranes, anchorage molecules and functional proteins that lead to changes in their chemical structures creating new modified epitopes (neoepitopes), which are highly immunogenic. The abovementioned pathways together with decreased antioxidant levels, including zinc, coenzyme Q10, glutathione and vitamin E, and melatonin are intimately involved in different aspects of depression, including mitochondrial functions and the regulation of cAMP/circadian genes, allowing for impacts across different aspects of symptom patterning. Immuno-inflammatory and O&NS processes may additionally cause alterations in blood-brain barrier permeability and neuroprogression, that is tissue damage, including neurodegeneration and apoptosis, and decreased neurogenesis and neuroplasticity. Activation of those interconnected pathways is relevant to the pathophysiology of acute and chronic depression and the progressive course (staging) of clinical depression. This implies that compounds that target these pathways may be useful to treat acute episodes and prevent further progression of the disease. We herein review some promising compounds, such as melatonin, melatonin receptor agonists, allopregnanolone, PDE4 inhibitors, statins, aspirin, sodium benzoate, tryptophan-enriched diets, and antioxidants, including epigallocatechin gallate, curcumin, quercitin, alpha-lipoic acid and resveratrol. © 2014 Bentham Science Publishers.

Anderson G.,CRC | Maes M.,Piyavate Hospital | Berk M.,Deakin University | Berk M.,Orygen Youth Health Research Center | And 2 more authors.
Advances in Protein Chemistry and Structural Biology | Year: 2012

A recent study - comparing those with depression, somatization, comorbid depression + somatization, and controls - showed specific changes in the tryptophan catabolite (TRYCAT) pathway in somatization, specifically lowered tryptophan and kynurenic acid, and increased kynurenine/kynurenic acid (KY/KA) and kynurenine/tryptophan ratios. These findings suggest that somatization and depression with somatization are characterized by increased activity of indoleamine 2,3-dioxygenase and disorders in kynurenine aminotransferase activity, which carry a neurotoxic potential. This chapter reviews the evidence that the TRYCAT pathway may play a pathophysiological role in the onset of somatization and depression with somatization and, furthermore, suggests treatment options based on identified pathophysiological processes. Lowered plasma tryptophan may be associated with enhanced pain, autonomic nervous system responses, gut motility, peripheral nerve function, ventilation, and cardiac dysfunctions. The imbalance in the KY/KA ratio may increase pain, intestinal hypermotility, and peripheral neuropathy through effects of KY and KA acid, both centrally and peripherally, at the N-methyl-d-aspartate receptor (NMDAR), G-protein-coupled receptor-35 (GPR35), and aryl hydrocarbon receptor (AHr). These alterations in the TRYCAT pathway in somatization and depression may interface with the role of the mu-opioid, serotonin, and oxytocin systems in the regulation of stress reactions and early attachment. It is hypothesized that irregular parenting and insecure attachment paralleled by chronic stress play a key role in the expression of variations in the TRYCAT pathway - both centrally and peripherally - driving the etiology of somatization through interactions with the mu-opioid receptors. Therefore, the TRYCAT pathway, NMDARs, GPR35, and AHrs may be new drug targets in somatization and depression with somatizing. We lastly review new pathophysiologically driven drug candidates for somatization, including St. John's wort, resveratrol, melatonin, agomelatine, Garcinia mangostana (γ-mangostin), N-acetyl cysteine, and pamoic acid. © 2012 Elsevier Inc.

Maes M.,Deakin University | Maes M.,Chulalongkorn University | Anderson G.,CRC | Kubera M.,Polish Academy of Sciences | And 2 more authors.
Expert Opinion on Therapeutic Targets | Year: 2014

Introduction: Increased IL-6 and soluble IL-6 receptor (sIL-6R) levels in depressed patients was first shown over 20 years ago. The pro-inflammatory effects of IL-6 are predominantly mediated by IL-6 trans-signalling via the sIL-6R, whereas IL-6R membrane signalling has anti-inflammatory effects. Areas covered: We review data on IL-6 and sIL-6R in inflammation, depression, animal models of depression and the effects of different classes of antidepressants. The biological context for IL-6 trans-signalling as a pathogenic factor in depression involves its role in the acute phase response, disorders in zinc and the erythron, hypothalamic-pituitary-adrenal axis activation, induction of the tryptophan catabolite pathway, oxidative stress, bacterial translocation, transition towards sensitisation, autoimmune processes and neuroprogression and the multicausal aetiology of depression, considering that psychosocial stressors and comorbid immune-inflammatory diseases are associated with the onset of depression. Expert opinion: The homeostatic functions of IL-6 imply that ubiquitous IL-6 inhibitors, for example, tocilizumab, may not be the optimal treatment target in depression. A more promising target may be to increase soluble glycoprotein 130 (sgp130) inhibition of IL-6 trans-signalling, while allowing the maintenance of IL-6R membrane signalling. Future research should delineate the effects of treatments with sgp130Fc in combination with antidepressants in various animal models of chronic depression. © 2014 Informa UK, Ltd.

Anderson G.,CRC | Rodriguez M.,Rochester College
European Journal of Neurology | Year: 2011

To review the treatment and mechanisms underlying the increased prevalence of seizures associated with multiple sclerosis (MS). We carried out an extensive review of the literature pertaining to seizures in MS. We propose that an increase in interleukin-18, and its associated induction of indoleamine 2, 3-dioxygenase and quinolinic acid, mediates seizure activity in MS at least in part via an increase in interferon-gamma (IFNg). Increased kynurenine pathway activity decreases the availability of serotonin and melatonin. Increases in blood-brain barrier and circumventricular organ permeability are linked to these changes. Antiepileptic drugs modulate wider MS symptomatology, interacting with melatonin and vitamin D3. This manuscript provides a framework for the wider understanding and treatment of seizures in MS and wider MS symptomatology. © 2010 The Author(s). European Journal of Neurology © 2010 EFNS.

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