Current Pharmaceutical Design - Volume 22, Issue 8, 2016

Depression is a major cause of worldwide disability. Although its etiology is unclear, for over sixty years the study of its pathophysiology has focused mainly on serotonin (5-HT) and serotonergic neurotransmission. Generally, the study of the pathophysiological processes underpinning depression have led to the appreciation of its complexity, although such study continues to support the role of 5-HT in this disorder. The aim of this review is to briefly summarize the available findings on 5-HT and depression, with a special focus on alterations in tryptophan (TRP) metabolism that can shift from 5-HT synthesis towards other, potentially neurotoxic, compounds, such as the tryptophan catabolite, quinolinic acid. The evidence that the TRP shunt may be promoted by stress hormones and proinflammatory cytokines strongly supports the notion that depression should now be considered a systemic disorder that can be triggered by different factors that ultimately target the 5-HT system in vulnerable individuals. In addition, such intriguing findings suggest biochemical targets for novel treatment options in depression.

Separating emotions from cognition seems impossible in everyday experiences of a human being. Emotional processes have an impact on the ability of planning and solving problems, or decision-making skills. They are a valuable source of information about ourselves, our partners in interactions and the surrounding world. Recent years have shown that axial symptoms of depression are caused by emotion regulation disorders, dysfunctions in the reward system and deficits of cognitive processes. There is a few studies concerning a link between emotional and inflammatory processes in depression. The aim of this article is to present results of contemporary research studies over mutual connections between social cognition, cognitive processes and inflammatory factors significant for the aetiology of recurrent depressive disorders, with particular reference to the role of kynurenine pathways.

Many, if not all, chronic medical, neurodegenerative and neuroprogressive illnesses are characterised by chronic immune activation, oxidative and nitrosative stress (O) and systemic inflammation. These factors, notably elevated pro-inflammatory cytokines, activate indoleamine 2,3-dioxygenase (IDO) leading to an upregulated tryptophan catabolite (TRYCAT) pathway of tryptophan degradation in the periphery and in the brain. In such conditions the TRYCAT pathway becomes the predominant system for tryptophan degradation in all body compartments. In this paper we review the pathways whereby TRYCATs may play a role in neuro-inflammatory and neuroprogressive disease. Thus chronic activation of the TRYCAT pathway leads to the production of a range of neuroactive, neuroprotective and neurotoxic TRYCATs. Some TRYCATs such as quinolinic acid act as potent neurotoxins which inhibit ATP production by mitochondria, provoke increases in O, disrupt neuron glial communication and blood brain barrier integrity, induce apoptosis of glial cells, directly damage neurons and function as a N-methyl D-aspartate (NMDA) receptor agonist. Other TRYCATs such as kynurenic acid function as antagonists of NMDA, α- amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate receptors and act to regulate levels of glutamate and dopamine. The neuroprotective functions of this TRYCAT are likely exercised via engagement with alpha7 nicotinic acetylcholine and aryl hydrocarbon receptors but the neuroprotective effects stemming from elevated kynurenic acid levels come at the price of severely compromised neurocognitive function and emotional processing. Other TRYCATS also possess neurotoxic or neuroprotective properties via pro-oxidant and antioxidant effects. Here we discuss the involvement of the abovementioned TRYCAT pathways in schizophrenia, Alzheimer’s disease and chronic fatigue syndrome.

Melatonin is an important neuroprotective factor and its receptors are expressed in the fetal brain. During normal pregnancy, maternal melatonin level increases progressively until term and is highly transferred to the fetus, with an important role in brain formation and differentiation. Maternal melatonin provides the first circadian signal to the fetus. This indolamine is also produced de novo and plays a protective role in the human placenta. In pregnancy disorders, both maternal and placental melatonin levels are decreased. Alteration in maternal melatonin level has been associated with disrupted brain programming with long-term effects. Melatonin has strong antioxidant protective effects directly and indirectly via the activation of its receptors. The fetal brain is highly susceptible to oxygenation variation and oxidative stress that can lead to neuronal development disruption. Based on that, several approaches have been tested as a treatment in case of pregnancy disorders and melatonin, through its neuroprotective effect, has been recently accepted against fetal brain injury. This review provides an overview about the protective effects of melatonin during pregnancy and on fetal brain development.

Bipolar disorder (BD) is a long-recognized severe and common psychiatric disorder, with a complex and often diverse range of presentations. BD is a heterogenous disorder that has traditionally, if rather simply, been defined by the recurrences of manic and depressive episodes, and presents with numerous immune-inflammatory and circadian/sleep abnormalities. A number of different lines of research have investigated the biological underpinnings of BD and demonstrate a heritability of about 80-90%. This genetic contribution is thought to be mediated by a wide array of genetic factors, rather than being strongly influenced by a couple of genes. In this context, a clearer formulation of the biological underpinnings of BD is needed in order to encompass the diverse effects of multiple susceptibility genes. The biological underpinnings of BD includes work that has focussed on the role played by increased immune inflammatory activity, particularly changes in pro-inflammatory cytokines, as measured both centrally and systemically. Changes in immune- inflammatory activity are intimately associated with alterations in levels of oxidative and nitrosative stress (O), which are increased in BD. Many of the neuroregulatory changes driven by O and immune-inflammatory activity are mediated by the tryptophan catabolite (TRYCAT) pathways, with changes in TRYCATs being evident both centrally and peripherally. A consequence of increased pro-inflammatory cytokines, is their induction of indoleamine 2,3-dioxygenase (IDO), which takes tryptophan away from serotonin, Nacetylserotonin and melatonin synthesis, driving it to the synthesis of neuroregulatory TRYCATs. Most work exploring such changes has emphasized the role of TRYCATs in enhancing or decreasing neuronal activity. However, a relatively overlooked consequence of cytokine induced IDO and TRYCAT pathway activation is the impact that this has on aryl hydrocarbon receptor (AhR) activation and in decreasing melatonergic pathway activity. Melatonin is classically associated with night-time synthesis by the pineal gland, in turn regulating circadian rhythms. However, melatonin is produced by many, if not all mitochondria containing cells, with consequences for gut regulation, as well as glia and immune cell reactivity. The melatonergic pathways are genetic susceptibility factors for BD. Interactive changes in O, immune-inflammatory activity, TRYCATs and the melatonergic pathways form an emerging biological perspective on the etiology, course and management of BD. Here, we review such changes in BD, and how this better integrates the diverse array of BD presentations and comorbidities, including addiction and cardiovascular disorders as well as decreased life-expectancy. We then look at the future directions such research may take.

Migraine is a highly disabling neurological condition affecting around 15% of the population worldwide. Decades of intensive research shed some light on diseases pathomechanism, but information is still missing about the initiation of the attack. In the past century, serotonin emerged as the main target of both basic and therapeutic research. As a result, the triptans, the only approved migraine specific drugs were developed. The involvement of glutamatergic mechanism in migraine headache development such as cortical hyperexcitability, and cortical spreading depression as the pathological correlate of migraine aura called the attention to the kynurenine pathway in migraine pathomechanism. The serotonin and kynurenine pathways are closely connected, as they both are the metabolic routes of the amino acid tryptophan. Kynurenine catabolites are important participants in glutamatergic neurotransmission, regulation also nociceptive processing of the trigeminal system. The current work attempts to collect recent data on both serotonin and kynurenine research related to migraine and emphasizes the importance of further research on this topic.

Methamphetamine (METH), an illegal psycho-stimulant, is widely known as a recreational drug. In addition to its addictive effect, METH induces neurotoxicity via multiple mechanisms. The major contributors to METH-induced neurotoxicity are reactive oxygen species, which lead to cell death through apoptotic pathway and disturbances in mitochondria, the generation of neuroinflammation, and autophagy. Melatonin, a neurohormone secreted by the pineal gland, is a potent antioxidant compound that plays a beneficial role by protecting against the oxidative stress caused by METH. Melatonin also plays a role in maintaining mitochondrial homeostasis. Nanomolar concentrations of melatonin have been shown to protect against the inflammation caused by METH and to prevent the decrease in neurogenesis caused by METH in progenitor cells obtained from adult rat hippocampal tissue. The intent of this review is to describe the underlying mechanisms involving melatonin that protect against the neurodegeneration caused by METH.

Primary glioma, as well as secondary metastases, provide significant treatment challenges. An understanding of the biological underpinnings of glioma is likely to provide new pharmaceutical targets that will improve patient survival. Here, we look at the role that the kynurenine pathways and associated tyrptophan catabolites (TRYCATs) play in glioma, linking this to changes in oxidative and nitrosative stress (O), immuneinflammatory activity, the aryl hydrocarbon receptor (AhR), and the melatoninergic pathways. It is suggested that the interactions of O and the immune-inflammatory processes in glioma contribute to the induction of the TRYCATs via the kynurenine activation of the AhR, leading to increased indoleamine 2,3-dioxygenase, which deprives tryptophan for the necessary serotonin that is required as a precursor for the melatoninergic pathways. A diverse array of data pertaining to glioma can be linked to these pathways, including changes in miRNAs, epigenetic processes, estrogen receptors, 14-3-3, chromosome 4q35, neurotrophins, tristetraprolin and the N-acetylserotonin (NAS)/melatonin ratio. As many of these factors directly or indirectly act on the melatoninergic pathways, including variations in the NAS/melatonin ratio, it is suggested that the melatoninergic pathways may act as a hub that co-ordinate the multitude of changes occurring in glioma. Consequently, the melatoninergic pathways may be a significant pharmaceutical target for the treatment of this still very poorly managed condition.

Accumulating evidence demonstrates involvement of tryptophan metabolites and in particular activation of the kynurenine pathway (KP) in neurocognitive disorders under CNS inflammatory conditions. The KP is involved in several brain-associated disorders including Parkinson’s disease, AIDS dementia, Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, schizophrenia, and brain tumors. Our review is an attempt to address any relevant association between dysregulation of KP and multiple sclerosis (MS), an inflammatory CNS disorder that ultimately leads to demyelinated brain areas and severe neurological deficits. Modulation of KP is a new topic for the field of MS and warrants further research. The availability of potential KP modulators approved for MS may shed some light into the therapeutic potential of KP antagonists for the treatment of MS patients.

Kynurenines are a wide range of catabolites which derive from tryptophan through the “Kynurenine Pathway” (KP). In addition to its peripheral role, increasing evidence shows a role of the KP in the central nervous system (CNS), mediating both physiological and pathological functions. Indeed, an imbalance in this route has been associated with several neurodegenerative disorders such as Alzheimer´s and Huntington´s diseases. Altered KP catabolism has also been described during both acute and chronic phases of stroke; however the contribution of the KP to the pathophysiology of acute ischemic damage and of post-stroke disorders during the chronic phase including depression and vascular dementia, and the exact mechanisms implicated in the regulation of the KP after stroke are not well established yet. A better understanding of the regulation and activity of the KP after stroke could provide new pharmacological tools in both acute and chronic phases of stroke. In this review, we will make an overview of CNS modulation by the KP. We will detail the KP contribution in the ischemic damage, how the unbalance of the KP might trigger an alteration of the cognitive function after stroke as well as potential targets for the development of new drugs.

Activation of the trptophan catabolite (TRYCAT) pathways by oxidative and nitrosative stress and proinflammatory cytokine-driven indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) leads to the synthesis of a number of neuroregulatory TRYCATs, such as kynurenic acid and quinolinic acid. Such TRYCATs have significant impacts on neuronal functioning and survival contributing to the changes seen in Alzheimer's disease (AD), including in its association with depression as well as alterations in the reactivity of immune and glia cells. By decreasing the availability of tryptophan for serotonin synthesis, such IDO and TDO-driven TRYCATs, also decrease the availability of serotonin for N-acetylserotonin (NAS) and melatonin synthesis. The loss of NAS and melatonin has significant consequences for the etiology, course and treatment of AD, including via interactions with altered TRYCATs, but also by changing the levels of trophic support and modulating the patterning of immune activity. In this review, we look at how such interactions of the TRYCAT and melatoninergic pathways link a plethora of previously diffuse data in AD as well as the treatment implications and future research directions that such data would suggest.

Melatonin and the following approved or investigational synthetic melatoninergic agonists are compared with regard to half-life, receptor affinity, metabolism and additional properties: TIK-301, piromelatine, GG-012, AH-001, AH-017, agomelatine, ramelteon, GR 196429, MA-2, tasimelteon, UCM765, and UCM924. Apart from restrictions from the respective approvals, theoretical limits of treatment are outlined as they result from chronobiological, genetic, epigenetic, degenerative or toxicological considerations. Melatoninergic agonists have been shown to reliably entrain circadian rhythms, if chronobiological phase response rules are followed. This allows the treatment of dysphased rhythms, circadian rhythm sleep disorders, and forms of depression with an etiology of circadian dysfunction, such as bipolar disorder and seasonal affective disorders. Entrainment and induction of sleep onset requires only short actions, with low doses of immediate-release melatonin likely to be sufficient. However, sleep maintenance is poorly supported by any of the agonists, despite statistically demonstrable effects. The combinations of melatoninergic properties with the inhibition of 5-HT2C receptors, as in agomelatine and TIK-30, may result in moderate direct antidepressive actions. Other limits of a successful treatment can arise from genetic or epigenetic silencing of melatonin receptor genes, perhaps also from imbalances between parallel signaling pathways in receptor mutants, and from neurodegeneration, especially in the suprachiasmatic nucleus. Variants of circadian clock genes cause rhythm deviations that may be corrected by melatoninergic treatment, provided that the spontaneous oscillation period is not beyond the entrainment range. Caveats concerning melatonin’s roles as an immune modulator and in certain pathologies, such as Parkinson’s disease, as well as toxicological considerations for agonists and their metabolites are also addressed.