George Anderson - Academia.edu (original) (raw)

Papers by George Anderson

Journal of breastfeeding biology, Jul 22, 2016

Advances in integrative medicine, Apr 1, 2015

Current Pharmaceutical Design, Feb 15, 2016

Oxford University Press eBooks, Feb 1, 2019

Neuroprogressive processes in major depressive disorder (MDD) can occur in association with recur... more Neuroprogressive processes in major depressive disorder (MDD) can occur in association with recurrent episodes. The primary biological underpinnings are mediated by increases in the levels of immune-inflammation, tryptophan catabolites, mitochondrial dysfunction, and oxidative and nitrosative stress. Such biochemical alterations may be driven by changes in many peripheral and central sites, including in the gut, as well as by early developmental priming, such as prenatal stressors and breastfeeding consequences. As such, the conceptualization of MDD is shifted from simple psychological and central biochemical models to one that includes whole body processes over a developmental timescale. This provides a model that better integrates wider bodies of data relevant to the aetiology and course of MDD, and which therefore underpins the neuroprogressive processes that can occur over the course of MDD. This also significantly challenges current MDD (and wider psychiatric) classification by shifting classification to one based on biological processes rather than one based on subjective phenomenology.

When tryptophan is taken up by the body, some is used for the synthesis of sero-tonin. As well as... more When tryptophan is taken up by the body, some is used for the synthesis of sero-tonin. As well as having neuroregulatory effects, serotonin is also the precursor for the synthesis of N-acetylserotonin (NAS) and melatonin, which form the melatonergic pathways. The melatonergic pathways are associated with many of the changes that are thought to be important in the pathophysi-ology of Alzheimer's disease, Parkinson's disease, multiple sclerosis, and major depressive disorder. As well as being produced by the pineal gland at night, and thereby contributing to the circadian rhythm, melatonin is also very highly produced in other organs and tissues, including the gut, where CONTENTS

Reactive Oxygen Species, 2018

Journal of Neuroimmunology, 2012

Neuroprotective potential of estrogens and estrogenic compounds against amyloid-beta and oxidativ... more Neuroprotective potential of estrogens and estrogenic compounds against amyloid-beta and oxidative stress

John Wiley & Sons, Ltd eBooks, Oct 11, 2013

Metabolic dysregulation is intimately associated with a wide array of seemingly unrelated disorde... more Metabolic dysregulation is intimately associated with a wide array of seemingly unrelated disorders, including schizophrenia, Alzheimer disease, and depression. Genetic susceptibility genes show significant overlap between Alzheimer disease and schizophrenia, suggesting overlap in underlying biological processes, including metabolic. The high levels of depression in both disorders is linked to these shared processes. This chapter reviews the data suggesting that changes in leptin levels and leptin resistance mediate many of these metabolic changes, including the regulation of tryptophan catabolites (TRYCATs) and neuropeptides, which in turn drives alterations in cognition, neurogenesis, and apoptotic pathways. On the basis of this, treatment implications are proposed including the use of melatonin, together with leptin, in the prevention and treatment of these poorly managed disorders.

Journal of evaluation in clinical practice, Aug 17, 2018

Major affective disorders including bipolar disorder (BD) and major depressive disorder (MDD) are... more Major affective disorders including bipolar disorder (BD) and major depressive disorder (MDD) are associated with impaired health-related quality of life (HRQoL). Oxidative stress and subtle thyroid abnormalities may play a pathophysiological role in both disorders. Thus, the current study was performed to examine whether neuro-oxidative biomarkers and thyroid-stimulating hormone (TSH) levels could predict HRQoL in BD and MDD. This cross-sectional study enrolled 68 BD and 37 MDD patients and 66 healthy controls. The World Health Organization (WHO) QoL-BREF scale was used to assess 4 QoL subdomains. Peripheral blood malondialdehyde (MDA), advanced oxidation protein products, paraoxonaxe/CMPAase activity, a composite index of nitro-oxidative stress, and basal TSH were measured. In the total WHOQoL score, 17.3% of the variance was explained by increased advanced oxidation protein products and TSH levels and lowered CMPAase activity and male gender. Physical HRQoL (14.4%) was associated...

Cells

Although previously restricted to a limited number of medical conditions, there is a growing appr... more Although previously restricted to a limited number of medical conditions, there is a growing appreciation that ‘autoimmune’ (or immune-mediated) processes are important aspects of a wide array of diverse medical conditions, including cancers, neurodegenerative diseases and psychiatric disorders. All of these classes of medical conditions are associated with alterations in mitochondrial function across an array of diverse cell types. Accumulating data indicate the presence of the mitochondrial melatonergic pathway in possibly all body cells, with important consequences for pathways crucial in driving CD8+ T cell and B-cell ‘autoimmune’-linked processes. Melatonin suppression coupled with the upregulation of oxidative stress suppress PTEN-induced kinase 1 (PINK1)/parkin-driven mitophagy, raising the levels of the major histocompatibility complex (MHC)-1, which underpins the chemoattraction of CD8+ T cells and the activation of antibody-producing B-cells. Many factors and processes clo...

International Journal of Molecular Sciences

There is a growing interest in the role of alterations in mitochondrial metabolism in the pathoet... more There is a growing interest in the role of alterations in mitochondrial metabolism in the pathoetiology and pathophysiology of cancers, including within the array of diverse cells that can form a given tumor microenvironment. The ‘exhaustion’ in natural killer cells and CD8+ t cells as well as the tolerogenic nature of dendritic cells in the tumor microenvironment seems determined by variations in mitochondrial function. Recent work has highlighted the important role played by the melatonergic pathway in optimizing mitochondrial function, limiting ROS production, endogenous antioxidants upregulation and consequent impacts of mitochondrial ROS on ROS-dependent microRNAs, thereby impacting on patterned gene expression. Within the tumor microenvironment, the tumor, in a quest for survival, seeks to ‘dominate’ the dynamic intercellular interactions by limiting the capacity of cells to optimally function, via the regulation of their mitochondrial melatonergic pathway. One aspect of this ...

International Journal of Molecular Sciences

Major depressive disorder (MDD) is widely accepted as having a heterogenous pathophysiology invol... more Major depressive disorder (MDD) is widely accepted as having a heterogenous pathophysiology involving a complex mixture of systemic and CNS processes. A developmental etiology coupled to genetic and epigenetic risk factors as well as lifestyle and social process influences add further to the complexity. Consequently, antidepressant treatment is generally regarded as open to improvement, undoubtedly as a consequence of inappropriately targeted pathophysiological processes. This article reviews the diverse array of pathophysiological processes linked to MDD, and integrates these within a perspective that emphasizes alterations in mitochondrial function, both centrally and systemically. It is proposed that the long-standing association of MDD with suppressed serotonin availability is reflective of the role of serotonin as a precursor for the mitochondrial melatonergic pathway. Astrocytes, and the astrocyte mitochondrial melatonergic pathway, are highlighted as crucial hubs in the integ...

International Journal of Molecular Sciences

Type 1 diabetes mellitus (T1DM) arises from the failure of pancreatic β-cells to produce adequate... more Type 1 diabetes mellitus (T1DM) arises from the failure of pancreatic β-cells to produce adequate insulin, usually as a consequence of extensive pancreatic β-cell destruction. T1DM is classed as an immune-mediated condition. However, the processes that drive pancreatic β-cell apoptosis remain to be determined, resulting in a failure to prevent ongoing cellular destruction. Alteration in mitochondrial function is clearly the major pathophysiological process underpinning pancreatic β-cell loss in T1DM. As with many medical conditions, there is a growing interest in T1DM as to the role of the gut microbiome, including the interactions of gut bacteria with Candida albicans fungal infection. Gut dysbiosis and gut permeability are intimately associated with raised levels of circulating lipopolysaccharide and suppressed butyrate levels, which can act to dysregulate immune responses and systemic mitochondrial function. This manuscript reviews broad bodies of data on T1DM pathophysiology, hi...

Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2017

CNS & Neurological Disorders - Drug Targets, 2014

In many psychiatric, neurodegenerative and systemic inflammatory disorders circadian melatonin is... more In many psychiatric, neurodegenerative and systemic inflammatory disorders circadian melatonin is decreased whilst melatonin enzymes and melatonin receptors are genetic susceptibility factors. Treatment with melatonin is useful in a diverse range of medical conditions, including bipolar disorder, Alzheimer's disease, depression and fibromyalgia. Decreased melatonin effects are classically attributed to lost pineal production. However, melatonin, along with its immediate precursor N-acetylserotonin (NAS), is produced by many, if not all, mitochondrial containing cells, including immune cells and central glia. Here we review the data on local melatonin and NAS production and propose that astrocyte melatonin and NAS efflux is crucial to local central inflammation regulation at the glia-neuronal interface. Melatonin and NAS provide antioxidant and anti-inflammatory effects, as well as increasing mitochondrial oxidative phosphorylation and functioning. Consequently, their decreased production at sites of local inflammation is proposed to underlie melatonin's genetic association with a diverse range of medical conditions. Similarly the benefits of serotonin boosting medications, including antidepressants, across a wide range of conditions are partly mediated by increasing serotonin availability for astrocytic local NAS and melatonin production. Such a conceptualization incorporates a plethora of data across different disorders, especially the commonalities in oxidative and nitrosative stress, anti-oxidants, tryptophan catabolites and mitochondrial dysregulation evident in a diverse array of medical conditions. Glia melatonin and NAS regulation are important treatment targets in psychiatric disorders, neurodegenerative disorders and glioma.

Progress in neuro-psychopharmacology & biological psychiatry, Jan 6, 2017

The aim of this study was to delineate the associations between the tryptophan catabolite (TRYCAT... more The aim of this study was to delineate the associations between the tryptophan catabolite (TRYCAT) pathway and affective symptoms in schizophrenia. Towards this end we measured immunoglobulin (Ig)A and IgM responses to relatively noxious TRYCATs, namely quinolinic (QA), xanthurenic (XA), picolinic (PA) acid and 3-OH-kynurenine (3HK), and generally protective TRYCATs, namely anthranilic (AA) and kynurenic (KA) acid in 80 patients with schizophrenia and 40 healthy controls. The Hamilton Rating Scale for Depression (HDRS) and anxiety (HAMA), Young Mania Rating Scale (YMRS) as well as the Positive and Negative Symptoms Scale of Schizophrenia (PANSS) were measured. Depression, anxiety and hypomanic as well as negative and positive symptoms were associated with increased IgA responses to PA. Increased IgA responses to XA were associated with anxiety, hypomanic and negative symptoms. Moreover, depressive, anxiety, hypomanic and negative symptoms were characterized by increased IgA response...

Metabolic brain disease, Aug 3, 2017

To investigate the frequency of physio-somatic symptoms (PS) symptoms in schizophrenia and their ... more To investigate the frequency of physio-somatic symptoms (PS) symptoms in schizophrenia and their relation to positive, negative and affective symptoms; neurocognitive deficits and impairments in the tryptophan catabolite (TRYCAT) pathway. Eighty four patients with schizophrenia and 40 healthy controls were assessed using the 12 item Fibromyalgia and Chronic Fatigue Syndrome Rating scale (FF) and scales for negative and positive symptoms, depression and anxiety. Cognitive functioning was tested using the Cambridge Neuropsychological Test Automated Battery (CANTAB). Other assessments included: immunoglobulin (Ig)A and IgM responses to tryptophan catabolites (TRYCATs), namely quinolinic (QA), 3-OH-kynurenine (3HK), picolinic (PA), xanthurenic (XA) and kynurenic acid (KA) and anthranilic acid (AA). More than 50% of the patients studied had elevated levels of physio-somatic (PS) symptoms, significantly co-occurring with depression and anxiety, but not with negative or positive symptoms. ...

John Wiley & Sons, Ltd eBooks, Oct 11, 2013

Metabolic dysregulation is intimately associated with a wide array of seemingly unrelated disorde... more Metabolic dysregulation is intimately associated with a wide array of seemingly unrelated disorders, including schizophrenia, Alzheimer disease, and depression. Genetic susceptibility genes show significant overlap between Alzheimer disease and schizophrenia, suggesting overlap in underlying biological processes, including metabolic. The high levels of depression in both disorders is linked to these shared processes. This chapter reviews the data suggesting that changes in leptin levels and leptin resistance mediate many of these metabolic changes, including the regulation of tryptophan catabolites (TRYCATs) and neuropeptides, which in turn drives alterations in cognition, neurogenesis, and apoptotic pathways. On the basis of this, treatment implications are proposed including the use of melatonin, together with leptin, in the prevention and treatment of these poorly managed disorders.

CNS & Neurological Disorders - Drug Targets, 2014

CNS & Neurological Disorders - Drug Targets, 2014

Journal of breastfeeding biology, Jul 22, 2016

Advances in integrative medicine, Apr 1, 2015

Current Pharmaceutical Design, Feb 15, 2016

Oxford University Press eBooks, Feb 1, 2019

Neuroprogressive processes in major depressive disorder (MDD) can occur in association with recur... more Neuroprogressive processes in major depressive disorder (MDD) can occur in association with recurrent episodes. The primary biological underpinnings are mediated by increases in the levels of immune-inflammation, tryptophan catabolites, mitochondrial dysfunction, and oxidative and nitrosative stress. Such biochemical alterations may be driven by changes in many peripheral and central sites, including in the gut, as well as by early developmental priming, such as prenatal stressors and breastfeeding consequences. As such, the conceptualization of MDD is shifted from simple psychological and central biochemical models to one that includes whole body processes over a developmental timescale. This provides a model that better integrates wider bodies of data relevant to the aetiology and course of MDD, and which therefore underpins the neuroprogressive processes that can occur over the course of MDD. This also significantly challenges current MDD (and wider psychiatric) classification by shifting classification to one based on biological processes rather than one based on subjective phenomenology.

When tryptophan is taken up by the body, some is used for the synthesis of sero-tonin. As well as... more When tryptophan is taken up by the body, some is used for the synthesis of sero-tonin. As well as having neuroregulatory effects, serotonin is also the precursor for the synthesis of N-acetylserotonin (NAS) and melatonin, which form the melatonergic pathways. The melatonergic pathways are associated with many of the changes that are thought to be important in the pathophysi-ology of Alzheimer's disease, Parkinson's disease, multiple sclerosis, and major depressive disorder. As well as being produced by the pineal gland at night, and thereby contributing to the circadian rhythm, melatonin is also very highly produced in other organs and tissues, including the gut, where CONTENTS

Reactive Oxygen Species, 2018

Journal of Neuroimmunology, 2012

Neuroprotective potential of estrogens and estrogenic compounds against amyloid-beta and oxidativ... more Neuroprotective potential of estrogens and estrogenic compounds against amyloid-beta and oxidative stress

John Wiley & Sons, Ltd eBooks, Oct 11, 2013

Metabolic dysregulation is intimately associated with a wide array of seemingly unrelated disorde... more Metabolic dysregulation is intimately associated with a wide array of seemingly unrelated disorders, including schizophrenia, Alzheimer disease, and depression. Genetic susceptibility genes show significant overlap between Alzheimer disease and schizophrenia, suggesting overlap in underlying biological processes, including metabolic. The high levels of depression in both disorders is linked to these shared processes. This chapter reviews the data suggesting that changes in leptin levels and leptin resistance mediate many of these metabolic changes, including the regulation of tryptophan catabolites (TRYCATs) and neuropeptides, which in turn drives alterations in cognition, neurogenesis, and apoptotic pathways. On the basis of this, treatment implications are proposed including the use of melatonin, together with leptin, in the prevention and treatment of these poorly managed disorders.

Journal of evaluation in clinical practice, Aug 17, 2018

Major affective disorders including bipolar disorder (BD) and major depressive disorder (MDD) are... more Major affective disorders including bipolar disorder (BD) and major depressive disorder (MDD) are associated with impaired health-related quality of life (HRQoL). Oxidative stress and subtle thyroid abnormalities may play a pathophysiological role in both disorders. Thus, the current study was performed to examine whether neuro-oxidative biomarkers and thyroid-stimulating hormone (TSH) levels could predict HRQoL in BD and MDD. This cross-sectional study enrolled 68 BD and 37 MDD patients and 66 healthy controls. The World Health Organization (WHO) QoL-BREF scale was used to assess 4 QoL subdomains. Peripheral blood malondialdehyde (MDA), advanced oxidation protein products, paraoxonaxe/CMPAase activity, a composite index of nitro-oxidative stress, and basal TSH were measured. In the total WHOQoL score, 17.3% of the variance was explained by increased advanced oxidation protein products and TSH levels and lowered CMPAase activity and male gender. Physical HRQoL (14.4%) was associated...

Cells

Although previously restricted to a limited number of medical conditions, there is a growing appr... more Although previously restricted to a limited number of medical conditions, there is a growing appreciation that ‘autoimmune’ (or immune-mediated) processes are important aspects of a wide array of diverse medical conditions, including cancers, neurodegenerative diseases and psychiatric disorders. All of these classes of medical conditions are associated with alterations in mitochondrial function across an array of diverse cell types. Accumulating data indicate the presence of the mitochondrial melatonergic pathway in possibly all body cells, with important consequences for pathways crucial in driving CD8+ T cell and B-cell ‘autoimmune’-linked processes. Melatonin suppression coupled with the upregulation of oxidative stress suppress PTEN-induced kinase 1 (PINK1)/parkin-driven mitophagy, raising the levels of the major histocompatibility complex (MHC)-1, which underpins the chemoattraction of CD8+ T cells and the activation of antibody-producing B-cells. Many factors and processes clo...

International Journal of Molecular Sciences

There is a growing interest in the role of alterations in mitochondrial metabolism in the pathoet... more There is a growing interest in the role of alterations in mitochondrial metabolism in the pathoetiology and pathophysiology of cancers, including within the array of diverse cells that can form a given tumor microenvironment. The ‘exhaustion’ in natural killer cells and CD8+ t cells as well as the tolerogenic nature of dendritic cells in the tumor microenvironment seems determined by variations in mitochondrial function. Recent work has highlighted the important role played by the melatonergic pathway in optimizing mitochondrial function, limiting ROS production, endogenous antioxidants upregulation and consequent impacts of mitochondrial ROS on ROS-dependent microRNAs, thereby impacting on patterned gene expression. Within the tumor microenvironment, the tumor, in a quest for survival, seeks to ‘dominate’ the dynamic intercellular interactions by limiting the capacity of cells to optimally function, via the regulation of their mitochondrial melatonergic pathway. One aspect of this ...

International Journal of Molecular Sciences

Major depressive disorder (MDD) is widely accepted as having a heterogenous pathophysiology invol... more Major depressive disorder (MDD) is widely accepted as having a heterogenous pathophysiology involving a complex mixture of systemic and CNS processes. A developmental etiology coupled to genetic and epigenetic risk factors as well as lifestyle and social process influences add further to the complexity. Consequently, antidepressant treatment is generally regarded as open to improvement, undoubtedly as a consequence of inappropriately targeted pathophysiological processes. This article reviews the diverse array of pathophysiological processes linked to MDD, and integrates these within a perspective that emphasizes alterations in mitochondrial function, both centrally and systemically. It is proposed that the long-standing association of MDD with suppressed serotonin availability is reflective of the role of serotonin as a precursor for the mitochondrial melatonergic pathway. Astrocytes, and the astrocyte mitochondrial melatonergic pathway, are highlighted as crucial hubs in the integ...

International Journal of Molecular Sciences

Type 1 diabetes mellitus (T1DM) arises from the failure of pancreatic β-cells to produce adequate... more Type 1 diabetes mellitus (T1DM) arises from the failure of pancreatic β-cells to produce adequate insulin, usually as a consequence of extensive pancreatic β-cell destruction. T1DM is classed as an immune-mediated condition. However, the processes that drive pancreatic β-cell apoptosis remain to be determined, resulting in a failure to prevent ongoing cellular destruction. Alteration in mitochondrial function is clearly the major pathophysiological process underpinning pancreatic β-cell loss in T1DM. As with many medical conditions, there is a growing interest in T1DM as to the role of the gut microbiome, including the interactions of gut bacteria with Candida albicans fungal infection. Gut dysbiosis and gut permeability are intimately associated with raised levels of circulating lipopolysaccharide and suppressed butyrate levels, which can act to dysregulate immune responses and systemic mitochondrial function. This manuscript reviews broad bodies of data on T1DM pathophysiology, hi...

Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2017

CNS & Neurological Disorders - Drug Targets, 2014

In many psychiatric, neurodegenerative and systemic inflammatory disorders circadian melatonin is... more In many psychiatric, neurodegenerative and systemic inflammatory disorders circadian melatonin is decreased whilst melatonin enzymes and melatonin receptors are genetic susceptibility factors. Treatment with melatonin is useful in a diverse range of medical conditions, including bipolar disorder, Alzheimer's disease, depression and fibromyalgia. Decreased melatonin effects are classically attributed to lost pineal production. However, melatonin, along with its immediate precursor N-acetylserotonin (NAS), is produced by many, if not all, mitochondrial containing cells, including immune cells and central glia. Here we review the data on local melatonin and NAS production and propose that astrocyte melatonin and NAS efflux is crucial to local central inflammation regulation at the glia-neuronal interface. Melatonin and NAS provide antioxidant and anti-inflammatory effects, as well as increasing mitochondrial oxidative phosphorylation and functioning. Consequently, their decreased production at sites of local inflammation is proposed to underlie melatonin's genetic association with a diverse range of medical conditions. Similarly the benefits of serotonin boosting medications, including antidepressants, across a wide range of conditions are partly mediated by increasing serotonin availability for astrocytic local NAS and melatonin production. Such a conceptualization incorporates a plethora of data across different disorders, especially the commonalities in oxidative and nitrosative stress, anti-oxidants, tryptophan catabolites and mitochondrial dysregulation evident in a diverse array of medical conditions. Glia melatonin and NAS regulation are important treatment targets in psychiatric disorders, neurodegenerative disorders and glioma.

Progress in neuro-psychopharmacology & biological psychiatry, Jan 6, 2017

The aim of this study was to delineate the associations between the tryptophan catabolite (TRYCAT... more The aim of this study was to delineate the associations between the tryptophan catabolite (TRYCAT) pathway and affective symptoms in schizophrenia. Towards this end we measured immunoglobulin (Ig)A and IgM responses to relatively noxious TRYCATs, namely quinolinic (QA), xanthurenic (XA), picolinic (PA) acid and 3-OH-kynurenine (3HK), and generally protective TRYCATs, namely anthranilic (AA) and kynurenic (KA) acid in 80 patients with schizophrenia and 40 healthy controls. The Hamilton Rating Scale for Depression (HDRS) and anxiety (HAMA), Young Mania Rating Scale (YMRS) as well as the Positive and Negative Symptoms Scale of Schizophrenia (PANSS) were measured. Depression, anxiety and hypomanic as well as negative and positive symptoms were associated with increased IgA responses to PA. Increased IgA responses to XA were associated with anxiety, hypomanic and negative symptoms. Moreover, depressive, anxiety, hypomanic and negative symptoms were characterized by increased IgA response...

Metabolic brain disease, Aug 3, 2017

To investigate the frequency of physio-somatic symptoms (PS) symptoms in schizophrenia and their ... more To investigate the frequency of physio-somatic symptoms (PS) symptoms in schizophrenia and their relation to positive, negative and affective symptoms; neurocognitive deficits and impairments in the tryptophan catabolite (TRYCAT) pathway. Eighty four patients with schizophrenia and 40 healthy controls were assessed using the 12 item Fibromyalgia and Chronic Fatigue Syndrome Rating scale (FF) and scales for negative and positive symptoms, depression and anxiety. Cognitive functioning was tested using the Cambridge Neuropsychological Test Automated Battery (CANTAB). Other assessments included: immunoglobulin (Ig)A and IgM responses to tryptophan catabolites (TRYCATs), namely quinolinic (QA), 3-OH-kynurenine (3HK), picolinic (PA), xanthurenic (XA) and kynurenic acid (KA) and anthranilic acid (AA). More than 50% of the patients studied had elevated levels of physio-somatic (PS) symptoms, significantly co-occurring with depression and anxiety, but not with negative or positive symptoms. ...

John Wiley & Sons, Ltd eBooks, Oct 11, 2013

Metabolic dysregulation is intimately associated with a wide array of seemingly unrelated disorde... more Metabolic dysregulation is intimately associated with a wide array of seemingly unrelated disorders, including schizophrenia, Alzheimer disease, and depression. Genetic susceptibility genes show significant overlap between Alzheimer disease and schizophrenia, suggesting overlap in underlying biological processes, including metabolic. The high levels of depression in both disorders is linked to these shared processes. This chapter reviews the data suggesting that changes in leptin levels and leptin resistance mediate many of these metabolic changes, including the regulation of tryptophan catabolites (TRYCATs) and neuropeptides, which in turn drives alterations in cognition, neurogenesis, and apoptotic pathways. On the basis of this, treatment implications are proposed including the use of melatonin, together with leptin, in the prevention and treatment of these poorly managed disorders.

CNS & Neurological Disorders - Drug Targets, 2014

CNS & Neurological Disorders - Drug Targets, 2014

Advances in Protein Chemistry and Structural Biology, Volume 88 # 2012 , 2012

A recent study—comparing those with depression, somatization, comorbid depressionþsomatization, a... more A recent study—comparing those with depression, somatization, comorbid
depressionþsomatization, 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-proteincoupled
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 (g-mangostin), N-acetyl cysteine, and pamoic acid.

Frontiers in Clinical Drug Research-Central Nervous System, 2017

Alpha 7 Nicotinic Receptor Agonist Modulatory Interactions With Melatonin: Relevance Not Only To ... more Alpha 7 Nicotinic Receptor Agonist Modulatory Interactions With Melatonin: Relevance Not Only To Cognition, But To Wider Neuropsychiatric And Immune Inflammatory Disorders.