TOXINS CAUSING METABOLISM DISORDERS

This blog explores links between mitochondrial toxins like hexachlorophene and disorders like major depression and the metabolic syndrome.

The first article is a good overview of depression and its relationship to the metabolic syndrome.

Ann Clin Psychiatry. 2007 Oct-Dec;19(4):257-64.
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Should Depressive Syndromes Be Reclassified as "Metabolic Syndrome Type II"?McIntyre RS, Soczynska JK, Konarski JZ, Woldeyohannes HO, Law CW, Miranda A, Fulgosi D, Kennedy SH.Mood Disorders Psychopharmacology Unit, University Health Network, University of Toronto, Toronto, ON, Canada. roger.mcintyre@uhn.on.caBACKGROUND: A nascent explanatory theory regarding the pathophysiology of major depressive disorder posits that alterations in metabolic networks (e.g., insulin and glucocorticoid signaling) mediate allostasis. METHOD: We conducted a PubMed search of all English-language articles published between January 1966 and September 2006. The search terms were: neurobiology, cognition, neuroprotection, inflammation, oxidative stress, glucocorticoids, metabolic syndrome, diabetes mellitus, insulin, and antidiabetic agents, cross-referenced with the individual names of DSM-III-R/IV/-TR-defined mood disorders. The search was augmented with a manual review of article reference lists; articles selected for review were determined by author consensus. RESULTS: Disturbances in metabolic networks: e.g., insulin-glucose homeostasis, immuno-inflammatory processes, adipokine synthesis and secretion, intra-cellular signaling cascades, and mitochondrial respiration are implicated in the pathophysiology, brain volumetric changes, symptomatic expression (e.g., neurocognitive decline), and medical comorbidity in depressive disorders. The central nervous system, like the pancreas, is a critical modulator of the metabolic milieu and is endangered by chronic abnormalities in metabolic processes. We propose the notion of "metabolic syndrome type II" as a neuropsychiatric syndrome in which alterations in metabolic networks are a defining pathophysiological component. CONCLUSION: A comprehensive management approach for depressive disorders should routinely include opportunistic screening and primary prevention strategies targeting metabolically mediated comorbidity (e.g., cardiovascular disease). Innovative treatments for mood disorders, which primarily target aberrant metabolic networks, may constitute potentially novel, and disease-modifying, treatment avenues.

Here are some excerpts from the article:

INTRODUCTION
Mood disorders are highly prevalent syndromes associated with a high rate of non-recovery, recurrence, and inter-episodic dysfunction (1,2). Despite intensified efforts to characterize and uncover pathoetiological factors subserving the “surface-based” phenomena of mood disorders, a clear, comprehensive, and coherent disease model in affective disorders does not currently exist (3). Nonetheless, alterations in neuronal plasticity, cellular resilience, and cytoarchitecture, along with associated regional abnormalities in neuronal (and glial) density and morphology are reported (4). The rationale for scrutinizing the metabolic system as a potential explanatory factor in mood disorders, and a platform for novel drug discovery, is supported by several lines of research (5).
Firstly, a concatenation of findings indicates that major depressive disorder (MDD) is an independent risk factor for new-onset type II diabetes mellitus (DM) (6). Secondly, MDD is associated with significant alterations in disparate physiological processes (e.g., decreased insulin sensitivity, immuno-inflammatory activation), which presage the depressed individual's vulnerability to type II DM (7). Thirdly, neuroimaging studies (e.g., positron emission tomography; PET, functional magnetic resonance imaging; fMRI) have persuasively reported regional alterations in brain metabolic activity at rest and following emotional/cognitive provocation (8). Also, similar to diabetic populations, the single largest cause of premature mortality in persons with mood disorders relates to abnormal insulin sensitivity (i.e., cardiovascular disease) (9,10). This latter observation has important implications for patient management and public-health initiatives (11).
Herein, we propose that MDD could be conceptualized as a “metabolic disorder” (i.e., “metabolic syndrome type II”), in which alterations in metabolic networks are a salient pathophysiological component and potential target for novel, potentially disease-modifying treatments. Towards this aim, we highlight the reciprocal relationship between MDD and DM with respect to neuroimaging abnormalities, neurocognitive deficits, and potential mediators linking these syndromes..........................

"NOTE HERE THAT IN OTHER RESEARCH OXIDATIVE STRESS IS RELATED TO THE NEUROTOXIC EFFECT OF DEPLETION ADENOSINE TRIPHOSPHATE IN THE CELL'S MITOCHONDRIA" - AGAIN, AS IS USUAL, BOLD IS BY ME.

Oxidative Stress
Reports from several investigations press the point that oxidative stress may be salient to the pathogenesis of mood disorders. The CNS is vulnerable to the effects of oxidative stress due to its high oxidative metabolic activity, polyunsaturated fatty acid content, and relatively low endogenous anti-oxidant capacity (75)................
The electron transport chain of the mitochondria, the non-enzymatic glycosylation reaction, and hexosamine are the major sources of ROS production in cells. Alterations in mitochondrial respiration are reported in both DM and depressive syndromes and may be a non-canonical target of antidepressant treatment (77,78). The β-cells of the pancreas have relatively low expression of the antioxidant enzymes catalase and GP (78). As a result, the pancreas is susceptible to the toxic effects of oxidative stress mechanisms................. Although it may be a strong pronouncement that altered NO signaling is a critical component in the pathophysiology (and somatic complications) of MDD and DM, a persuasive body of evidence indicates that NO may be salient to their pathophysiology.
Taken together, oxidative stress is associated with neuronal endangerment and β-cell toxicity. The oxidative stress-mediated activation of signal transduction pathways may underlie the cytotoxic effects documented in both MDD and DM. Treatment strategies capable of reducing oxidative stress constitute biologically plausible treatment avenues.
For example, antidepressant treatment is associated with a decrease in NO concentration and increase in SOD activity. Moreover, thiazolidinedione (TZD) therapy, indicated for the management of Type II DM, has been documented to reduce markers of pro-inflammation and oxidative stress and increase anti-inflammatory/anti-oxidant activity. Historically, the salutary effects of TZDs were first noted as antioxidants. As a possible proof of concept, TZD therapy has been reported to enhance cognitive function in patients with Alzheimer's disease (5).

HERE AND ELSEWHERE THERE ARE CAUSAL LINKS BETWEEN CORTISOL, DEPRESSION, AND THE METABOLIC SYNDROME.

Glucocorticoid Signaling
Glucocorticoids are counter-regulatory hormones which exert an obverse effect on insulin action (7). The primary role of glucocorticoids and other counter-regulatory hormones are to initiate and sustain a rise in blood glucose in response to stress. The mechanisms involved include gluconeogenesis, glycogenolysis, lipolysis, and inhibition of peripheral glucose transport and utilization (7).
Persons with mood disorders exhibit a high prevalence of Hypothalmic-pituitary-adrenal axis (HPA-axis) disturbances, notably persons with bipolar disorder and psychotic unipolar depression (82). Neuroendocrine studies have shown that up to half of depressed patients are Dexamethasone Suppression Test (DST) non-suppressors (82). These results indicate that mood disorders are associated with disturbances in negative feedback of the HPA-axis. Moreover, post-mortem studies provide evidence of reduced glucocorticoid receptor mRNA expression in post-mortem brain tissue samples from patients with bipolar disorder (83).
It is also reported that there is a direct correlation between peripheral cortisol levels and the severity of depressive symptoms and neurocognitive deficits (84). The hippocampus is a hormonally sensitive organ highly endowed with glucocorticoid receptors (GR). It is hypothesized that the link between HPA dysfunction and somatic toxicity in depression (i.e., allostatis) is mediated through neuronal GR within the hippocampus and other tissues throughout the body.
Taken together, mood disorders are characterized by abnormalities in biomarkers of inflammation, cellular respiration, excitotoxicity, and glucocorticoid signaling which alone, or together, may mediate the effects on neuronal integrity and function. The anti-oxidant effects of TZDs suggest a potential role in altering the neurotoxic biological effects of stress systems on neuronal structure and function.