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    ABSTRACT: Free radical-mediated abnormalities may contribute to the development of tardive dyskinesia (TD) and specific aspects of schizophrenia symptomatology such as cognitive deficits. Superoxide dismutase (SOD), a critical enzyme in the detoxification of superoxide radicals, was found to be abnormal in TD. While most of previous studies focused on the manganese isoform located in mitochondria, this study investigated the activities of isoform CuZnSOD present in the plasma. We recruited 113 male chronic patients with TD (n = 43) and without TD (n = 70) meeting DSM-IV criteria for schizophrenia, and 84 male control subjects. We examined the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), CuZnSOD activity for both the patient and control groups along with total antioxidant status (TAS) and malondialdehyde (MDA) levels in a subset of the cohort. Positive and Negative Symptom Scale (PANSS) and the Abnormal Involuntary Movement Scale (AIMS) were assessed in the patient group. Our results showed lower CuZnSOD activity and TAS levels, but higher MDA levels in patients with TD than those without TD (all p < 0.05). Patients with TD had lower RBANS subscales of Visuospatial/Constructional (p < 0.05) and attention (p < 0.01) than those without TD. Multiple regression analysis showed that in either TD or non-TD group, CuZnSOD was an independent contributor to the attention index of RBANS (both p < 0.05). These results implicated that TD patients suffered greater oxidative stress and cognitive dysfunction than non-TD patients. Oxidative stress could contribute to both TD development and cognitive impairment.
    Journal of Psychiatric Research 08/2014; 58. DOI:10.1016/j.jpsychires.2014.07.028 · 4.09 Impact Factor
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    ABSTRACT: Use of phencyclidine (PCP) in rodents can mimic some aspects of schizophrenia. However, the underlying mechanism is still unclear. Growing evidence indicates that neuroinflammation plays a significant role in the pathophysiology of schizophrenia. In this study, we focused on inflammatory responses as target of PCP for inducing schizophrenia-like symptoms. 3-month-old C57BL/6J mice received daily injections of PCP (20 mg/kg, i.p.) or saline for one week. PCP-injected mice produced schizophrenia-like behaviours including impaired spatial short-term memory assessed by the Y-maze task and sensorimotor gating deficits in a prepulse inhibition task. Simultaneously, chronic PCP administration induced astrocyte and microglial activation in both the cortex and hippocampus. Additionally, the proinflammatory cytokine interleukin-1β was significantly up-regulated in PCP administrated mice. Furthermore, PCP treatment decreased ratio of the phospho-Ser9 epitope of glycogen synthase kinase-3β (GSK3β) over total GSK3β, which is indicative of increased GSK3β activity. These data demonstrate that chronic PCP in mouse produces inflammatory responses and GSK3β activation.
    Neurochemical Research 10/2014; DOI:10.1007/s11064-014-1441-9 · 2.55 Impact Factor
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    ABSTRACT: The medical, research and general community is unable to effect significantly decreased rates of central obesity and related type II diabetes mellitus (TIIDM), cardiovascular disease (CVD) and cancer. All conditions seem to be linked by the concept of the metabolic syndrome (MetS), but the underlying causes are not known. MetS markers may have been mistaken for causes, thus many treatments are destined to be suboptimal. The current paper aims to critique current paradigms, give explanations for their persistence, and to return to first principles in an attempt to determine and clarify likely causes of MetS and obesity related comorbidities. A wide literature has been mined, study concepts analysed and the basics of human evolution and new biochemistry reviewed. A plausible, multifaceted composite unifying theory is formulated. The basis of the theory is that the proportionately large, energy-demanding human brain may have driven co-adaptive mechanisms to provide, or conserve, energy for the brain. A 'dual system' is proposed. 1) The enlarged, complex cortico-limbic-striatal system increases dietary energy by developing strong neural self-reward/motivation pathways for the acquisition of energy dense food, and (2) the nuclear factor-erythroid 2-related factor 2 (NRF2) cellular protection system amplifies antioxidant, antitoxicant and repair activity by employing plant chemicals, becoming highly energy efficient in humans. The still-evolving, complex human cortico-limbic-striatal system generates strong behavioural drives for energy dense food procurement, including motivating agricultural technologies and social system development. Addiction to such foods, leading to neglect of nutritious but less appetizing 'common or garden' food, appears to have occurred. Insufficient consumption of food micronutrients prevents optimal human NRF2 function. Inefficient oxidation of excess energy forces central and non-adipose cells to store excess toxic lipid. Oxidative stress and metabolic inflammation, or metaflammation, allow susceptibility to infectious, degenerative atherosclerotic cardiovascular, autoimmune, neurodegenerative and dysplastic diseases. Other relevant human-specific co-adaptations are examined, and encompass the unusual ability to store fat, certain vitamin pathways, the generalised but flexible intestine and microbiota, and slow development and longevity. This theory has significant past and future corollaries, which are explored in a separate article by McGill, A-T, in Archives of Public Health, 72: 31.