Marked reduction of soluble superoxide dismutase-1 (SOD1) in cerebrospinal fluid of patients with recent-onset schizophrenia

Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Molecular Psychiatry (Impact Factor: 14.5). 02/2012; 18(1). DOI: 10.1038/mp.2012.6
Source: PubMed


Molecular Psychiatry publishes work aimed at elucidating biological mechanisms underlying psychiatric disorders and their treatment

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    ABSTRACT: Abstract Health messages on low-energy diets for healthy weight loss are muddled and not working, and obesity rates are rising. Are there missing links? Accumulating evidence shows that humans have well developed 'self-addictive' appetite pathways to enhance the uptake of highly energy-dense food. Humans synthesize fewer co-factors and vitamins than other mammals and must ingest them. Both processes probably arose to maximize available energy for the developing, large association cortex of the human brain. The default phenotype resulting from consuming an 'addictive', westernized, highly refined, energy-dense, hypomicronutrient diet is 'malnutritive obesity' or 'malnubesity'. A relative lack of antioxidant (and other) co-factors contributes to inefficiently oxidized energy. This 'stress' leads to central fat deposition, disordered energy use by cell mitochondria, especially in muscle and liver, and malfunctioning immune, coagulation, endothelial, and other systems. The resultant problems appear to range from epigenetic reprogramming in utero to end organ damage of the metabolic syndrome and the immune failure of cancer. Treatment of 'malnubesity' may require: (1) understanding the drivers and mechanisms of addictions, (2) reprioritizing satiating, micronutrient-dense whole foods, (3) nonjudgmental general, psychological, and medical support for those at risk or affected by obesity; and (4) practical incentives/regulation for healthy food production and distribution.
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    ABSTRACT: Background: Our previous studies indicated that N-methyl-D-aspartate receptor (NMDAR) deletion from a subset of corticolimbic interneurons in the mouse brain during early postnatal development is sufficient to trigger several behavioral and pathophysiological features resembling the symptoms of human schizophrenia. Interestingly, many of these behavioral phenotypes are exacerbated by social isolation stress. However, the mechanisms underlying the exacerbating effects of social isolation are unclear. Methods: With γ-aminobutyric acid-ergic interneuron-specific NMDAR hypofunction mouse model (Ppp1r2-Cre/fGluN1 knockout [KO] mice), we investigated whether oxidative stress is implicated in the social isolation-induced exacerbation of schizophrenia-like phenotypes and further explored the underlying mechanism of elevated oxidative stress in KO mice. Results: The reactive oxygen species (ROS) level in the cortex of group-housed KO mice was normal at 8 weeks although increased at 16 weeks old. Postweaning social isolation (PWSI) augmented the ROS levels in KO mice at both ages, which was accompanied by the onset of behavioral phenotype. Chronic treatment with apocynin, an ROS scavenger, abolished markers of oxidative stress and partially alleviated schizophrenia-like behavioral phenotypes in KO mice. Markers of oxidative stress after PWSI were especially prominent in cortical parvalbumin (PV)-positive interneurons. The vulnerability of PV interneurons to oxidative stress was associated with downregulation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a master regulator of mitochondrial energy metabolism and antioxidation. Conclusions: These results suggest that a PWSI-mediated impairment in antioxidant defense mechanisms, presumably mediated by PGC-1α downregulation in the NMDAR-deleted PV-positive interneurons, results in oxidative stress, which, in turn, might contribute to exacerbation of schizophrenia-like behavioral phenotypes.
    Biological psychiatry 01/2013; 73(10). DOI:10.1016/j.biopsych.2012.12.004 · 10.26 Impact Factor
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    ABSTRACT: Multiple lines of evidence support the pathogenic role of neuroinflammation in psychiatric illness. While systemic autoimmune diseases are well-documented causes of neuropsychiatric disorders, synaptic autoimmune encephalitides with psychotic symptoms often go under-recognized. Parallel to the link between psychiatric symptoms and autoimmunity in autoimmune diseases, neuroimmunological abnormalities occur in classical psychiatric disorders (for example, major depressive, bipolar, schizophrenia, and obsessive-compulsive disorders). The pathophysiology of these conditions traditionally stressed dysregulation of the glutamatergic and monoaminergic systems, but the mechanisms causing these neurotransmitter abnormalities remained elusive. We review autoimmunity and neuropsychiatric disorders, and the human and experimental evidence supporting the pathogenic role of neuroinflammation in selected classical psychiatric disorders. Understanding how psychosocial, genetic, immunological and neurotransmitter systems interact can reveal pathogenic clues and help target new preventive and symptomatic therapies.
    Journal of Neuroinflammation 04/2013; 10(1):43. DOI:10.1186/1742-2094-10-43 · 5.41 Impact Factor
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