Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology

Abstract

Mice with the C3H background show greater behavioral propensity for schizophrenia, including lower prepulse inhibition (PPI), than C57BL/6 (B6) mice. To characterize as‐yet‐unknown pathophysiologies of schizophrenia, we undertook proteomics analysis of the brain in these strains, and detected elevated levels of Mpst, a hydrogen sulfide (H2S)/polysulfide‐producing enzyme, and greater sulfide deposition in C3H than B6 mice. Mpst‐deficient mice exhibited improved PPI with reduced storage sulfide levels, while Mpst‐transgenic (Tg) mice showed deteriorated PPI, suggesting that “sulfide stress” may be linked to PPI impairment. Analysis of human samples demonstrated that the H2S/polysulfides production system is upregulated in schizophrenia. Mechanistically, the Mpst‐Tg brain revealed dampened energy metabolism, while maternal immune activation model mice showed upregulation of genes for H2S/polysulfides production along with typical antioxidative genes, partly via epigenetic modifications. These results suggest that inflammatory/oxidative insults in early brain development result in upregulated H2S/polysulfides production as an antioxidative response, which in turn cause deficits in bioenergetic processes. Collectively, this study presents a novel aspect of the neurodevelopmental theory for schizophrenia, unraveling a role of excess H2S/polysulfides production.

Role of 3-Mercaptopyruvate Sulfurtransferase in the Regulation of Proliferation and Cellular Bioenergetics in Human Down Syndrome Fibroblasts

“…Moreover, forced overexpression of CBS in mice has been shown to produce disturbances in serotonin and dopamine pathways in the brain of mice [51] and to cause neurobehavioral deficits in some (but not all) experiments conducted to date [29,52]. With respect to 3-MST, there are also in vivo studies showing that both its deletion and its overexpression can impair various neurobehavioral parameters in mice [53,54]. In addition, ethylmalonic encephalopathy, an autosomal recessive disease which is associated with neurological impairment is, at least in part, due to the excessive accumulation of H 2 S; in this instance this is caused by ETHE1 mutations, which decrease the clearance of H 2 S due to the downregulation of mitochondrial sulfur dioxygenase [55].…”

Oxidative-Antioxidant Imbalance and Impaired Glucose Metabolism in Schizophrenia

“…This suggests that patients subjected to sulfuric stress have stronger psychotic symptoms. Studies show that elevated H 2 S levels in schizophrenic patients already occur at an early stage of the disease development [89]. Blood and plasma tests of schizophrenic and FEP patients showed elevated homocysteine levels, which probably correlates with the severity of the symptoms.…”

“…The ratio of lactate and pyruvic acid concentrations is significantly reduced suggesting the predominance of pyruvate formation [88]. A different level of lactates can be observed in the cerebrospinal fluid (CSF), where its increase indicates an intensified extra-mitochondrial anaerobic glucose metabolism [89]. Imaging techniques and metabolomics assessing mitochondrial functions have allowed the determination of metabolites dependent on oxidative stress or inflammation to identify pathological changes in the brains of patients with varying degrees of schizophrenia [90][91][92][93].…”

“…This suggests that patients with this disease subjected to sulfuric stress have stronger psychotic symptoms. Studies show that increased levels of H 2 S in schizophrenic patients occur at an early stage of the disease development [89].…”

Hydrogen Sulfide in Pharmacotherapy, Beyond the Hydrogen Sulfide-Donors

“…There is some evidence that the H 2 S/polysulfide production system is upregulated in schizophrenia. A more detailed explanation of the role of sulfide stress in the development of schizophrenia may give a new direction to develop a more effective treatment for this disorder [208]. However, it is worth stressing that several sulfur-based drugs are used in the treatment of schizophrenia, including Sulpiride and Sultopride.…”