Investigation of betaine as a novel psychotherapeutic for schizophrenia

Abstract

Number of words in the abstract: 217 Number of words in the article body: 4714 Number of figures: 8 Number of tables: 0 Number of supplementary information: 1 -Number of supplementary tables: 13 -Number of supplementary figures: 10 2 ABSTRACTBetaine is known to act against various biological stresses and its levels were reported to be decreased in schizophrenia patients. Using Chdh (a gene for betaine synthesis)-deficient mice and betaine-supplemented inbred mice, we assessed the role of betaine in psychiatric pathophysiology, and its potential as a novel psychotherapeutic, by leveraging metabolomics, behavioral-, transcriptomics and DNA methylation analyses. The Chdh-deficient mice revealed remnants of psychiatric behaviors along with schizophrenia-related molecular perturbations. Betaine supplementation elicited genetic background-dependent improvement in cognitive performance, and suppressed methamphetamine (MAP)-induced behavioral sensitization. Furthermore, betaine rectified the altered antioxidative and proinflammatory responses induced by MAP and in vitro phencyclidine treatments. Notably, betaine levels were decreased in the postmortem brains from schizophrenia, and a coexisting elevated carbonyl stress, a form of oxidative stress, demarcated a subset of schizophrenia with "betaine deficit-oxidative stress pathology". We revealed the decrease of betaine levels in glyoxylase 1 (GLO1)-deficient hiPSCs, which shows elevated carbonyl stress, and the efficacy of betaine in alleviating it, thus supporting a causal link between betaine and oxidative stress conditions. Furthermore, a CHDH variant, rs35518479, was identified as a cis-expression quantitative trait locus (QTL) for CHDH expression in postmortem brains from schizophrenia, allowing genotype-based stratification of schizophrenia patients for betaine efficacy. In conclusion, the present study underscores the potential benefit of betaine in a subset of schizophrenia.

Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology

“…To verify the idea of upregulated H 2 S/polysulfides production state in schizophrenia, we examined a different postmortem brain sample set (BA17) (2 nd sample set) (Ohnishi et al , ) () and evaluated phenotypic features of schizophrenia that are associated with elevated H 2 S production system. In this sample set, the MPST protein expression levels were higher in the schizophrenia than in the control groups (Fig A).…”

The influence of choline treatment on behavioral and neurochemical autistic-like phenotype in Mthfr-deficient mice

“…Betaine, derived from dietary choline, is also a methyl-donor participating in re-methylation in the methionine cycle. It protects cells and proteins from environmental stress 79,80 . Choline supplementation has previously been reported to be beneficial in a variety of conditions, unrelated, indirectly-and directly-related to autism.…”

Mitochondrial Metabolism in Astrocytes Regulates Brain Bioenergetics, Neurotransmission and Redox Balance

“…While remethylation of homocysteine to methionine can be accomplished by the activity of methionine synthase, in the liver and kidney mitochondria, betaine-homocysteine S-methyltransferase (BHMT) also produces methionine from homocysteine, linking the mitochondrial oxidation of choline to betaine with the TSP ( Figure 4.5 ). Brain genetic variants of BHMT have been linked to schizophrenia ( Ohnishi et al, 2019 ). However, the presence of BHMT and its significance to the remethylation of homocysteine hasn’t been confirmed in astrocytes ( Kempson et al, 2014 ).…”