Carbonyl stress and schizophrenia

Abstract

Appropriate biological treatment and psychosocial support are essential to achieve and maintain recovery for patients with schizophrenia. Despite extensive efforts to clarify the underlying disease mechanisms, the main cause and pathophysiology of schizophrenia remain unclear. This is due in large part to disease heterogeneity, which results in biochemical differences within a single disease entity. Other factors include variability across clinical symptoms and disease course, along with varied risk factors and treatment responses. Although schizophrenia's positive symptoms are largely managed through treatment with atypical antipsychotics, new classes of drugs are needed to address the unmet medical need for improving cognitive dysfunction and promoting recovery of negative symptoms in these patients. Accumulation of toxic reactive dicarbonyls, such as methylglyoxal, are typical indicators of carbonyl stress, and result in the modification of proteins and the formation of advanced glycation end products, such as pentosidine. In June 2010, we reported on idiopathic carbonyl stress in a subpopulation of schizophrenia patients, leading to a failure of metabolic systems with plasma pentosidine accumulation and serum pyridoxal depletion. Our findings suggest two markers, pentosidine and pyridoxal, as beneficial for distinguishing a specific subgroup of schizophrenics. We believe that this information, derived from in vitro and in vivo studies, is beneficial in the search for personalized and hopefully more effective treatment regimens in schizophrenia. Here, we define a subtype of schizophrenia based on carbonyl stress and the potential for using carbonyl stress as a biomarker in the challenge of overcoming heterogeneity in schizophrenia treatment.

Cutting‐edge morphological studies of post‐mortem brains of patients with schizophrenia and potential applications of X‐ray nanotomography (nano‐CT)

“…From previous biological research, it is thought that the etiological condition of schizophrenia involves multiple factors. As one of these factors, a nearly uniform population of schizophrenia cases was determined by using a chemical pathology marker called ‘carbonyl stress.’ A methodology to obtain reproducible observations regarding this subgroup has also been proposed . These studies have evolved into a clinical trial that is now underway .…”

“…56,78,79 A methodology to obtain reproducible observations regarding this subgroup has also been proposed. 79 These studies have evolved into a clinical trial that is now underway. 58 Here, it is truly interesting that the schizophrenia case with the highest neurite curvature carried a mutation related to carbonyl stress.…”

“…78 This schizophrenia patient may have sustained neurite thinning damage from peculiar metabolic disturbances, called 'carbonyl stress,' due to the GLO1 gene mutation. 79 Of course, we cannot preclude the involvement of multiple factors and multiple genes in the etiology of this schizophrenia case, though the effect size of the GLO1 frameshift is so large as to overwhelm other accompanying mutational variations or environmental factors of which the effect size is comparably small. Indeed, the frameshift mutation of the GLO1 gene has been found only in a limited number of patients among carbonyl stress cases.…”

“…The schizophrenia case that exhibited the highest neurite curvature (the purple line in Figure a) carried a frameshift mutation in the GLO1 gene and has been reported to be resistant to treatment . This schizophrenia patient may have sustained neurite thinning damage from peculiar metabolic disturbances, called ‘carbonyl stress,’ due to the GLO1 gene mutation . Of course, we cannot preclude the involvement of multiple factors and multiple genes in the etiology of this schizophrenia case, though the effect size of the GLO1 frameshift is so large as to overwhelm other accompanying mutational variations or environmental factors of which the effect size is comparably small.…”

Association between serum folate levels and schizophrenia based on sex

“…Growing evidence relating to the pathophysiology of schizophrenia indicates a potential effect of altered one-carbon metabolism, including epigenetic dysregulation. [1][2][3][4][5][6][7][8][9][10] Folate and related Bvitamins are involved in one-carbon metabolism and in the production of S-adenosylmethionine, a universal methyl donor required for various reactions, including the production of neurotransmitters. 11 To date, several studies have investigated the relation between blood folate levels and schizophrenia.…”