Glutathione Deficiency and Alterations in the Sulfur Amino Acid Homeostasis during Early Postnatal Development as Potential Triggering Factors for Schizophrenia-Like Behavior in Adult Rats

Abstract

Impaired glutathione (GSH) synthesis and dopaminergic transmission are important factors in the pathophysiology of schizophrenia. Our research aimed to assess the effects of l-buthionine-(S,R)-sulfoximine (BSO), a GSH synthesis inhibitor, and GBR 12909, a dopamine reuptake inhibitor, administered alone or in combination, to Sprague–Dawley rats during early postnatal development (p5–p16), on the levels of GSH, sulfur amino acids, global DNA methylation, and schizophrenia-like behavior. GSH, methionine (Met), homocysteine (Hcy), and cysteine (Cys) contents were determined in the liver, kidney, and in the prefrontal cortex (PFC) and hippocampus (HIP) of 16-day-old rats. DNA methylation in the PFC and HIP and schizophrenia-like behavior were assessed in adulthood (p90–p93). BSO caused the tissue-dependent decreases in GSH content and alterations in Met, Hcy, and Cys levels in the peripheral tissues and in the PFC and HIP. The changes in these parameters were accompanied by alterations in the global DNA methylation in the studied brain structures. Parallel to changes in the global DNA methylation, deficits in the social behaviors and cognitive functions were observed in adulthood. Only BSO + GBR 12909-treated rats exhibited behavioral alterations resembling positive symptoms in schizophrenia patients. Our results suggest the usefulness of this neurodevelopmental model for research on the pathomechanism of schizophrenia.

Alterations in the Antioxidant Enzyme Activities in the Neurodevelopmental Rat Model of Schizophrenia Induced by Glutathione Deficiency during Early Postnatal Life

“…Similarly to other clinical studies, the occurrence of schizophrenia-like symptoms [ 18 , 19 , 20 , 21 , 22 , 23 ]—as well as numerous biochemical and morphological alterations, reminiscent of those observed in patients—have been described in experimental animals [ 24 , 25 , 26 , 27 , 28 ], in which the GSH deficit was induced by genetic manipulation in genes encoding GCL enzyme [ 29 , 30 , 31 ], or by specific compounds that reduce GSH concentration [ 32 , 33 ]. In our recently published study (Górny et al [ 34 ]), the chronic administration of l -buthionine-(S,R)-sulfoximine (BSO), a specific GCL inhibitor, to newborn male Sprague-Dawley rats between the postnatal day p5 and p16, has been shown to induce the tissue-dependent decreases in GSH contents, paralleled by alterations in homeostasis of sulfur-containing amino acids (Met and Cys), when measured 4 h after the last dose. As a consequence of the changes in the contents of these thiols in peripheral tissues (liver, kidneys), and in certain brain structures (prefrontal cortex, PFC; hippocampus, HIP) during early postnatal development, schizophrenia-like behaviors appeared in adulthood (p90–p93), which were accompanied by changes in the global DNA methylation status in the studied brain structures [ 34 ].…”

“…In our recently published study (Górny et al [ 34 ]), the chronic administration of l -buthionine-(S,R)-sulfoximine (BSO), a specific GCL inhibitor, to newborn male Sprague-Dawley rats between the postnatal day p5 and p16, has been shown to induce the tissue-dependent decreases in GSH contents, paralleled by alterations in homeostasis of sulfur-containing amino acids (Met and Cys), when measured 4 h after the last dose. As a consequence of the changes in the contents of these thiols in peripheral tissues (liver, kidneys), and in certain brain structures (prefrontal cortex, PFC; hippocampus, HIP) during early postnatal development, schizophrenia-like behaviors appeared in adulthood (p90–p93), which were accompanied by changes in the global DNA methylation status in the studied brain structures [ 34 ]. However, to date, the activities of antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione disulfide reductase (GR) that control the levels of reactive oxygen species (ROS), such as superoxide anion radical (O 2 •− ) and hydrogen peroxide (H 2 O 2 ), and are principal determinants of the redox state of cells, have not been studied in the rat model of schizophrenia induced by BSO treatment during the early postnatal life.…”

“…Therefore, to clarify this issue, and to find a relationship between changes in the activity of antioxidant enzymes (SOD, CAT, GPx, GR), and the contents of GSH and sulfur amino acids (Cys, Met), described in our recently published study [ 34 ], we measured the activities of these enzymes and the levels of ROS as well as lipid peroxidation expressed as malondialdehyde (MDA) level, in the same groups of 16 day-old Sprague-Dawley rats administered chronically with BSO and the compound GBR 12909, which is an inhibitor of dopamine transporter (DAT), alone or in combination. The rationale for the administration of the DAT inhibitor was to check whether an increase in the extracellular dopamine (DA) level may exert some specific additional effect on both the activities of these enzymes and ROS levels.…”

“…The rationale for the administration of the DAT inhibitor was to check whether an increase in the extracellular dopamine (DA) level may exert some specific additional effect on both the activities of these enzymes and ROS levels. As in our earlier study [ 34 ], these model compounds (BSO, GBR 12909) were administered chronically between the postnatal day 5 and 16. Similarly, the activities of antioxidant enzymes were determined in the tissue homogenates of peripheral organs (liver and kidney) and the brain structures involved in the expression of schizophrenia-like symptoms (PFC and HIP), 4 h after the last BSO, and/or GBR 12909 doses.…”

Oxidative-Antioxidant Imbalance and Impaired Glucose Metabolism in Schizophrenia

“…The severity of symptoms is the result of sulfuric stress and is positively correlated with high levels of homocysteine and the failure of transsulfuration process, which metabolizes homocysteine in the l-cysteine pathway [143,268]. l-cysteine deficiency and lack of response from the transsulfuration pathway (low activity of cystathionine β-synthase and cystathionine γ-lyase) become the cause of the recorded low levels of glutathione and glutathione pathway enzymes (i.e., GPx) in the brain and blood of patients with schizophrenia [269]. As a consequence, the level of hydrogen sulfide (H 2 S) decreases and the oxidative phosphorylation (OXPHOS) pathway containing a number of proteins that have iron and sulfur in their structure is impaired.…”