Impact of repeated co-treatment with escitalopram and aripiprazole on the schizophrenia-like behaviors and BDNF mRNA expression in the adult Sprague–Dawley rats exposed to glutathione deficit during early postnatal development of the brain

Abstract Background Preclinical and clinical studies have indicated that impaired endogenous synthesis of glutathione during early postnatal development plays a significant role in the pathophysiology of schizophrenia. Moreover, some studies have suggested that antidepressants are able to increase the activity of atypical antipsychotics which may efficiently improve the treatment of negative and cognitive symptoms of schizophrenia. Methods In the present study, we investigated the influence of repeated co-treatment with escitalopram and aripiprazole on the schizophrenia-like behavior and BDNF mRNA expression in adult rats exposed to glutathione deficit during early postnatal development. Male pups between the postnatal days p5–p16 were treated with the inhibitor of glutathione synthesis, BSO (L-buthionine-(S,R)-sulfoximine) and the dopamine uptake inhibitor, GBR 12,909 alone or in combination. Escitalopram and aripiprazole were given repeatedly for 21 days before the tests. On p90–92 rats were evaluated in the behavioral and biochemical tests. Results BSO given alone and together with GBR 12,909 induced deficits in the studied behavioral tests and decreased the expression of BDNF mRNA. Repeated aripiprazole administration at a higher dose reversed these behavioral deficits. Co-treatment with aripiprazole and an ineffective dose of escitalopram also abolished the behavioral deficits in the studied tests. Conclusion The obtained data indicated that the inhibition of glutathione synthesis in early postnatal development induced long-term deficits corresponding to schizophrenia-like behavior and decreased the BDNF mRNA expression in adult rats, and these behavioral deficits were reversed by repeated treatment with a higher dose of aripiprazole and also by co-treatment with aripiprazole and ineffective dose of escitalopram.

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Glutathione Deficiency during Early Postnatal Development Causes Schizophrenia-Like Symptoms and a Reduction in BDNF Levels in the Cortex and Hippocampus of Adult Sprague–Dawley Rats

International Journal of Molecular Sciences ◽

10.3390/ijms22126171 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6171

Author(s):

Marta Anna Lech ◽

Monika Leśkiewicz ◽

Kinga Kamińska ◽

Zofia Rogóż ◽

Elżbieta Lorenc-Koci

Keyword(s):

Postnatal Development ◽

Time Course ◽

Postnatal Life ◽

Positive Symptoms ◽

Gbr 12909 ◽

Sprague Dawley ◽

Bdnf Mrna ◽

Synthesis Inhibitor ◽

Early Postnatal Development ◽

Middle Adolescence

Growing body of evidence points to dysregulation of redox status in the brain as an important factor in the pathogenesis of schizophrenia. The aim of our study was to evaluate the effects of l-buthionine-(S,R)-sulfoximine (BSO), a glutathione (GSH) synthesis inhibitor, and 1-[2-Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine dihydrochloride (GBR 12909), a dopamine reuptake inhibitor, given alone or in combination, to Sprague–Dawley pups during early postnatal development (p5–p16), on the time course of the onset of schizophrenia-like behaviors, and on the expression of brain-derived neurotrophic factor (BDNF) mRNA and its protein in the prefrontal cortex (PFC) and hippocampus (HIP) during adulthood. BSO administered alone decreased the levels of BDNF mRNA and its protein both in the PFC and HIP. Treatment with the combination of BSO + GBR 12909 also decreased BDNF mRNA and its protein in the PFC, but in the HIP, only the level of BDNF protein was decreased. Schizophrenia-like behaviors in rats were assessed at three time points of adolescence (p30, p42–p44, p60–p62) and in early adulthood (p90–p92) using the social interaction test, novel object recognition test, and open field test. Social and cognitive deficits first appeared in the middle adolescence stage and continued to occur into adulthood, both in rats treated with BSO alone or with the BSO + GBR 12909 combination. Behavior corresponding to positive symptoms in humans occurred in the middle adolescence period, only in rats treated with BSO + GBR 12909. Only in the latter group, amphetamine exacerbated the existing positive symptoms in adulthood. Our data show that rats receiving the BSO + GBR 12909 combination in the early postnatal life reproduced virtually all symptoms observed in patients with schizophrenia and, therefore, can be considered a valuable neurodevelopmental model of this disease.

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In vivo MRI evaluation of early postnatal development in normal and impaired rat eyes

Scientific Reports ◽

10.1038/s41598-021-93991-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jeannie M. Au ◽

Swarupa Kancherla ◽

Malack Hamade ◽

Monica Mendoza ◽

Kevin C. Chan

Keyword(s):

Postnatal Development ◽

Potassium Dichromate ◽

Growth Patterns ◽

Monocular Deprivation ◽

Posterior Chamber ◽

Sprague Dawley ◽

Adult Rats ◽

Early Postnatal Development ◽

Magnetic Resonance Imaging Mri

AbstractThis study employed in vivo 7-T magnetic resonance imaging (MRI) to evaluate the postnatal ocular growth patterns under normal development or neonatal impairments in Sprague–Dawley rats. Using T2-weighted imaging on healthy rats from postnatal day (P) 1 (newborn) to P60 (adult), the volumes of the anterior chamber and posterior chamber (ACPC), lens, and vitreous humor increased logistically with ACPC expanding by 33-fold and the others by fivefold. Intravitreal potassium dichromate injection at P1, P7, and P14 led to T1-weighted signal enhancement in the developing retina by 188–289%. Upon unilateral hypoxic-ischemic encephalopathy at P7, monocular deprivation at P15, and monocular enucleation at P1, T2-weighted imaging of the adult rats showed decreased ocular volumes to different extents. In summary, in vivo high-field MRI allows for non-invasive evaluation of early postnatal development in the normal and impaired rat eyes. Chromium-enhanced MRI appeared effective in examining the developing retina before natural eyelid opening at P14 with relevance to lipid metabolism. The reduced ocular volumes upon neonatal visual impairments provided evidence to the emerging problems of why some impaired visual outcomes cannot be solely predicted by neurological assessments and suggested the need to look into both the eye and the brain under such conditions.

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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

Molecules ◽

10.3390/molecules24234253 ◽

2019 ◽

Vol 24 (23) ◽

pp. 4253 ◽

Cited By ~ 3

Author(s):

Magdalena Górny ◽

Agnieszka Wnuk ◽

Adrianna Kamińska ◽

Kinga Kamińska ◽

Grażyna Chwatko ◽

...

Keyword(s):

Dna Methylation ◽

Postnatal Development ◽

Brain Structures ◽

Global Dna Methylation ◽

Gbr 12909 ◽

Sprague Dawley ◽

Synthesis Inhibitor ◽

Adult Rats ◽

Peripheral Tissues ◽

Early Postnatal Development

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.

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Specific expression of lactase in the jejunum and colon during postnatal development and hormone treatments in the rat

Biochemical Journal ◽

10.1042/bj2680099 ◽

1990 ◽

Vol 268 (1) ◽

pp. 99-103 ◽

Cited By ~ 20

Author(s):

J N Freund ◽

I Duluc ◽

C Foltzer-Jourdainne ◽

F Gosse ◽

F Raul

Keyword(s):

Postnatal Development ◽

Specific Activity ◽

Single Gene ◽

Enzymic Activity ◽

Transcriptional Level ◽

Adult Rats ◽

Specific Expression ◽

Early Postnatal Development ◽

Epidermal Growth ◽

Large Decline

The expression of lactase was compared in the jejunum and colon of the rat at the levels of enzyme activity and protein and RNA content. We found that the enzyme proteins and the corresponding mRNAs share common features and are encoded by a single gene in both intestinal segments. In the jejunum, large amounts of lactase mRNA and proteins were detected during postnatal development as well as in adult rats, despite the 10-fold decline in lactase specific activity which occurs at weaning. In contrast, in the colon the expression of lactase was restricted to early postnatal development. In the colon, the enzymic activity of lactase and the amounts of protein and mRNA followed parallel development profiles with a peak at day 4 after birth. Injections of thryoxine or epidermal growth factor into neonates led to small modifications in the expression of lactase in the jejunum. On the other hand, these treatments caused a large decline in lactase activity in the colon that paralleled a decrease in the amount of lactase protein and mRNA. These data indicate that the expression of lactase is mainly regulated at the post-transcriptional level in the jejunum, whereas it is controlled at the pretranslational level in the colon.

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Maternally Administered Cyclic Glycine-Proline Increases Insulin-Like Growth Factor-1 Bioavailability and Novelty Recognition in Developing Offspring

Endocrinology ◽

10.1210/en.2016-1189 ◽

2016 ◽

Vol 157 (8) ◽

pp. 3130-3139 ◽

Cited By ~ 12

Author(s):

Gagandeep Singh-Mallah ◽

Kuljeet Singh ◽

Christopher D. McMahon ◽

Paul Harris ◽

Margaret A. Brimble ◽

...

Keyword(s):

Recognition Memory ◽

Postnatal Development ◽

Behavioral Tests ◽

Control Groups ◽

Adult Rats ◽

Early Postnatal Development ◽

Igf Binding ◽

Igf Binding Protein ◽

Peak Lactation ◽

Igfbp 3

Cyclic glycine-proline (cGP), a metabolite of IGF-1, is an endogenous neuropeptide that improves memory in adult rats. The presence and concentrations of endogenous cGP, and its association with IGF-1 and IGF binding protein-3 (IGFBP-3) in rat milk and plasma, were evaluated during postnatal development. Maternal-infantile transfer of cGP during lactation and its efficacy on the memory of developing offspring were also investigated. Dams were gavaged with either cGP (3 mg/kg) or saline daily from postnatal days 8–22. Concentrations of cGP were measured in dams' milk, and concentrations of cGP, IGF-1, and IGFBP-3 were measured in the plasma of dams, pups, and young adults. The recognition memory, locomotor function, and anxiety-like behavior of offspring were evaluated using behavioral tests. Endogenous cGP was detected in rat milk, and its concentration was higher during peak lactation compared with late lactation. Comparisons within control groups showed low endogenous IGF-1 and IGFBP-3 and high endogenous cGP concentrations in the plasma of male pups. The reduced IGFBP-3 and increased cGP may be a response to increase the bioavailability of IGF-1 during infancy. Exogenous cGP showed oral bioavailability and effective maternal-infantile transfer through milk. Maternally transferred cGP also led to improved recognition memory in the developing offspring, possibly through increased IGF-1 bioavailability, with no effect on locomotor activity and anxiety-like behavior. These results show that cGP is an essential endogenous peptide during early postnatal development as it improves the bioavailability of IGF-1 during infancy. Furthermore, maternal cGP supplementation offers an effective and natural route of administration for improving memory in the developing offspring.

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BDNF mRNA expression during postnatal development, maturation and aging of the human prefrontal cortex

Developmental Brain Research ◽

10.1016/s0165-3806(02)00540-0 ◽

2002 ◽

Vol 139 (2) ◽

pp. 139-150 ◽

Cited By ~ 117

Author(s):

Maree J Webster ◽

Cynthia Shannon Weickert ◽

Mary M Herman ◽

Joel E Kleinman

Keyword(s):

Prefrontal Cortex ◽

Mrna Expression ◽

Postnatal Development ◽

Bdnf Mrna

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

Antioxidants ◽

10.3390/antiox9060538 ◽

2020 ◽

Vol 9 (6) ◽

pp. 538

Author(s):

Magdalena Górny ◽

Anna Bilska-Wilkosz ◽

Małgorzata Iciek ◽

Marta Hereta ◽

Kinga Kamińska ◽

...

Keyword(s):

Lipid Peroxidation ◽

Postnatal Development ◽

Postnatal Life ◽

Antioxidant Enzyme Activities ◽

Gbr 12909 ◽

Sprague Dawley ◽

Synthesis Inhibitor ◽

Peripheral Tissues ◽

Early Postnatal Development ◽

Functional Changes

The aim of the present study was to assess the effects of l-buthionine-(S,R)-sulfoximine (BSO), a glutathione (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 reactive oxygen species (ROS), lipid peroxidation (LP) and the activities of antioxidant enzymes: superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione disulfide reductase (GR) in peripheral tissues (liver, kidney) and selected brain structures (prefrontal cortex, PFC; hippocampus, HIP; and striatum, STR) of 16-day-old rats. The studied parameters were analyzed with reference to the content of GSH and sulfur amino acids, methionine (Met) and cysteine (Cys) described in our previous study. This analysis showed that treatment with a BSO + GBR 12909 combination caused significant decreases in the lipid peroxidation levels in the PFC and HIP, in spite of there being no changes in ROS. The reduction of lipid peroxidation indicates a weakening of the oxidative power of the cells, and a shift in balance in favor of reducing processes. Such changes in cellular redox signaling in the PFC and HIP during early postnatal development may result in functional changes in adulthood.

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