The Effect of Glutathione Deficit During Early Postnatal Brain Development on the Prepulse Inhibition and Monoamine Levels in Brain Structures of Adult Sprague-Dawley Rats.

Recent studies suggest that impaired glutathione synthesis and distorted dopaminergic transmission are important factors in the pathophysiology of schizophrenia. In the present study, on the postnatal days p5-p16, male pups were treated with the inhibitor of glutathione synthesis, L-buthionine-(S,R)- sulfoximine (BSO, 3.8 or 7.6 mmol/kg), and the dopamine uptake inhibitor, GBR 12,909 (5 mg/kg) alone or in combination, and prepulse inhibition of the acoustic startle response (PPI) was evaluated in adult 90-day-old rats. Moreover, the monoamine levels in the cortex and hippocampus of 16-day-old rats or 91-day-old rats were measured. The present results showed that administration of BSO at 3.8 mmol/kg led to a decreasing tendency in PPI for all tested prepulse intensities. In contrast, a combined treatment with BSO in both studied doses and GBR 12,909 did not induce significant deficits in PPI. Moreover, the results of biochemical studies indicated that treatment with BSO or GBR 12,909 alone induced a weak increase in the activity of dopaminergic, serotonergic, and noradrenergic systems in the frontal cortex and hippocampus of 16-day-old rats and 91-day-old rats. However, the combined administration of both substances allowed for maintaining the normal activity of monoaminergic systems in the rat brain. The most significant changes in the functioning of monoaminergic systems were observed in the frontal cortex of 16-day-old rats. Therefore, it seems that the frontal cortex of rat puppies is most sensitive to glutathione deficiencies resulting in increased oxidative stress in neurons. As a result, it can lead to cognitive and memory impairment.

N-Acetylcysteine and Aripiprazole Improve Social Behavior and Cognition and Modulate Brain BDNF Levels in a Rat Model of Schizophrenia.

Treatment of negative symptoms and cognitive disorders in patients with schizophrenia is still a serious clinical problem. The aim of our study was to compare the efficacy of chronic administration of the atypical antipsychotic drug aripiprazole (7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl] butoxy}-3,4-dihydro-2(1H)-quinolinone; ARI) and the well-known antioxidant N-acetylcysteine (NAC) both in alleviating schizophrenia-like social and cognitive deficits and in reducing the decreases in the levels of the brain-derived neurotrophic factor (BDNF) in the prefrontal cortex (PFC) and hippocampus (HIP) of adult Sprague-Dawley rats, that have been induced by chronic administration of the model compound L-buthionine-(S, R)-sulfoximine (BSO) during the early postnatal development (p5-p16). ARI was administered at doses of 0.1 and 0.3 mg/kg while NAC at doses of 10 and 30 mg/kg, alone or in combination. Administration of higher doses of ARI or NAC alone, or co-treatment with lower, ineffective doses of these drugs significantly improved social and cognitive performance as assessed in behavioral tests. Both doses of NAC and 0.3 mg/kg of ARI increased the expression of BDNF mRNA in the PFC, while all doses of these drugs and their combinations enhanced the levels of BDNF protein in this brain structure. In the HIP, only 0,3 mg/kg ARI increased the levels of both BDNF mRNA and its protein. These data show that in the rat BSO-induced neurodevelopmental model of schizophrenia, ARI and NAC differently modulated BDNF levels in the PFC and HIP.

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.

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.

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.

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.

Fabrication of Polyurethane/Polylactide (PU/PLDL) Nanofibers Using Electrospinning Method.

Polylactide and aliphatic polyurethane are biodegradable synthetic polymers which are broadly used as biomaterials in regenerative medicine for implants and scaffolds for tissue engineering. In this paper, the detailed studies of the fabrication of the electrospun fibers of polyurethane/polylactide mixtures were described. The influence of the used solvent (dimethylformamide (DMF)) and diluents (acetone and dichloromethane (DCM)) on the rheological parameters and electrospinning of the described mixtures was examined. Rheological studies showed that polyure-thane/polylactide mixtures have mostly non-Newtonian character, strongly influenced by the diluent. Solutions containing 50 wt.% or more of polyurethane became less viscous after the addition of DCM or acetone, whereas those with bigger amount of polylactide showed higher viscosity after the addition of DCM and lower viscosity after the addition of acetone. Optimized electrospinning process has been elaborated. Fibers with diameters from 250 nm up to 1 µm have been produced and compared. Pure acetone worsened the electrospinning process, but the more DCM was in the mixture, the thinner and more aligned fibers were produced.

[Fetal pulmonary artery blood flow depending on fetal lung maturity]. / Analiza przeplywu krwi w tetnicy plucnej w zaleznosci od stopnia dojrzalosci pluc plodu.

The ultrasonographic assessment of fetal lung maturity by evaluating the elasticity of lung tissue, Dynamic Lung Score (DLS) has been being performed since 1986 in ObGyn Department in Tychy (Medical University of Silesia). The lung elasticity is evaluated on the cross sections of fetal thorax, on the level of heart ventricles. The result of the evaluation is given as the three degree scale, in which I degree indicates the lack of elasticity and fetal lung immaturity, II degrees indicates partially expressed elasticity, corresponding with incomplete maturity of lung tissue, and III degrees represents full elasticity and indicates complete maturity of fetal lungs. This study was designed to compare fetal pulmonary artery blood flow with the maturity of fetal lung tissue evaluated during the ultrasonographic assessment of fetal lung tissue elasticity. The examination was performed on pregnant women, beginning on 27th week gestation. During the examination the mean Pulsatility Index was decreased, particularly in fetuses with II degrees lung maturity. The Resistance Index (RI) was found to be stable and independent of gestational age. In the group with I degree lung maturity (DLS I), the mean PI = 2.643 (+/- 0.229), mean RI = 0.879 (+/- 0.036), in DLS II group PI = 2.039 (+/- 0.262), RI = 0.868 (+/- 0.037), and in DLS III group PI = 2,500 (+/- 0.100), RI = 0.900 (+/- 0.100). Comparing the ultrasonographic evaluation of fetal lung maturity with fetal pulmonary artery blood flow allows more accurate assessment of fetal lung maturity. Fetal lung maturity can not be evaluated univocally on the basis of blood flow assessment. Because of the divergence of blood flow parameters further studies including bigger population seem to be necessary for verification of the results and for establishing the reference values.