Szabina Kulcsár

BACKGROUND: Mitochondrial dysfunction, oxidative stress and their interplay are core pathological features of Parkinson's disease. In dopaminergic neurons, monoamines and their metabolites provide an additional source of reactive free radicals during their breakdown by monoamine oxidase or auto-oxidation. Moreover, mitochondrial dysfunction and oxidative stress have a supraadditive impact on the pathological, cytoplasmic accumulation of dopamine and its subsequent release. Here we report the effects of a novel series of potent and selective MAO-B inhibitory (hetero)arylalkenylpropargylamine compounds having protective properties against the supraadditive effect of mitochondrial dysfunction and oxidative stress. RESULTS: The (hetero)arylalkenylpropargylamines were tested in vitro, on acute rat striatal slices, pretreated with the complex I inhibitor rotenone and in vivo, using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced acute, subchronic, and chronic experimental models of Parkinson's disease in mice. The compounds exhibited consistent protective effects against i) in vitro oxidative stress induced pathological dopamine release and the formation of toxic dopamine quinone in the rat striatum and rescued tyrosine hydroxylase positive neurons in the substantia nigra after rotenone treatment; ii) in vivo MPTP-induced striatal dopamine depletion and motor dysfunction in mice using acute and subchronic, delayed application protocols. One compound (SZV558) was also examined and proved to be protective in a chronic mouse model of MPTP plus probenecid (MPTPp) administration, which induces a progressive loss of nigrostriatal dopaminergic neurons. CONCLUSIONS: Simultaneous inhibition of MAO-B and oxidative stress induced pathological dopamine release by the novel propargylamines is protective in animal models and seems a plausible strategy to combat Parkinson's disease.

Journal Article EFFECTS OF CHLORPROMAZINE ONPITUITARY FUNCTION Get access WOLFE Z. POLISHUK, M.D., WOLFE Z. POLISHUK, M.D. 1Rambam Government Hospital Haifa, Israel; Government Mental Hospital Acre, Israel Search for other works by this author on: Oxford Academic Google Scholar S. KULCSAR, M.D. S. KULCSAR, M.D. 1Rambam Government Hospital Haifa, Israel; Government Mental Hospital Acre, Israel Search for other works by this author on: Oxford Academic Google Scholar The Journal of Clinical Endocrinology & Metabolism, Volume 16, Issue 2, 1 February 1956, Pages 292–293, https://doi.org/10.1210/jcem-16-2-292 Published: 01 February 1956

Authors studied the effect of sterigmatocystin from infected corn (STC), purified sterigmatocystin (PSTC), and aflatoxin B1 from infected corn (AFB1) on lipid peroxidation and glutathione redox parameters, including the expression of their encoding genes in a sub-chronic (14 days) trial. A total of 144 three-week-old cockerels was divided into four experimental groups (n = 36 in each). Control feed was contaminated with STC or PSTC (1590 µg STC/kg or 1570.5 µg STC/kg feed), or with AFB1 (149.1 µg AFB1/kg feed). Six birds from each group were sampled at day 1, 2, 3, 7 and 14 of mycotoxin exposure. As parameters of lipid peroxidation, conjugated dienes (CD) and trienes (CT) were measured in the liver, while malondialdehyde (MDA) concentration was determined in blood plasma, red blood cell hemolysate and liver. Reduced glutathione (GSH) concentration and glutathione peroxidase (GPx) activity were determined in the same samples, and expression of glutathione peroxidase 4 (GPX4), glutathione synthetase (GSS) and glutathione reductase (GSR) genes was measured by RT-PCR in the liver. STC, PSTC or AFB1 caused a slight, but not significant, increase in CD and CT levels; however, in the case of MDA, no increase was found in the liver. Glutathione redox system was activated in the liver by AFB1, but less markedly by STC/PSTC. PSTC and AFB1 resulted in a higher expression of GPX4, while GSS expression was down-regulated by AFB1 on day 1, but up-regulated by STC on day 2 and by both mycotoxins on day 7. However, on day 14, GSS expression was down-regulated by PSTC. Expression of GSR was low on day 1 in AFB1 and PSTC groups, but later it was up-regulated by AFB1. The observed changes regarding gene expression strengthen the hypothesis that the mild oxidative stress, caused by the applied STC doses, activates the glutathione redox system of broiler chickens.

It has been proven by several studies that Fusarium mycotoxins induce oxidative stress in animals, consequently inducing lipid peroxidation, which the glutathione system can neutralize. A short-term (3-day) in vivo feeding trial was performed with laying hens using a double dose of the EU recommendation for mycotoxin contamination (T-2 toxin 0.5 mg/kg feed; deoxynivalenol (DON) 10 mg/kg feed; fumonisin B1 (FB1) 40 mg/kg feed). Some lipid peroxidation and glutathione redox system parameters and gene expression levels were measured in the liver. The results show that FB1 significantly decreased the reduced glutathione (GSH) content and the activity of glutathione peroxidase (GPx) compared to the control and the two other mycotoxin-treated groups on day 3. Lipid peroxidation was affected by all three mycotoxins. Significantly lower values were observed in the case of conjugated dienes for all of the three mycotoxins and malondialdehyde concentration as an effect of DON on day 3. T-2 toxin and DON upregulated the expression of the GPX4 gene. The results show that Fusarium mycotoxins had different effects at the end of the trial. The FB1 exposure caused a decrease in the glutathione redox markers, while DON decreased the formation of malondialdehyde. The results suggest that the Fusarium mycotoxins investigated individually differently activated the antioxidant defense and caused low-level oxidative stress at the dose applied.

Abstract The effects of a single oral dose of 1.82 mg kg −1 bw of T-2 and HT-2 toxin (T-2), 1.75 mg kg −1 bw deoxynivalenol (DON) and 15-acetyl DON, 1.96 mg kg −1 bw fumonisin B 1 (FB 1 ) or 1.85 mg kg −1 bw ochratoxin A (OTA) were investigated in common carp juveniles on lipid peroxidation, the parameters of the glutathione redox system including the expression of their encoding genes in a short-term (24 h) experiment. Markers of the initiation phase of lipid peroxidation, conjugated dienes, and trienes, were slightly affected by DON and OTA treatment at 16-h sampling. The termination marker, malondialdehyde, concentration increased only as an effect of FB 1 . Glutathione content and glutathione peroxidase activity showed significantly higher levels in the T-2 and FB 1 groups at 8 h, and in the DON and FB 1 groups at 16 h. The expression of glutathione peroxidase genes ( gpx4a, gpx4b ) showed a dual response. Downregulation of gpxa was observed at 8 h, as the effect of DON, FB 1 , and OTA, but an upregulation in the T-2 group. At 16 h gpx4a upregulated as an effect of DON, T-2, and FB 1, and at 24 h in the DON and T-2 groups. Expression of gpx4b downregulated at 8 h, except in the T-2 group, and upregulation observed as an effect of T-2 at 24 h. The lack of an increase in the expression of nrf2, except as the effect of DON at 8 h, and a decrease in the keap1 expression suggests that the antioxidant defence system was activated at gene and protein levels through Keap1–Nrf2 independent pathways.