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Background: Epilepsy is a chronic brain disease affecting millions of people worldwide, but little is known about the impact of anti-seizure medications on redox homeostasis. Methods: This study aimed to compare the effects of the long-term use of oral anti-seizure medications in monotherapy (lamotrigine, carbamazepine, and valproate) on antioxidant enzymes: superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, haemoglobin, and methaemoglobin content in erythrocytes, and concentrations of total proteins and thiols, nitrites, lipid peroxides and total glutathione in the plasma of epilepsy patients and drug-naïve patients. Results: The results showed that lamotrigine therapy led to lower superoxide dismutase activity (p < 0.005) and lower concentrations of total thiols (p < 0.01) and lipid peroxides (p < 0.01) compared to controls. On the other hand, therapy with carbamazepine increased nitrite levels (p < 0.01) but reduced superoxide dismutase activity (p < 0.005). In the valproate group, only a decrease in catalase activity was observed (p < 0.005). Canonical discriminant analysis showed that the composition of antioxidant enzymes in erythrocytes was different for both the lamotrigine and carbamazepine groups, while the controls were separated from all others. Conclusions: Monotherapy with anti-seizure medications discretely alters redox homeostasis, followed by distinct relationships between antioxidant components.

Plejotropni efekti lekova obuhvataju delovanja na mesta i strukture u telu za koje oni nisu posebno razvijeni i obično su neočekivani. Atipični antipsihotici podležu intenzivnom metabolizmu u jetri, uz stvaranje toksičnih slobodno-radikalskih intermedijera kao jedan od predloženih mehanizama oštećenja jetre kod pacijenata hronično tretiranim ovim psihofarmacima. Cilj prvog dela disertacije bio je da istraži da li atipični antipsihotici klozapin, sertindol ili ziprazidon utiču na enzimski sistem antioksidativne zaštite u jetri. Ekspresija i aktivnost superoksid-dismutaze (SOD), katalaze (CAT), glutation-peroksidaze (GPx), glutation-reduktaze (GR) i glutation-S-transferaze (GST) su izmereni u jetri pacova pri dozama koje odgovaraju ljudskoj terapiji antipsihoticima. Klozapin je povećao aktivnost SOD tipova 1 i 2, GR i GST, uz smanjenje CAT aktivnosti, dok je tretman sertindolom povećao aktivnost obe SOD. U ziprazidonom-tretiranoj grupi pacova jedino je nađeno smanjenje CAT aktivnosti. Sva tri antipsihotika su proizvela blage do umerene histopatološke promene, okarakterisane kao regenerativne promene jetre. Nisu primećeni očigledni znaci infiltracije imunskih ćelija, mikrovezikularnih ili makrovezikularnih masnih promena, ili hepatociti u mitozi. U zaključku, tretman atipičnim antipsihoticima u trajanju od 28 dana promenio je aktivnost zaštitnih antioksidativnih enzima i izazvao histopatološke promene u jetri, pre svega kod pacova tretiranih klozapinom. Rezultati povrđuju da poremećaji u redoks-homeostazi mogu da doprinose disfunkciji jetre nakon dugotrajnog lečenja atipičnim antipsihoticima. Prepuni hemoglobinom, esencijalnim proteinom za transport kiseonika kroz telo, eritrociti čoveka su takođe pogodan model sistem za testiranje plejotropnih efekata lipofilnih lekova. U drugom delu disertacije najpre je ispitano vezivanje klozapina, ziprazidona i sertindola za humani hemoglobin pod simuliranim fiziološkim uslovima. Analiza gašenja (kvenčinga) fluorescencije proteina, Pleiotropic effects of drugs include actions on places and structures in the body for which they have not been specifically developed and are usually unexpected. Atypical antipsychotics are subject to intensive metabolism in the liver, with the formation of toxic free-radical intermediates as one of the proposed mechanisms of liver damage in patients chronically treated with these psychopharmaceuticals. The aim of the first part of the dissertation was to investigate whether the atypical antipsychotics clozapine, sertindole, or ziprasidone affect the enzyme system of antioxidant protection in the liver. Expression and activity of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione-S-transferase (GST) were measured in rat liver at doses corresponding to human antipsychotic therapy. Clozapine increased the activity of SOD types 1 and 2, GR and GST while decreasing CAT activity, while sertindole treatment increased the activity of both SODs. Only a decrease in CAT activity was found in the ziprasidone-treated group of rats. All three antipsychotics produced mild to moderate histopathological changes characterized as regenerative liver alterations. No obvious signs of immune cell infiltration, micro-vesicular or macrovesicular fatty changes, or hepatocytes in mitosis were observed. In conclusion, treatment with atypical antipsychotics for 28 days changed the activity of the protective antioxidant enzyme and caused histopathological changes in the liver, primarily in rats treated with clozapine. The results suggest that disturbances in redox homeostasis may contribute to liver dysfunction after long-term treatment with atypical antipsychotics. Loaded with hemoglobin, an essential protein for transporting oxygen throughout the body, human erythrocytes are also a convenient model system for testing the pleiotropic effects of lipophilic drugs. In the second part of the dissertation, the binding of clozapine

Plejotropni efekti lekova obuhvataju delovanja na mesta i strukture u telu za koje oni nisu posebno razvijeni i obično su neočekivani. Atipični antipsihotici podležu intenzivnom metabolizmu u jetri, uz stvaranje toksičnih slobodno-radikalskih intermedijera kao jedan od predloženih mehanizama oštećenja jetre kod pacijenata hronično tretiranim ovim psihofarmacima. Cilj prvog dela disertacije bio je da istraži da li atipični antipsihotici klozapin, sertindol ili ziprazidon utiču na enzimski sistem antioksidativne zaštite u jetri. Ekspresija i aktivnost superoksid-dismutaze (SOD), katalaze (CAT), glutation-peroksidaze (GPx), glutation-reduktaze (GR) i glutation-S-transferaze (GST) su izmereni u jetri pacova pri dozama koje odgovaraju ljudskoj terapiji antipsihoticima. Klozapin je povećao aktivnost SOD tipova 1 i 2, GR i GST, uz smanjenje CAT aktivnosti, dok je tretman sertindolom povećao aktivnost obe SOD. U ziprazidonom-tretiranoj grupi pacova jedino je nađeno smanjenje CAT aktivnosti. Sva tri antipsihotika su proizvela blage do umerene histopatološke promene, okarakterisane kao regenerativne promene jetre. Nisu primećeni očigledni znaci infiltracije imunskih ćelija, mikrovezikularnih ili makrovezikularnih masnih promena, ili hepatociti u mitozi. U zaključku, tretman atipičnim antipsihoticima u trajanju od 28 dana promenio je aktivnost zaštitnih antioksidativnih enzima i izazvao histopatološke promene u jetri, pre svega kod pacova tretiranih klozapinom. Rezultati povrđuju da poremećaji u redoks-homeostazi mogu da doprinose disfunkciji jetre nakon dugotrajnog lečenja atipičnim antipsihoticima.Prepuni hemoglobinom, esencijalnim proteinom za transport kiseonika kroz telo, eritrociti čoveka su takođe pogodan model sistem za testiranje plejotropnih efekata lipofilnih lekova. U drugom delu disertacije najpre je ispitano vezivanje klozapina, ziprazidona i sertindola za humani hemoglobin pod simuliranim fiziološkim uslovima. Analiza gašenja (kvenčinga) fluorescencije proteina, Pleiotropic effects of drugs include actions on places and structures in the body for which they have not been specifically developed and are usually unexpected. Atypical antipsychotics are subject to intensive metabolism in the liver, with the formation of toxic free-radical intermediates as one of the proposed mechanisms of liver damage in patients chronically treated with these psychopharmaceuticals. The aim of the first part of the dissertation was to investigate whether the atypical antipsychotics clozapine, sertindole, or ziprasidone affect the enzyme system of antioxidant protection in the liver. Expression and activity of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione-S-transferase (GST) were measured in rat liver at doses corresponding to human antipsychotic therapy. Clozapine increased the activity of SOD types 1 and 2, GR and GST while decreasing CAT activity, while sertindole treatment increased the activity of both SODs. Only a decrease in CAT activity was found in the ziprasidone-treated group of rats. All three antipsychotics produced mild to moderate histopathological changes characterized as regenerative liver alterations. No obvious signs of immune cell infiltration, micro-vesicular or macrovesicular fatty changes, or hepatocytes in mitosis were observed. In conclusion, treatment with atypical antipsychotics for 28 days changed the activity of the protective antioxidant enzyme and caused histopathological changes in the liver, primarily in rats treated with clozapine. The results suggest that disturbances in redox homeostasis may contribute to liver dysfunction after long-term treatment with atypical antipsychotics.Loaded with hemoglobin, an essential protein for transporting oxygen throughout the body, human erythrocytes are also a convenient model system for testing the pleiotropic effects of lipophilic drugs. In the second part of the dissertation, the binding of clozapine, z

Aims: CYP2C19 transgenic mouse expresses the human CYP2C19 gene in the liver and developing brain, and it exhibits altered neurodevelopment associated with impairments in emotionality and locomotion. Because the validation of new animal models is essential for the understanding of the aetiology and pathophysiology of movement disorders, the objective was to characterise motoric phenotype in CYP2C19 transgenic mice and to investigate its validity as a new animal model of ataxia. Methods: The rotarod, paw-print and beam-walking tests were utilised to characterise the motoric phenotype. The volumes of 20 brain regions in CYP2C19 transgenic and wild-type mice were quantified by 9.4T gadolinium-enhanced post-mortem structural neuroimaging. Antioxidative enzymatic activity was quantified biochemically. Dopaminergic alterations were characterised by chromatographic quantification of concentrations of dopamine and its metabolites and by subsequent immunohistochemical analyses. The beam-walking test was repeated after the treatment with dopamine receptor antagonists ecopipam and raclopride. Results: CYP2C19 transgenic mice exhibit abnormal, unilateral ataxia-like gait, clasping reflex and 5.6-fold more paw-slips in the beam-walking test; the motoric phenotype was more pronounced in youth. Transgenic mice exhibited a profound reduction of 12% in cerebellar volume and a moderate reduction of 4% in hippocampal volume; both regions exhibited an increased antioxidative enzyme activity. CYP2C19 mice were hyperdopaminergic; however, the motoric impairment was not ameliorated by dopamine receptor antagonists, and there was no alteration in the number of midbrain dopaminergic neurons in CYP2C19 mice. Conclusions: Humanised CYP2C19 transgenic mice exhibit altered gait and functional motoric impairments; this phenotype is likely caused by an aberrant cerebellar development., QC 20231204

Sexual dysfunction, as a noticeable adverse effect of atypical antipsychotic drugs (APDs) for the treatment of schizophrenia, has not been investigated in detail. A study was undertaken to investigate whether 28-day long treatment with clozapine, ziprasidone or sertindole (using a recommended daily dose for atypical antipsychotic therapy), induced histopathological changes both in rat testicles and prostate, changed the activity of the antioxidant defence system and altered blood testosterone and prolactin. Clozapine, ziprasidone and sertindole induced histopathological changes in rat testicular tissue, which could be attributed to a disturbed testicular antioxidant defence system in addition to an altered prolactin to testosterone ratio. None of the APD treatments induced histopathological changes in prostate. Our results demonstrate that APDs have the capacity to change both redox and endocrinological balance. One or both outcomes could underline testicular degeneration and disturbed spermatogenesis.

Sexual dysfunction, as a noticeable adverse effect of atypical antipsychotic drugs (APDs) for the treatment of schizophrenia, has not been investigated in detail. A study was undertaken to investigate whether 28-day long treatment with clozapine, ziprasidone or sertindole (using a recommended daily dose for atypical antipsychotic therapy), induced histopathological changes both in rat testicles and prostate, changed the activity of the antioxidant defence system and altered blood testosterone and prolactin. Clozapine, ziprasidone and sertindole induced histopathological changes in rat testicular tissue, which could be attributed to a disturbed testicular antioxidant defence system in addition to an altered prolactin to testosterone ratio. None of the APD treatments induced histopathological changes in prostate. Our results demonstrate that APDs have the capacity to change both redox and endocrinological balance. One or both outcomes could underline testicular degeneration and disturbed spermatogenesis.

The effects of a fructose-rich diet and chronic stress on copper metabolism in the kidneys are still understudied. We investigated whether fructose and/or chronic unpredictable stress modulate copper metabolism in a way that affects redox homeostasis, thus contributing to progression of metabolic disturbances in the kidney. We determined protein level of copper transporters, chaperones, and cuproenzymes including cytochrome c oxidase, as well as antioxidant enzymes function in the kidneys of male Wistar rats subjected to 20% liquid fructose supplementation and/or chronic stress. Liquid fructose supplementation increased level of copper chaperone of superoxide dismutase and decreased metallothionein level, while rendering the level of copper importer and copper chaperones involved in copper delivery to mitochondria and trans Golgi network unaffected. Stress had no effect on renal copper metabolism. The activity and expression of renal antioxidant enzymes remained unaltered in all experimental groups. In conclusion, fructose, independently of stress, decreased renal copper level, and modulated renal copper metabolism as to preserve vital cellular function including mitochondrial energy production and antioxidative defense, at the expense of intracellular copper storage.

Chronic use of atypical antipsychotics may produce hepatic damage. Atypical antipsychotics, including clozapine, sertindole, and ziprasidone, are extensively metabolized by the liver and this process generates toxic-free radical metabolic intermediates which may contribute to liver damage. The aim of this study was to investigate whether clozapine, sertindole, or ziprasidone affected hepatic antioxidant defense enzymes which consequently led to disturbed redox homeostasis. The expression and activity of antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT), and glutathione-S-transferases (GST) were measured in rat livers at doses corresponding to human antipsychotic therapy. Clozapine increased activity of SOD types 1 and 2, GR and GST, but reduced CAT activity. Sertindole elevated activities of both SODs. In ziprasidone-treated rats only decreased CAT activity was found. All three antipsychotics produced mild-to-moderate hepatic histopathological changes categorized as regenerative alterations. No apparent signs of immune cell infiltration, microvesicular or macrovesicular fatty change, or hepatocytes in mitosis were observed. In conclusion, a 4-week long daily treatment with clozapine, sertindole, or ziprasidone altered hepatic antioxidant enzyme activities and induced histopathological changes in liver. The most severe alterations were noted in clozapine-treated rats. Data indicate that redox disturbances may contribute to liver dysfunction after long-term atypical antipsychotic drug treatment.

Chronic use of atypical antipsychotics may produce hepatic damage. Atypical antipsychotics, including clozapine, sertindole, and ziprasidone, are extensively metabolized by the liver and this process generates toxic-free radical metabolic intermediates which may contribute to liver damage. The aim of this study was to investigate whether clozapine, sertindole, or ziprasidone affected hepatic antioxidant defense enzymes which consequently led to disturbed redox homeostasis. The expression and activity of antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT), and glutathione-S-transferases (GST) were measured in rat livers at doses corresponding to human antipsychotic therapy. Clozapine increased activity of SOD types 1 and 2, GR and GST, but reduced CAT activity. Sertindole elevated activities of both SODs. In ziprasidone-treated rats only decreased CAT activity was found. All three antipsychotics produced mild-to-moderate hepatic histopathological changes categorized as regenerative alterations. No apparent signs of immune cell infiltration, microvesicular or macrovesicular fatty change, or hepatocytes in mitosis were observed. In conclusion, a 4-week long daily treatment with clozapine, sertindole, or ziprasidone altered hepatic antioxidant enzyme activities and induced histopathological changes in liver. The most severe alterations were noted in clozapine-treated rats. Data indicate that redox disturbances may contribute to liver dysfunction after long-term atypical antipsychotic drug treatment.