Effects of agmatine on chlorpromazine-induced neuronal injury in rat

This study was aimed to study the potentially beneficial effects of agmatine on oxidative/nitrosative stress development in the brain of Wistar rats during subacute chlorpromazine treatment. The animals were divided into control (0.9% saline), chlorpromazine (38.7 mg/kg b.w.), chlorpromazine+agmatine (agmatine 75 mg/kg b.w. immediately after chlorpromazine, 38.7 mg/ kg b.w. i.p.) and agmatine (75 mg/kg b.w.) groups. All the tested substances were administered intraperitoneally for 15 consecutive days and the rats were sacrificed by decapitation on day 15. Subacute administration of chlorpromazine resulted in increased lipid peroxidation, nitric oxide concentration and superoxide anion production, while completely damaging the antioxidant defence system in the cerebral cortex, striatum, and hippocampus. However, the combined treatment with chlorpromazine and agmatine significantly attenuated the oxidative/nitrosative stress indices and restored the antioxidant capacity to the control values in all of the examined brain regions. Western blot analysis supported biochemical findings in all groups, but the most notable changes were found in the hippocampus. Our results suggest potentially beneficial effects of agmatine, which may be useful in the modified antioxidant approach in chlorpromazine-therapy

Oxidative stress induced by chlorpromazine in patients treated and acutely poisoned with the drug

Background/Aim. Although chlorpromazine (CPZ) is an antipsychotic drug widely used in clinical practice for a long time, its mechanism of action has not been entirely defined. An extremely difficult managing of patients acutely poisoned with CPZ is additional reason for detailed studying its toxicity mechanisms. In this clinical study, we investigated whether the oxidative stress (OS) mediates CPZ toxic effects in the exposed patients. Methods. The patients were organized into 3 groups: the T-group - hospitalized patients receiving therapeutic doses of 75-150 mg CPZ/day; the overdosed group, divided into two subgroups: the group M and the group S - mildly (CPZ serum concentration: 0.21 ± 0.05 mg/L) and severely (CPZ serum concentration: 2.66 ± 0.25 mg/L) poisoned patients, respectively, and the group C (control group of healthy volunteers). Oxidative stress parameters [total antioxidative status (TAS) and malondialdehyde (MDA) in plasma)] and superoxide dismutase (SOD) activity in erythrocytes were measured spectrophotometrically, and CPZ concentrations in serum were monitored chromatographically. One set of measurements was performed in the group C and T, whereas two sets of measurements (after 24 hours and 48 hours) were done in the poisoned patients, groups M and S. Results. A decrease of TAS and increase of SOD activity were obtained in both subgroups of the poisoned patients, compared to the controls and the group receiving therapeutic doses of CPZ. A significant increase of MDA was achieved in severely poisoned patients, compared to all other groups. Conclusion. Changed oxidative stress parameters in patients poisoned with chlorpromazine indicate involvement of oxidative stress in the toxicity mechanism(s) of chlorpromazine. [Military Medical Academy, Project No. МФВМА/6/15-17

Agmatine prevents acute chlorpromazine-induced neurotoxicity in rats

The present study was directed to potentially beneficial effects of agmatine (AGM) on oxidative/nitrosative stress development in selective vulnerable brain regions during chlorpromazine (HPZ) treatment in rats. All tested compounds were administered intraperitoneally (i.p.) in one single dose. The animals were divided into control (K, 0.9 % saline solution), HPZ (HPZ, 38.7 mg/kg b.w.), HPZ+AGM (AGM, 75 mg/kg b.w. immediately after HPZ, 38.7 mg/kg b.w. i.p.) and AGM (AGM, 75 mg/kg b.w.) groups. Rats were sacrificed by decapitation 24 hours after the treatment. Analysis of data showed that HPZ+AGM injection significantly decreased drug concentration compared with HPZ-animals (p<0.05). HPZ application increased lipid peroxidation (p<0.001 in cortex, striatum and hippocampus), nitrite and nitrate concentration (p<0.001 in all three brain regions) and superoxide anion production (p<0.05 in all three brain structures), while completely damaged enzymatic antioxidative defense system (superoxide dismutase in both cortex and striatum p<0.05 and hippocampus p<0.001; glutathion reductase in both cortex and striatum p<0.001 and hippocampus p<0.05; catalase in cortex p<0.001 and both striatum and hippocampus p<0.05). However, treatment with AGM significantly attenuated the oxidative stress parameters compared to HPZ-group (lipid peroxidation in cortex p<0.001, striatum p<0.01 and hippocampus p<0.05; nitrite and nitrate concentration in all three brain structures p<0.001) and restores antioxidant capacity to control values in all examined brain structures. Immunohistochemical staining of GFAP molecules in rats showed an increase in the number of positive cells 24 h after acute HPZ-administration. All these results indicate that AGM may be effective in the protection of HPZ-induced brain injury in rats

Protective effects of agmatine against chlorpromazine-induced toxicity in the liver of wistar rats

Summary The metabolic pathways of chlorpromazine (CPZ) toxicity were tracked by assessing oxidative/nitrosative stress markers. The main objective of the study was to test the hypothesis that agmatine (AGM) prevents oxidative/nitrosative stress in the liver of Wistar rats 15 days after administration of CPZ. All tested substances were administered intraperitoneally (i.p.) for 15 consecutive days. The rats were divided into four groups: the control group (C, 0.9 % saline solution), the CPZ group (CPZ, 38.7 mg/kg b.w.), the CPZ+AGM group (AGM, 75 mg/kg b.w. immediately after CPZ, 38.7 mg/kg b.w. i.p.) and the AGM group (AGM, 75 mg/kg b.w.). Rats were decapitated 15 days after the appropriate treatment. In the CPZ group, CPZ concentration was significantly increased compared to C values (p<0.01), while AGM treatment induced the significant decrease in CPZ concentration in the CPZ+AGM group (p<0.05) and the AGM group (p<0.01). CPZ application to healthy rats did not lead to any changes of lipid peroxidation in the liver compared to the C group, but AGM treatment decreased that parameter compared to the CPZ group (p<0.05). In CPZ liver homogenates, nitrite and nitrate concentrations were increased compared to controls (p<0.001), and AGM treatment diminished that parameter in the CPZ group (p<0.05), as well as in the AGM group (p<0.001). In CPZ animals, glutathione level and catalase activity were decreased in comparison with C values (p<0.01 respectively), but AGM treatment increased the activity of catalase in comparison with CPZ animals (p<0.05 respectively). Western blot analysis supported biochemical findings in all groups. Our results showed that treatment with AGM significantly supressed the oxidative/nitrosative stress parameters and restored antioxidant defense in rat liver

Effects of agmatine on chlorpromazine toxicity in the liver of Wistar rats: the possible role of oxidant/antioxidant imbalance

Chlorpromazine (CPZ) is a member of a widely used class of antipsychotic agents. The metabolic pathways of CPZ toxicity were examined by monitoring oxidative/nitrosative stress markers. The aim of the study was to investigate the hypothesis that agmatine (AGM) prevents oxidative stress in the liver of Wistar rats 48 h after administration of CPZ. All tested compounds were administered intraperitoneally (i.p.) in one single dose. The animals were divided into control (C, 0.9% saline solution), CPZ (CPZ, 38.7 mg/kg b.w.), CPZ+AGM (AGM, 75 mg/kg b.w. immediately after CPZ, 38.7 mg/kg b.w. i.p.), and AGM (AGM, 75 mg/kg b.w.) groups. Rats were sacrificed by decapitation 48 h after treatment. The CPZ and CPZ+AGM treatments significantly increased thiobarbituric acid reactive substances (TBARS), the nitrite and nitrate (NO2+NO3) concentration, and superoxide anion (O2 •-) production in rat liver homogenates compared with C values. CPZ injection decreased the capacity of the antioxidant defense system: superoxide dismutase (SOD) activity, catalase (CAT) activity, total glutathione (GSH) content, glutathione peroxidase (GPx) activity, and glutathione reductase (GR) activity compared with the values of the C group. However, treatment with AGM increased antioxidant capacity in the rat liver; it increased the CAT activity, GSH concentration, GPx activity, and GR activity compared with the values of the CPZ rats. Immunohistochemical staining of ED1 in rats showed an increase in the number of positive cells 48 h after acute CPZ administration compared with the C group. Our results showed that AGM has no protective effects on parameters of oxidative and/or nitrosative stress in the liver but that it absolutely protective effects on the antioxidant defense system and restores the antioxidant capacity in liver tissue after administration of CPZ.Experimental Animals (2017), 66(1): 17-2

Oxidative stress, bioelements and androgen status in testes of rats subacutely exposed to cadmium

The objective of our study was to examine testicular toxicity of cadmium (Cd), focusing on oxidative stress (OS), essential metals and androgenic status and morphological changes. Male Wistar rats [controls and four Cd-subgroups (n = 6) organized according to the exposure (1, 3, 10 and 21 days)] were intraperitoneally (i.p.) treated with 1 mg CdCl2/kg/day. Testicular Cd deposition was noticed from the 1st day. After 10 and 21 days, copper (Cu) and iron (Fe) increased by 60-109% and 43-67%, respectively, while zinc (Zn) decreased by 24-33%. During 121 days of the exposure, decrease in testicular total superoxide dismutase (SOD) and total glutathione-s-transferase (GST) activities occurred gradually by 30-78% and 15-84%, respectively, while superoxide anion radical (O-2(center dot-)) increased gradually by 114-271%. After 10-21 days, decrease in testicular catalase (CAT) activity appeared by 13-31%. After 21 days, malondialdehyde (MDA) decreased by 44% and the ratio of oxidized glutathione/reduced glutathione (GSSG/GSH) increased by 130% in testes of the rats exposed to Cd. Additionally, decreased testicular testosterone level and the relative testes mass, along with induced microscopic and macroscopic changes were occured, what can be explained as the consequence of instantly developed OS, impaired essential metals status and Cd testicular deposition