Agmatine protection against chlorpromazine-induced forebrain cortex injury in rats

Dejanović, Bratislav; Stevanović, Ivana; Ninković, Milica; Stojanović, Ivana; Lavrnja, Irena; Radicevic, Tatjana; Pavlović, Marija

doi:10.4142/jvs.2016.17.1.53

Cited by 13 publications

(10 citation statements)

References 35 publications

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“…In line with previous findings showing that the largest amount of CPZ is deposited in the liver, where it exerts harmful effects [ 9 , 13 ], this study shows that CPZ causes an increase in drug concentration after 48 h compared with the concentration in controls but that the use of AGM with CPZ significantly reduces the concentration in the rat liver ( Table 1 ).…”

Section: Discussionsupporting

confidence: 93%

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

et al. 2017

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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.

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Section: Discussionsupporting

confidence: 93%

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

et al. 2017

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“…Interestingly, microglial cell activation on P10 was significantly higher in contralateral gray matter in animals treated with medium-dose LMP. This is in accordance with a study in Wistar rats reporting an increase in microglial activation status and numbers in both gray and white matter following treatment with chlorpromazine ( Dejanovic et al, 2016 ). However, absolute numbers in our study were small and the clinical relevance of this finding is questionable.…”

Section: Discussionsupporting

confidence: 93%

The effect of levomepromazine on the healthy and injured developing mouse brain – An in vitro and in vivo study

et al. 2020

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“…It confirms previous findings of the largest amount of deposited CPZ in the liver with the most important role for the manifestation of its harmful effects (25,26). Subacute application of CPZ during 15 days induced the increase of concentration of the drug in rat liver compared with the control values (Table 1).…”

Section: Discussionsupporting

confidence: 80%

Protective Effects of Agmatine against Chlorpromazine- Induced Toxicity in the Liver of Wistar Rats

Dejanović¹,

Stevanović²,

Ninković³

et al. 2016

Acta Facultatis Medicae Naissensis

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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. O r i g i n a l a r t i c l e I NT ROD U CT I ONOxidative and nitrosative stress are involved in the pathophysiology of various neurological disorders. Chronic treatment with neuroleptics increases the production of free radicals and the development of oxidative stress (OS) (1). Typical antipsychotics lead to increased OS by altering the levels of antioxidant enzymes, and cause oxidative damage, particularly lipid peroxidation (LPO) in the brain (2).Chlorpromazine (CPZ) is a typical antipsychotic that may cause distressing side effects involving the extrapyramidal tract (3). The mechanism of CPZinduced liver injury has been proposed, but has not been fully clarified, since many factors were found to be implicated in its adverse effects on the liver. CPZ leads to a dose-related impairment in bile secretion and changing hepatocyte and canalicular membrane fluidity, which consequently affects the functional integrity of these sites. It has been shown that oral administration of CPZ for two weeks causes infiltration of inflammatory cells and leads to focal necrosis (4).The mechanism responsible for CPZ-induced injury includes damage initiated by the activation of Kupffer cells, which release proinflammatory cytokines and stimulate the migration and a...

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Agmatine protection against chlorpromazine-induced forebrain cortex injury in rats

Cited by 13 publications

References 35 publications

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

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

The effect of levomepromazine on the healthy and injured developing mouse brain – An in vitro and in vivo study

Protective Effects of Agmatine against Chlorpromazine- Induced Toxicity in the Liver of Wistar Rats

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