Artesunate prevents rats from the clozapine-induced hepatic steatosis and elevation in plasma triglycerides

Abstract

Clozapine is an atypical antipsychotic with therapeutic efficacy in treatment-resistant schizophrenia patients and low incidence of extrapyramidal side effects. However, the use of clozapine has been limited by its adverse effects on metabolism. Artesunate is a semisynthetic derivative of artemisinin and was shown to decrease the plasma cholesterol and triglyceride in rabbits and rats in recent studies. The aim of this study was to examine possible effects of artesunate on the clozapine-induced metabolic alterations in rats given saline, clozapine, artesunate, or clozapine plus artesunate for 6 weeks. The clozapine group showed significantly high plasma levels of triglyceride, hepatic steatosis, and fibrosis along with high levels of C-reactive protein, alanine aminotransferase, and aspartate aminotransferase compared to the saline group. But the treatment had no effect on weight gain and caused no hyperglycemia, hyperinsulinemia, and behavioral changes in the rats. More significantly, these clozapine-induced changes were not seen in rats coadministered with clozapine plus artesunate. These results added evidence supporting psychiatrists to try add-on treatment of artesunate in schizophrenia patients to ameliorate clozapine-induced adverse metabolic effects.

Antidepressants- and antipsychotics-induced hepatotoxicity

“…These findings were confirmed in our in vivo study, where clozapine was shown to induce rat liver steatosis (Zlatković et al 2014 ). Liver steatosis, as well as an increase in plasma triglycerides and FFAs, due to clozapine treatment, was confirmed by later studies (Li et al 2017 ; Liu et al 2017 ). Moreover, a single intraperitoneal injection of clozapine (50 mg/kg) was demonstrated to down-regulate genes involved in FFA β-oxidation and lipolysis, leading to lipid accumulation in rat liver (Fernø et al 2009 ) (Fig.…”

<p>Atypical antipsychotics-induced metabolic syndrome and nonalcoholic fatty liver disease: a critical review</p>

“…In a more recent study, olanzapine-administered (for 2 weeks) rats showed severe liver damage indicated by loss of normal architecture, vacuolar degeneration of hepatocytes and fatty changes in the liver 100. In a study from our group, daily intraperitoneal injection of clozapine for 6 weeks significantly increased plasma levels of triglycerides, led to hepatic steatosis and fibrosis along with increased activities of alanine aminotransferase and aspartate aminotransferase in male Wistar rats, but showed no effects on blood glucose, insulin levels, and total cholesterol 101…”

Sex-dependent effects of long-term clozapine or haloperidol medication on red blood cells and liver iron metabolism in Sprague Dawley rats as a model of metabolic syndrome

“…Hematological abnormalities and anemia of diverse etiology are frequently associated with chronic liver diseases [ 26 , 27 ]. In rats, clozapine induces hepatic oxidative stress leading to liver injury [ 28 ] and hepatic steatosis with elevated triglyceride levels [ 29 ]. In our study, MCV, measuring the average volume of red blood cells, is unchanged in the medicated groups compared to controls (Table 1 ).…”

“…In contrast to haloperidol, which seems to show only rare hematological effects, it is known that clozapine induces dyscrasias of leukocytes [ 58 ] and erythrocytes [ 7 ] in humans, and chronic liver injury in mice [ 59 ] and rats [ 28 , 29 ]. There is growing evidence that clozapine medication is associated with severe drug-induced hepatic injury in patients [ 60 ].…”