Evidência de segurança e efeito tipo-antidepressivo de derivados de isatinas e oximas frente a toxicidade induzida pelo malation

Abstract

The poisoning caused by exposure to organophosphate (OFS) have become a global health problem and the use of standard clinical drugs still can not be fully effective against toxicity induced by most of these compounds. In this case, clinical treatment against OPs poisoning involves the use of atropine and oximes in which oximes have the role of reversing the inhibition of acetylcholinesterase (AChE), the main mechanism of toxic action of OPs. In addition, exposure to OPs is being linked to emotional disorders, such as depression. Thus, the aim of our study was to investigate the toxicological profile of novel oxime and isatin (PHBO, Cl-HIN, Cl-OXHS) and its effects on exposure to malathion. The LC50 of the Cl-HIN and Cl-OXHS compounds were calculated to be greater than 1000 μM while the LC50 of the PHBO was 38 μM in Artemia salina. Our results in this animal model indicate that the Cl-HIN oxime is the most promising molecule among the compounds tested, as it protects Artemia salina from death and inhibition of AChE induced by malathion. The HIN-Cl showed low toxicity in rats, with a similar safety oximes used in the clinic. In addition, Cl-HIN protected the inhibition of cholinesterase activity (AChE and BChE) in rats exposed to malathion. Considering the potential behavioral disturbance caused by malathion, rats exposed to malathion (250mg/kg, i.p) presented a depressive-like behavior and a single Cl-HIN dose (50mg/kg, orally) prevented the increase of the time of immobility in forced swimming and decreased gooming behavior indicative of depressive-like behavior caused by malathion intoxication in rats. BDNF levels were decreased in the prefrontal cortex on exposure to malathion and these were increased with Cl-HIN treatment at the control levels. Thus, it can be inferred that the protection of AChE inhibition and the decrease of BDNF levels are the mechanisms by which Cl-HIN exerts its beneficial effects. These results demonstrated that Cl-HIN was the most promising molecule with low toxicity in both rodent models and proved to be a potential therapeutic agent with antidepressant and neuroprotective properties providing promising results for effective and alternative treatments for OFs poisoning.