Pre‐clinical evidence of safety and protective effect of isatin and oxime derivatives against malathion‐induced toxicity. Issue 4 (2nd December 2019)

• Record Type: Journal Article
• Authors: Savall, Anne Suély Pinto; Fidélis, Eduarda Monteiro; Gutierrez, Maria Eduarda Ziani; Martins, Bianca Barreto; Gervini, Vanessa Carratú; Puntel, Robson Luiz; Roos, Daniel Henrique; Ávila, Daiana Silva; Pinton, Simone
• Is Part Of: Basic & clinical pharmacology & toxicology. Volume 126:Issue 4(2020)
• Page Start: 399
• Page End: 410
• Publication Date: 2019-12-02
• Subjects: isatin -- malathion -- oxime -- protective -- toxicity; Pharmacology -- Periodicals; Toxicology -- Periodicals; Pharmacology -- Periodicals; Toxicology -- Periodicals; Pharmacology, Clinical -- Periodicals; Computer network resources; Electronic journals; 615.1
• DOI: 10.1111/bcpt.13359
• Languages: English
• ISSNs: 1742-7835

Abstract

Abstract: The inhibition of acetylcholinesterase (AChE) is a common outcome caused by organophosphorus (OPs) intoxication. Although inconsistent, the standard treatment consists of a muscarinic receptor antagonist (atropine) and AChE‐reactivating molecules such as oximes. This study proposes to test unpublished compounds which contain the moieties of isatin and/or oxime have protective effects against the toxicity induced by malathion in two animal models: Artemia salina and Rattus norvegicus (Wistar rats). The lethality was assessed in A salina, and the calculated LD50 to (3Z)‐5‐chloro‐3‐(hydroxyimino) indolin‐2‐one oxime (Cℓ‐HIN) and 2‐(5‐chloro‐2‐oxoindolin‐3‐ylidene)‐hydrazinecarbothioamide (Cℓ‐OXHS) was higher than 1000 µM while to 3‐(phenylhydrazono) butan‐2‐one oxime (PHBO) was 38 µM. Our screening showed that Cℓ‐HIN seems to be the most promising molecule, with low toxicity to A salina, protection against mortality (with or without atropine) and AChE inhibition induced by malathion. Similarly, the oral administration of 300 mg/kg of Cℓ‐HIN induced low or no toxicity in rats. The plasma butyrylcholinesterase (BChE) and cortical AChE activities were reactivated by Cℓ‐HIN (50 mg/kg, p.o.) in rats exposed to malathion (250 mg/kg, i.p). No difference was observed in paraoxonase‐1 (PON‐1) activity among groups treated. In conclusion, Cℓ‐HIN restored the cholinesterase activities inhibited by malathion in A salina and rats with low toxicity in both. Thus, the data provide evidence that Cℓ‐HIN, a compound that combines isatin and oxime functional groups, is safe and has important properties to reactivate the cholinesterases inhibited by malathion. In addition, we demonstrate the importance of a preliminary assessment in an alternative model in order to reduce the use of mammalians in drug discovery.