Reactivator Report for: Cl-HIN

AChE inhibition caused by exposure to organophosphate (OP) compounds is strongly related to behavioral disorders such as depression. Malathion is an OP that already has a relationship between its exposure and behavioral changes, although few data still have its effects in a longer exposure protocol. In addition, intoxication therapy is based on the use of atropine-oxime which still has its controversial efficacy depending on the type of compound. For this, (3Z)-5-Chloro-3-(hydroxyimino)indolin-2-one (Cl-HIN), a compound that has properties of isatin and oxime in its structure, have shown reactivating properties in the activity of AChE that have been added to antidepressant-like effects in rats exposed to malathion in acute protocol. In this sense, effects of Cl -HIN on the depressive-like behavior and AChE activity were evaluated in a protocol of subchronic exposure to malathion in rats. Male wistar rats were co-treated with Cl-HIN [5 mg/kg, p.o.] and/or malathion [1 or 10 mg/kg, i.p] for 20 days. The exposure to both doses of malathion increased immobility time of rats on the forced swimming test (FST). Besides, malathion inhibited the AChE activity in the prefrontal cortex of rats, but any significant difference was observed in the hippocampus. Cl-HIN protected against increased immobility time in the FST of those rats exposed to a dose of 1 mg/kg of malathion. Similarly, Cl -HIN was able to reactivate AChE activity only in that group exposed to the lowest dose of malathion. Collectively, the results of this study suggest that Cl -HIN is an oxime capable of reactivating AChE inhibited and presents na antidepressant-like effect in cases of prolonged exposure to malathion.

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 This study proposes to test unpublished compounds which contain the moieties of isatin and/or oxime have protective effects against the toxicity induced by malathion in two animal models: Artemia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 microM while to 3-(phenylhydrazono) butan-2-one oxime (PHBO) was 38 microM. 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.

BACKGROUND: Organophosphorus pesticides exert their toxic effects mainly by the inhibition of acetylcholinesterase (AChE), which is related to emotional disorders, such as depression. Atropine-oximes therapy is commonly used; however, the efficacy of oximes in the reactivation of AChE has been inconsistent. The objective of this study was to investigate the possible neuroprotective effect of (3Z)-5-Chloro-3-(hydroxyimino)indolin-2-one (Cl-HIN), a compound that combines the isatin and oxime functional groups, in rats exposed to malathion. The effect of Cl-HIN on the AChE activity and the BDNF-Trkbeta pathway in the prefrontal cortex of malathion-exposed rats were tested. METHODS: Wistar male rats were co-treated with Cl-HIN [50mg/kg (p.o.) (3ml/kg)] and/or malathion [250mg/kg (i.p.) (5ml/kg)] and performed behavioral tests twelve hours after these exposures. RESULTS: The Cl-HIN reversed the increased immobility time in the forced swimming test and the decreased grooming time in the splash test induced by malathion, but any significant difference was observed in locomotion analysis. These results demonstrate the antidepressant-like effect of Cl-HIN. The cortical AChE activity was reactivated by Cl-HIN in rats exposed to malathion. Malathion induced an increase in Trkbeta and a decrease in BDNF levels in the prefrontal cortex of rats, which were avoided by Cl-HIN. CONCLUSION: These findings support the hypothesis that Cl-HIN is an AChE reactivator with antidepressant-like properties, which is related to the improvement of BDNF-Trkbeta signaling after acute exposure to malathion in rats. Thus, the results allow suggesting the potential use of Cl-HIN as an oxime-based therapy against the neurotoxic effects of malathion.

AChE inhibition caused by exposure to organophosphate (OP) compounds is strongly related to behavioral disorders such as depression. Malathion is an OP that already has a relationship between its exposure and behavioral changes, although few data still have its effects in a longer exposure protocol. In addition, intoxication therapy is based on the use of atropine-oxime which still has its controversial efficacy depending on the type of compound. For this, (3Z)-5-Chloro-3-(hydroxyimino)indolin-2-one (Cl-HIN), a compound that has properties of isatin and oxime in its structure, have shown reactivating properties in the activity of AChE that have been added to antidepressant-like effects in rats exposed to malathion in acute protocol. In this sense, effects of Cl -HIN on the depressive-like behavior and AChE activity were evaluated in a protocol of subchronic exposure to malathion in rats. Male wistar rats were co-treated with Cl-HIN [5 mg/kg, p.o.] and/or malathion [1 or 10 mg/kg, i.p] for 20 days. The exposure to both doses of malathion increased immobility time of rats on the forced swimming test (FST). Besides, malathion inhibited the AChE activity in the prefrontal cortex of rats, but any significant difference was observed in the hippocampus. Cl-HIN protected against increased immobility time in the FST of those rats exposed to a dose of 1 mg/kg of malathion. Similarly, Cl -HIN was able to reactivate AChE activity only in that group exposed to the lowest dose of malathion. Collectively, the results of this study suggest that Cl -HIN is an oxime capable of reactivating AChE inhibited and presents na antidepressant-like effect in cases of prolonged exposure to malathion.

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 microM while to 3-(phenylhydrazono) butan-2-one oxime (PHBO) was 38 microM. 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.

BACKGROUND: Organophosphorus pesticides exert their toxic effects mainly by the inhibition of acetylcholinesterase (AChE), which is related to emotional disorders, such as depression. Atropine-oximes therapy is commonly used; however, the efficacy of oximes in the reactivation of AChE has been inconsistent. The objective of this study was to investigate the possible neuroprotective effect of (3Z)-5-Chloro-3-(hydroxyimino)indolin-2-one (Cl-HIN), a compound that combines the isatin and oxime functional groups, in rats exposed to malathion. The effect of Cl-HIN on the AChE activity and the BDNF-Trkbeta pathway in the prefrontal cortex of malathion-exposed rats were tested. METHODS: Wistar male rats were co-treated with Cl-HIN [50mg/kg (p.o.) (3ml/kg)] and/or malathion [250mg/kg (i.p.) (5ml/kg)] and performed behavioral tests twelve hours after these exposures. RESULTS: The Cl-HIN reversed the increased immobility time in the forced swimming test and the decreased grooming time in the splash test induced by malathion, but any significant difference was observed in locomotion analysis. These results demonstrate the antidepressant-like effect of Cl-HIN. The cortical AChE activity was reactivated by Cl-HIN in rats exposed to malathion. Malathion induced an increase in Trkbeta and a decrease in BDNF levels in the prefrontal cortex of rats, which were avoided by Cl-HIN. CONCLUSION: These findings support the hypothesis that Cl-HIN is an AChE reactivator with antidepressant-like properties, which is related to the improvement of BDNF-Trkbeta signaling after acute exposure to malathion in rats. Thus, the results allow suggesting the potential use of Cl-HIN as an oxime-based therapy against the neurotoxic effects of malathion.

Background: Organophosphorus pesticides (OP's) are heavily constituted in agriculture, gardens, home and veterinary and although it is useful, there are concerns about the environment, safety and health of human and animals. In this study, we investigated the effects of a new oxime, (3Z)-5-Chloro-3-(Hydroxyimino)indolin-2-one (OXIME) against the alterations induced by malathion, an OP insecticide, acute exposure on markers of hepatic damage, glucose homeostasis, oxidative stress in rats cholinesterase (ChE) activity in rats. Methods: Adult male Wistar rats were divided into four groups: Control; Malathion; OXIME; and Malathion+OXIME. Twelve hours after co-treatment with malathion (250 mg/kg, i.p.) and/or OXIME (50 mg/kg, i.g.), the plasma and liver samples were collected for biochemical analyses. Results: The OXIME blocked the increase of plasma markers of hepatic function (AST and ALP) and the enzymatic inhibition of catalase and glutathione reductase in the liver of malathion-treated rats. Moreover, the hepatic cholinesterases inhibition induced by malathion acute exposure was suppressed by OXIME treatment. As assessed, a single dose of OXIME lowered the glycemia levels and hepatic glycogen content enhanced by malathion. Conclusions: This study suggests promise effects of (3Z)-5-Chloro-3-(Hydroxyimino) indolin-2-one against the hyperglycemia and the hepatic damage induced by malathion acute exposure, as well as its use as a ChE activity reactivator.