Effects of K074 and pralidoxime on antioxidant and acetylcholinesterase response in malathion-poisoned mice

Abstract

The organophosphorus (OP) pesticide malathion is a highly neurotoxic compound and its toxicity is primarily caused by the inhibition of acetylcholinesterase (AChE), leading to cholinergic syndrome. Although oximes have been used as potential antidotal treatments in malathion poisoning because of their potential capability to reactivate the inhibited enzyme, the clinical experience with the clinically available oximes (e.g. pralidoxime) is disappointing and their routine use has been questioned. In the present study, we investigated the potency of pralidoxime and K074 in reactivating AChE after acute exposure to malathion, as well as in preventing malathion-induced changes in oxidative-stress related parameters in mice. Malathion (1.25 g/kg, s.c.) induced a significant decrease in cortico-cerebral, hippocampal and blood AChE activities at 24h after exposure. Oxime treatments (1/4 of LD(50), i.m., 6h after malathion poisoning) showed that pralidoxime significantly reversed malathion-induced blood AChE inhibition, although no significant effects were observed after K074 treatment. Interestingly, both oximes tested were unable to reactivate the cortico-cerebral and hippocampal enzymes after intramuscular or intracerebroventricular injection (1/4 of LD(50), 6h after malathion poisoning). Biochemical parameters related to oxidative stress (cerebro-cortical and hippocampal glutathione peroxidase, glutathione reductase and catalase activities, as well as lipid peroxidation) were not affected in animals treated with malathion, oximes or atropine alone. However, pralidoxime and K074, administered intramuscularly 6h after malathion poisoning, were able to increase the endogenous activities of these antioxidant enzymes in the prefrontal cortex and hippocampus. Taken together, the results presented herein showed that pralidoxime (the most common clinically used oxime) and the recently developed oxime K074, administered 6h after malathion poisoning, were unable to reactivate the inhibited AChE in mouse prefrontal cortex and hippocampus. However, only pralidoxime significantly reversed the blood AChE inhibition induced by malathion poisoning. This indicates that peripheral and central AChE activities are not necessarily correlated after the treatment of OP compounds and/or oximes, which should be taken into account in the diagnosis and management of OP-exposed humans. In addition, considering that the available treatments to malathion poisoning appear to be ineffective, the present study reinforce the need to search for potential new AChE reactivators able to efficiently reactivate the brain and blood AChEs after malathion poisoning.

Kinin-B2 receptor exerted neuroprotection after diisopropylfluorophosphate-induced neuronal damage

“…Such hypotheses are supported by our present study, since 2-PAM, known to revert DFP-induced inhibition of AChE (dos Santos et al, 2011), was neuroprotective, even in the presence of the B1BKR agonist desArg 9 -BK, which abolished protection mediated by BK. The failure of BK inducing neuroprotective pathways in the presence of desArg 9 -BK suggests that B2BKR-mediated PS recovery which is not directly connected with AChE inhibition by DFP.…”

“…Pralidoxime (2-PAM), known to revert inhibition of acetylcholine esterase (dos Santos et al 2011) protected against neurotoxic effects of DFP that were not affected by the B1BKR agonist Lys-des-Arg9-BK (Figure 6). However, 2-PAM-induced PS recovery was reduced in the presence of BK and the B1BKR agonist, suggesting interference between B2BKR- and B1BKR-mediated signaling as reported previously (Martins et al 2012).…”

Acrylamide Influence on Activity of Acetylcholinesterase, Thiol Groups, and Malondialdehyde Content in the Brain of Swiss Mice

“…Moreover, ROS inhibits AChE activity. This effect was found in brain and in peripheral cholinergic nerves [31,32]. The neural system is protected by antioxidants against ROS.…”

Impaired Insulin/IGF Signaling in Experimental Alcohol-Related Myopathy

“…Therefore, the adverse effects of chronic ethanol exposure on cholinergic function in skeletal muscle are likely mediated by inhibition of AChE rather than ChAT. Since AChE is inhibited by oxidative stress [46,47,48,49], we postulate that ethanol-mediated impairment of insulin/IGF signaling and mitochondrial function, together with increased lipid peroxidation (HNE) promote chronic oxidative stress, which leads to inhibition of AChE expression in skeletal muscle. Previous studies demonstrated that inhibition of AChE is sufficient to cause myofiber atrophy and degeneration [50].…”