Bifunctional compounds eliciting anti-inflammatory and anti-cholinesterase activity as potential treatment of nerve and blister chemical agents poisoning

Abstract

Certain organophosphorus (OP) nerve agents (e.g. soman) induce neuroinflammatory processes during acute poisoning. An increased level of typical inflammation markers was also observed in poisoning by alkylating agents such as sulfur mustard (HD). The therapeutic potential of new bifunctional compounds was investigated, eliciting activity of non-steroidal anti-inflammatory drug (NSAID) and anti-cholinesterase (anti-ChE) activity, as an antidotal treatment for both soman and HD poisoning in mice. Three bifunctional compounds were used that include the ChE inhibitor pyridostigmine (PYR) coupled to either ibuprofen (IBU) or diclofenac (DICLO) through an eight (octyl) or ten (decyl) hydrocarbon chain spacer: IBU-PO, IBU-PD and DICLO-PD. These compounds are 15-25 fold less toxic than PYR in mice and exert peripheral and central anti-inflammatory and anti-ChE activity in vivo. IBU-PO (4 mg kg(-1), i.p.), IBU-PD (4 mg kg(-1), i.p.) and PYR (0.13 mg kg(-1), i.p.) reduced to control levels the brain edema in soman-poisoned mice (1.1 LD50, s.c.). Pre-treatment with IBU-PO, IBU-PD and DICLO-PD 4-5 h before soman challenge (2.2-2.3 LD50, s.c.) combined with antidotal treatment (atropine, 11 mg kg(-1), 2-PAM-Cl, 25 mg kg(-1), i.m.) afforded a longer 24 h survival rate (SR) than with PYR pre-treatment. DICLO-PD exhibited the largest protection efficacy (SR = 70% vs 17% with PYR). These results indicate a longer duration of action of bifunctional compounds compared with PYR. DICLO-PD (5% in propyleneglycol) reduced significantly the HD-induced edema in mouse ear-skin (51% increase in biopsy weight compared with 100% without treatment). Quantitative evaluation of ear-skin sections showed that only following DICLO-PD treatment was there a marked decrease in edema. DICLO-PD also elicited a significant decrease in HD-induced vesication as displayed by the reduced sub-epidermal blister level. The data indicate possible use of NSAID-ChEI bifunctional compounds for the medical treatment of both nerve and alkylating chemical agents.

Zebrafish is a predictive model for identifying compounds that protect against brain toxicity in severe acute organophosphorus intoxication

“…We found that post-treatment of zebrafish with these drugs significantly decreased the prevalence of brain toxicity, with the highest protection provided by MK-801 and caramiphen. The use of anti-inflammatory drugs has been proposed to counteract neuroinflammation during severe acute OP intoxication (Amitai et al 2006; Banks and Lein 2012; Dhote et al 2007; Spradling et al 2011). Post-treatment of the zebrafish with the anti-inflammatory agents ibuprofen and dexamethasone provided significant protection against brain toxicity, although this group of drugs was the least efficient of all tested treatments.…”

Neuropathologic Effects of Chemical Warfare Agents

“…This is accompanied by increased expression of central neuroinflammatory genes (Levy et al, 2004). These observations have led to the development of a novel class of anti-inflammatory, anti-cholinesterase (anti-ChE) drugs that may have utility in treating nerve agent poisoning (Amitai et al, 2005). In a rat model of AChE inhibitor intoxication, markers of reactive oxygen species (ROS) and reactive nitrogen species (RNS) were found to be elevated in susceptible regions of brain within 15 min to 1 h of exposure (Gupta et al, 2007;Zaja-Milatovic et al, 2009); this was accompanied by dendritic damage to the hippocampus, a sensitive morphologic marker of neuronal injury (Gupta et al, 2007; see also Figure 50.1).…”

Bivalent Ligands Derived from Huperzine A as Acetylcholinesterase Inhibitors

“…Bifunctional derivatives have also been developed which successfully fulfill the dual tasks of inhibiting the catalytic activity of AChE and slowing the rate of Aβ aggregation by the PAS [71,72]. Other bifunctional gorge-spanning ligands have been developed which serve as dual inhibitors of AChE and monoamine oxidase [73], as dual anti-ChE and anti-inflammatory agents [74,75], or as dual anti-ChE and protectants against reactive oxygen species [76]. As mentioned in the Introduction, (-)-HupA acts as a neuroprotectant against a variety of agents, whether as an N-methyl-D-aspartate (NMDA) receptor antagonist or by other mechanisms [8].…”