Attenuation of soman-induced lesions of skeletal muscle by acetylcholinesterase reactivating and non-reactivating antidotes

Abstract

It has been reported recently that some oximes reactivating acetylcholinesterase (AChE) exhibit concomitant ganglion-blocking effects which presumably could contribute independently to their powerful antidotal action in organophosphate inhibitor (OPI) poisoning, thus mimicking some unrelated substances which are effective antidotes without reactivating AChE. This raises the question whether OPI-induced muscle lesions, like some other symptoms could also be attenuated by oximes and other antidotes in the absence of AChE reactivation. To test this possibility, the oxime HI-6 was applied at increasing time intervals after the injection of soman until and beyond the point when soman-AChE complex becomes completely "aged" and not capable of reactivation. As the examples of OPI antidotes which do not reactivate AChE, the muscarinic antagonist atropine and the ganglion-blocking agent hexamethonium were also tested on possible attenuation of muscle lesions. The proportions of fibers with lesions, AChE inhibition and muscle fasciculations in experimental groups relative to the controls treated with soman only were evaluated. The results show that HI-6 can attenuate lesions only if AChE is partially reactivated and muscle fasciculations are permanently eliminated. However, atropine does not affect either AChE inhibition or muscle fasciculations and is also ineffective in counteracting the lesions in spite of its potency as an effective general antidote. Hexamethonium also does not affect AChE inhibition, but abolishes fasciculations and effectively attenuates muscle lesions. The latter findings reveal the existence of lesion-protecting mechanisms unrelated to AChE reactivation, which if further elucidated might become potentially relevant for additional treatment in OPI poisoning.

Early Expression of Ubiquitin in Myofibers of Rats in Organophosphate Intoxication

“…By electron microscopy the main changes of the myo"bers were loss of "laments, fragmentation of Z lines, and disorganization of mitochondrial cristae (Fenichel et al, 1972;Dekleva et al, 1989). The mechanisms and steps involved in muscle "ber necrosis induced by organophosphates are not completely known.…”

Miotoxicidade por organofosforados

“…Alterações estruturais e funcionais observadas nos músculos esqueléticos estão relacionadas com as estruturas químicas dos produtos e com o tipo de músculo, sendo o diafragma o mais afetado em estudos experimentais 3,4,5,8,9,13,14,15 . Necrose muscular, semelhante à observada em animais de laboratório, foi encontrada em músculos diafragma e intercostais de indivíduos intoxicados pelo parathion 6 , diazinon 1 , triclornato 7 e combinação de malathion e diazinon 18 .…”