Crotylsarin ligand of proteins in family: ACHE, BCHE
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Title: Central respiratory effects on motor nerve activities after organophosphate exposure in a working heart brainstem preparation of the rat Klein-Rodewald T, Seeger T, Dutschmann M, Worek F, Morschel M Ref: Toxicol Lett, 206:94, 2011 : PubMed
The impact of organophosphorus compound (OP) intoxication on the activity of central respiratory circuitry, causing acetylcholinesterase (AChE) inhibition and accumulation of acetylcholine in the respiratory brainstem circuits, is not understood. We investigated the central effect of the OP Crotylsarin (CRS) on respiratory network activity using the working heart brainstem preparation, which specifically allows for the analysis of central drug effects without changes in brainstem oxygenation possibly caused by drug effects on peripheral cardio-respiratory activity. Respiratory network activity was determined from phrenic and hypoglossal or vagal nerve activities (PNA, HNA, VNA). To investigate combined central and peripheral CRS effects hypo-perfusion was used mimicking additional peripheral cardiovascular collapse. Systemic CRS application induced a brief central apnea and complete AChE-inhibition in the brainstem. Subsequently, respiration was characterised by highly significant reduced PNA minute activity, while HNA showed expiratory related extra bursting indicative for activation of un-specified oro-pharyngeal behaviour. During hypo-perfusion CRS induced significantly prolonged apnoea. In all experiments respiratory activity fully recovered after 1h. We conclude that CRS mediated AChE inhibition causes only transient central breathing disturbance. Apparently intrinsic brainstem mechanisms can compensate for cholinergic over activation. Nevertheless, combination of hypo-perfusion and CRS exposure evoke the characteristic breathing arrests associated with OP poisoning.
A method was developed to study exclusively those therapeutic effects of oximes that are not related to reactivation of organophosphate-inhibited acetylcholinesterase (AChE). The model uses the organophosphorus compound crotylsarin (CRS), which proved to be a potent, irreversible, peripherally and centrally active AChE inhibitor with a very short biological half-life. CRS-inhibited AChE appeared to age very rapidly, because in vitro addition of oximes immediately following inhibition, did not result in any AChE reactivation. Anaesthetized, atropinized and artificially ventilated rats were intoxicated with 3 x LD50 CRS and treated 5 min later with the bispyridinium oxime HI-6. Fifty percent of these animals survived more than 24 h following termination of artificial ventilation at 10 min after oxime treatment. The mean survival time of the remaining animals was 66 min, whereas all untreated animals died within 4 min. HI-6, when added in vitro to isolated intact hemidiaphragms, or to diaphragm or brain homogenates from rats which had been killed 1 min following 3 x LD50 CRS, failed to reactivate the inhibited AChE. If blood was sampled (before and) after HI-6 administration to CRS-intoxicated rats, no HI-6-induced AChE reactivation was observed. Yet, a clear improvement of the neuromuscular transmission in the hindleg muscles of these animals was found following HI-6 injection. With this model, decisive evidence is obtained that non-reactivating effects of HI-6 by themselves are therapeutically relevant.
