| Medical scientists both civilian and military always pay close attention to the intoxication of cholinesterase inhibitors (ChEI). Intoxication of ChEI usually leads to MODS. Recent researches report, gastrointestinal tract is one of organs were directly influenced by ChEI. Intoxication of ChEI could give rise to functional disturbance of gastrointestinal mucosa barrier, simultaneous shift of bacterium and endotoxin, and directly or indirectly provoked to SIRS and MODS, which further evoke functional disturbance of gastrointestinal mucosa barrier. However, while present multi-drug treatments for ChEI intoxication offer robust protection against their lethality, convulsions and behavioral deficits are not completely prevented. Spatial learning and memory impairments are two major detrimental consequences of ChEI intoxication, with ensuing neuronal degeneration in CNS structures (e.g., hippocampus). So, there was an important significance to research the novel anti-cholinesterase.Our earlier studies showed that benthiactzine could antagonize against both M-receptors and N-receptors. It indicated that benthiactzine have a prior to antagonism blocking muscarinic acetylcholine receptors, but it is opposite to non-neuronal muscarinic acetylcholine receptor. This study shows that benthiactzine could protect the functional of gastrointestinal mucosa barrier. Besides, this study found that benthiactzine could effectively against convulsion and memory impairments induced by intoxication of ChEI.Basis theory of essay is follow:1. Effects of benthiactzine on functional disturbance of gastrointestinal mucosa barrier induced by ChEI.Kunming mice, female and male both half, were randomly assigned to five groups: normal group, DDVP poisoning (model) group, benthiactzine 2, 6, 18mg/kg groups, and atropine 2, 6, 18mg/kg groups. The drugs were respectively given 10 minutes before intragastric administration of DDVP in a dose of 55mg/kg. The diamine oxidase (DAO) activity and concentration of D-lactic acid in plasma were measured at 3 hours after DDVP poisoning. The results indicate that the DAO activity in model group was significantly increased compared with normal group (P<0.01). Whereas, the DAO activity in all pretreatment groups were significantly decreased compared with model group(all P<0.01). The effects of benthiactzine 6mg/kg pretreatment group was the best of all. The concentration of D-lactic acid in model group was significantly increased compared with normal group(P<0.01). However, the concentration of D-lactic acid in pretreatment groups was significantly decreased compared with model group(all P<0.01). The concentration of D-lactic acid could be gradually decreased by the increasing doses of benthiactzine.From these observations,it could be concluded: The diamine oxidase activity and concentration of D-lactic acid were significantly increased in the DDVP poisoning mice, which means the gut-barrier function was severely damaged. And the administration of benthiactzine could alleviate the injury to the gut-barrier function.2. Effects of benthiactzine on learning and memory impairment induced by ChEI.To investigate the functional changes of learning and memory induced by cholinesterase inhibitor VX poisoning and the therapeutic effect of benthiaczine. Male Wistar rats were randomly divided into six groups: control group, VX poisoning (model) group, Benthiaczine 0.5, 1.5, 4.5mg/kg groups, Atropine 4.5mg/kg group. The above mentioned drugs were respectively given (ip) 5 min after VX poisoning at the dose of 1×LD50 (sc). The clinical observations were recorded after the treatment; the morphological changes of the neurons in hippocampus were determined by electron microscope at 4 hours after VX poisoning; the function of learning and memory were measured by Morris water maze test 1 week after exposure to VX, including place navigation test, spatial probe test and transfer test. The results indicated that,manifestation of symptom(e.g., tremors, salivation, convulsions, and respiratory distress) in VX-treated rats appeared within 6 to 9 min after injection. The weight of control group increased 20% after one week, while the model group established a loss of weight (18%)72h following intoxication. All weight of treatment group increased 5%~20% in one week. The mortality rate (24h) was 8/15, and these rats experienced convulsions that lasted for several hours. In contrast, the mortality rate of all the rats treated with drug was higher than the model group. In Morris water maze test, escape latency and path length in model group were significantly increased compared with those of control group during the place navigation test and transfer test, (P<0.05 or P<0.01) , which indicated that the function of learning and memory in rats were significantly decreased after exposure to VX; control rats spent more time and swam a longer distance in the training quadrant than in the other three quadrants during the transfer test, in marked contrast, the time spent and the distance swum was equal in each of the four quadrants by model rats, which indicated that the function of spatial probe in rats were significantly decreased after exposure to VX. Escape latency and path length were significantly shortened compared with those of model group, and the time spent and the distance swum were similar to control group after administration of Benthiaczine at dose of 0.5, 1.5, 4.5mg/kg . The decrease of learning and memory in model rats could be improved or totally reversed after Benthiaczine administration. The neurons injury in hippocampus were obvious at the 4 hours after VX poisoning by electron microscope, including karyopycnosis, apomorphosis of endocytoplasmic reticulum, and organelles damage; These pathological changes could be improved dose-dependently after benthiaczine 0.5, 1.5, 4.5mg/kg administration.From the results above, the ChEI could seriously impair the function of learning and memory in rats. But benthiaczine could not only treat the poisoning symptoms, but also protect the pathology changes of neurons in hippocampus.From these observations,we come to conclusions as follow:The benthiactzine is a novel medicine of against acetylcholine M-receptors and N-receptors. In the earlier intoxiciation of cholinesterase inhibitors, benthiactzine could relieve the functional injury of gastrointestinal mucosa barrier induced by endotoxin in the blood, which could protect function of gastrointestinal mucosa barrier.Benthiactzine could not only treat the syndrome of respiratory failture, circulatory failture and convulsion, but also relieve the impairment of learning and memory induced by ChIE intoxication.
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