Bueters Tjerk J H, Groen Bas, Danhof Meindert, IJzerman Ad P, Van Helden Herman P M
Research Group Medical Countermeasures, TNO Prins Maurits Laboratory, Lange Kleiweg 137, PO Box 45, 2280 AA Rijswijk, The Netherlands.
Arch Toxicol. 2002 Nov;76(11):650-6. doi: 10.1007/s00204-002-0395-x. Epub 2002 Aug 21.
The objective of the present study was to investigate whether reduction of central acetylcholine (ACh) accumulation by adenosine receptor agonists could serve as a generic treatment against organophosphate (OP) poisoning. The OPs studied were tabun ( O-ethyl- N-dimethylphosphoramidocyanidate), sarin (isopropylmethylphosphonofluoridate), VX ( O-ethyl- S-2-diisopropylaminoethylmethylphosphonothiolate) and parathion ( O, O-diethyl- O-(4-nitrophenyl)phosphorothioate). The efficacy of the adenosine A(1) receptor agonist N(6)-cyclopentyladenosine (CPA) against an OP intoxication was examined on the basis of the occurrence of clinical symptoms that are directly associated with such intoxication. CPA (1-2 mg/kg) effectively attenuated the cholinergic symptoms and prevented mortality in lethally tabun- or sarin-intoxicated rats. In contrast, CPA (2 mg/kg) proved to be ineffective against VX or parathion intoxication. Intracerebral microdialysis studies revealed that survival of sarin-poisoned and CPA-treated animals coincided with a minor elevation of extracellular ACh concentrations in the brain relative to the baseline value, whereas an 11-fold increase in transmitter levels was observed in animals not treated with CPA. In VX-intoxicated rats, however, the ACh amounts increased 18-fold, irrespective of treatment with CPA. The striatal acetylcholinesterase (AChE) activity following a lethal sarin intoxication was completely abolished in the vehicle-treated animals, whereas 10% and 60% AChE activity remained in animals treated with 2 mg/kg CPA 1 min after or 2 min prior to the poisoning, respectively. In VX-intoxicated animals the AChE activity in the brain was strongly reduced (striatum 10%, hippocampus 1%) regardless of the CPA treatment. These results demonstrate that CPA is highly effective against tabun or sarin poisoning, but fails to protect against VX or parathion. Survival and attenuation of clinical signs in tabun- or sarin-poisoned animals are associated with a reduction of ACh accumulation and with protection of AChE activity in the brain.
本研究的目的是调查腺苷受体激动剂减少中枢乙酰胆碱（ACh）蓄积是否可作为有机磷酸酯（OP）中毒的通用治疗方法。所研究的有机磷酸酯包括塔崩（O - 乙基 - N，N - 二甲基磷酰胺氰化物）、沙林（异丙基甲基磷酰氟）、VX（O - 乙基 - S - 2 - 二异丙氨基乙基甲基硫代磷酸酯）和对硫磷（O，O - 二乙基 - O -（4 - 硝基苯基）硫代磷酸酯）。基于与OP中毒直接相关的临床症状的出现情况，研究了腺苷A(1)受体激动剂N(6)-环戊基腺苷（CPA）对OP中毒的疗效。CPA（1 - 2毫克/千克）有效减轻了胆碱能症状，并预防了致死剂量塔崩或沙林中毒大鼠的死亡。相比之下，CPA（2毫克/千克）被证明对VX或对硫磷中毒无效。脑内微透析研究表明，沙林中毒并经CPA治疗的动物存活与脑内细胞外ACh浓度相对于基线值的轻微升高一致，而未用CPA治疗的动物中递质水平增加了11倍。然而，在VX中毒的大鼠中，无论是否用CPA治疗，ACh量均增加了18倍。致死剂量沙林中毒后，溶剂处理组动物纹状体乙酰胆碱酯酶（AChE）活性完全丧失，而中毒前2分钟或中毒后1分钟用2毫克/千克CPA治疗的动物分别保留了10%和60%的AChE活性。在VX中毒的动物中，无论是否进行CPA治疗，脑内AChE活性均显著降低（纹状体10%，海马1%）。这些结果表明，CPA对塔崩或沙林中毒高度有效，但对VX或对硫磷中毒无效。塔崩或沙林中毒动物的存活和临床症状减轻与ACh蓄积减少及脑内AChE活性保护有关。
