Therapeutic efficacy of the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) against organophosphate intoxication.
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.
Bueters
Tjerk J H
TJ
Research Group Medical Countermeasures, TNO Prins Maurits Laboratory, Lange Kleiweg 137, PO Box 45, 2280 AA Rijswijk, The Netherlands. Bueters@pml.tno.nl
Groen
Bas
B
Danhof
Meindert
M
IJzerman
Ad P
AP
Van Helden
Herman P M
HP
D000109:Acetylcholine / Q000378:metabolism; D000241:Adenosine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000506:poisoning*; D002802:Cholinesterases / Q000378:metabolism; D003342:Corpus Striatum / Q000201:enzymology; D008297:Male; D017551:Microdialysis; D062025:Organophosphate Poisoning; D010755:Organophosphates; D009946:Organothiophosphorus Compounds / Q000506:poisoning*; D010278:Parathion / Q000506:poisoning*; D058906:Purinergic P1 Receptor Agonists; D051381:Rats; D017208:Rats, Wistar; D012524:Sarin / Q000506:poisoning*
D000109:Acetylcholine; D000241:Adenosine; D002800:Cholinesterase Inhibitors; D002802:Cholinesterases; D010755:Organophosphates; D009946:Organothiophosphorus Compounds; D010278:Parathion; D058906:Purinergic P1 Receptor Agonists; D012524:Sarin; C048599:N(6)-cyclopentyladenosine; C009680:VX-agent; C009374:tabun