Title
Therapeutic efficacy of the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) against organophosphate intoxication
Author
Bueters, T.J.H.
Groen, B.
Danhof, M.
IJzerman, A.P.
van Helden, H.P.M.
Prins Maurits Laboratorium TNO
Publication year
2002
Abstract
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 A1 receptor agonist N6-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.
Subject
Biology
Acetylcholine release
Adenosine A1 receptor
N6-Cyclopentyladenosine
Organophosphate
Adenosine A1 receptor agonist
Adenosine receptor stimulating agent
Cyclohexyladenosine
Methylphosphonothioic acid s (2 diisopropylaminoethyl) o ethyl ester
Adenosine receptor
Cholinesterase
Drug derivative
N(6) cyclopentyladenosine
Organophosphate
Phosphorothioic acid derivative
Bioaccumulation
Cholinergic system
Concentration response
Controlled study
Corpus striatum
Crug efficacy
Enzyme activity
Hippocampus
Intoxication
Male
Microdialysis
Nonhuman
Rat
Reduction
Animal
Drug potentiation
Enzymology
Metabolism
Secretion
Wistar rat
Animals
Cholinesterase Inhibitors
Cholinesterases
Corpus Striatum
Male
Microdialysis
Organothiophosphorus Compounds
Parathion
Phosphoric Acid Esters
Rats
Rats, Wistar
Receptors, Purinergic P1
Sarin
Acetylcholinesterase, 9000-81-1
Cyclohexyladenosine, 36396-99-3
Methylphosphonothioic acid s (2 diisopropylaminoethyl) o ethyl ester, 50782-69-9
Parathion, 3270-86-8, 56-38-2, 597-88-6
Sarin, 107-44-8; tabun, 77-81-6
Acetylcholine, 51-84-3
Adenosine, 58-61-7;
Cholinesterase Inhibitors
Cholinesterases, EC 3.1.1.8
N(6)-cyclopentyladenosine, 41552-82-3
Organothiophosphorus Compounds
Parathion, 56-38-
Phosphoric Acid Esters
Receptors, Purinergic P1
Sarin, 107-44-8
Tabun, 77-81-6
VX, 50782-69-9
To reference this document use:
http://resolver.tudelft.nl/uuid:5af04b23-6f73-4fc7-a29c-23051283cbcd
DOI
https://doi.org/10.1007/s00204-002-0395-x
TNO identifier
236420
ISSN
0340-5761
Source
Archives of Toxicology, 76 (11), 650-656
Document type
article