title: Adenosine A1 receptor agonist N6-cyclopentyladenosine affects the inactivation of acetylcholinesterase in blood and brain by sarin.
abstract: The objective of the present study was to develop a kinetics of pharmacodynamics model to properly describe and investigate the in vivo interaction between the selective adenosine A(1) agonist N(6)-cyclopentyladenosine (CPA), acetylcholinesterase (AChE) in blood and brain, and the AChE-inhibitor sarin (isopropylmethylphosphonofluoridate). The direct interaction of CPA (2 microM) on the inhibition of AChE by sarin was studied in vitro in heparinized rat blood and in 10% (w/v) brain homogenate. CPA did not directly influence the sarin-mediated inactivation of AChE in either system. In sarin-poisoned (144 microg/kg s.c.) rats not treated with CPA, AChE was completely inactivated in blood and brain within 7 min. CPA (2 mg/kg i.m.) treatment, 1 min after sarin administration, caused a small delay in the inhibition of AChE in blood. Treatment with CPA, 2 min before sarin, protected the neuronal AChE partially from being inhibited, but not the enzyme localized in blood. With a dose-response-time model the proportion of the dose of sarin reaching the site of action was estimated to be 48 +/- 12 or 13 +/- 3% after CPA post- or pretreatment, respectively. A correlation between the residual AChE activity in the brain and the incidence of cholinergic symptoms could be established with logistic regression analysis: lower inhibition of AChE in the brain precluded the onset of critical symptoms. In conclusion, CPA affects the concentration of sarin reaching the site of action, which contributes to the protection previously observed in sarin-poisoned rats.
authors.affiliation: Research Group Medical Countermeasures, TNO Prins Maurits Laboratory, Rijswijk, The Netherlands.
authors.forename: Tjerk J H
authors.initials: TJ
authors.lastname: Bueters
authors.forename: Marloes J A
authors.initials: MJ
authors.lastname: Joosen
authors.forename: Herman P M
authors.initials: HP
authors.lastname: van Helden
authors.forename: Ad P
authors.initials: AP
authors.lastname: Ijzerman
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
mesh_terms: D000110:Acetylcholinesterase / Q000097:blood*; D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D001769:Blood / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D002800:Cholinesterase Inhibitors / Q000493:pharmacokinetics / Q000633:toxicity*; D004347:Drug Interactions; D008297:Male; D008954:Models, Biological; D051381:Rats; D017208:Rats, Wistar; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D012524:Sarin / Q000493:pharmacokinetics / Q000633:toxicity*; D014018:Tissue Distribution
chemical_list: D002800:Cholinesterase Inhibitors; D018047:Receptors, Purinergic P1; C048599:N(6)-cyclopentyladenosine; D012524:Sarin; D000110:Acetylcholinesterase; D000241:Adenosine