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Protective Effect of Reversible Cholinesterase Inhibitors (Tacrine, Pyridostigmine) and Eqbuche Against Vx Poisoning and Brain Acetylcholinesterase Inhibition in Rats

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Protective Effect of Reversible Cholinesterase Inhibitors (Tacrine, Pyridostigmine) and Eqbuche Against Vx Poisoning and Brain Acetylcholinesterase Inhibition in Rats ORIGINAL ARTICLE PROTECTIVE EFFECT OF REVERSIBLE CHOLINESTERASE INHIBITORS (TACRINE, PYRIDOSTIGMINE) AND EQBUCHE AGAINST VX POISONING AND BRAIN ACETYLCHOLINESTERASE INHIBITION IN RATS Jiří Bajgar University of Defence, Faculty of Military Health Sciences, Hradec Králové, Czech Republic: Department of Toxicology Summary: The protective effect of the reversible cholinesterase inhibitors tacrine and pyridostigmine alone or in combi- nation with different drugs against acetylcholinesterase inhibition in the pontomedullar area and cerebellum of rats caused by VX agent (O-ethyl S-2-diisopropylaminoethyl methyl phosphonothiolate) in vivo (2xLD50) was studied along with sur- vival of animals pretreated with different combinations of the drugs used. The best prophylactic effect was observed in a combination of pyridostigmine with benactyzine, trihexyphenidyle and HI-6. Tacrine alone or in other combinations has had no better prophylactic effect in comparison with these combinations containing pyridostigmine. Equine butyrylcholin- esterase, also protected against VX poisoning very effectively. Key words: Benactyzine; Trihexyphenidyle; HI-6; Tacrine; VX; Rat; Prophylaxis; Acetylcholinesterase; Cerebellum; Pontomedullar area Introduction PAL was introduced into the Czech Army (3, 14). The pre- sence of these two anticholinergics allowed us to increase the Nerve agents are among the most dangereous chemical pyridostigmine dose and to increase its prophylactic efficacy. warfare agents (3, 29, 40, 45). They can be (and have been) Structurally different drugs/inhibitors were also studied. Pe- misused by terrorists (4, 31). Moreover, the whole spec- troianu et al. (34, 37) compared pretreatment with pyrido- trum of these agents of the same basic chemical structure stigmine and tiapride against paraoxon intoxication. The best covers organophosphorus insecticides (OP) – chemicals results were achieved with pyridostigmine pretreatment only. easily available, frequently used over the world and causing Some protective effects against paraoxon were achieved by professional, suicidal or accidental intoxications (4). All pretreatment with ranitidine (35) or metoclopramide (21). these facts underline the necessity to study these agents to From other studies of compounds preferably binding to the achieve better diagnosis, prophylaxis and treatment. AChE anionic site, tacrine, 7-methoxytacrine (7-MEOTA) Sarin, soman, tabun, and VX etc. are the most important and huperzine A were considered and experimentally studied representatives of the nerve agents. Keeping acetylcholin- with respect to prophylaxis against nerve agents in vitro and esterase (AChE, EC 3.1.1.7) – the main target for nerve in vivo (3, 6, 17, 27, 33). agent action – intact is a basic requirement for effective Diminishing the level of OP using enzymes which hyd- prophylaxis. It can be achieved using reversible inhibitors rolyze these agents or enzymes which bind the agents (to which are able to inhibit AChE reverzíbly, and after spon- specific proteins or to antibodies) and thus reducing the taneous recovery of the activity (decarbamylation), normal OP level and inhibition of cholinesterases – AChE and bu- AChE serves as a source of the active enzyme. Pyridostig- tyrylcholinesterase (BuChE, EC 3.1.1.8) (scavenger effect) mine and other carbamates were tested as the most pro- – in the organism can be described as detoxification (11, mising prophylactic drugs (e.g. 3, 14, 16, 33). Pyridostigmine 12, 41, 42). Another approach to prophylaxis is based on was introduced into some armies as a prophylactic antidote using present antidotes, especially reactivators such as HI- against nerve agents. Its prophylactic effect (like the effects 6 and other drugs (3, 5, 15). of other carbamates) is limited by its dose. With a higher New reversible inhibitors of acridine type or naturally dose, a higher efficacy was observed, but the side effects were occurring agents are being studied (3, 5, 32, 33). more expressed too (for a review, see 3, 5, 33). This problem The aim of this present study was to compare the pro- can be solved by adding pyridostigmine antagonizing drugs – phylactic effect of reversible acridine inhibitor – tacrine anticholinergics. The prophylactic combination of pyrido- (1,2,3,4-tetrahydroaminoacridine) and its combinations stigmine with trihexyphenidyle and benactyzine called PAN- with presently used prophylactics and equine butyrylcho- ACTA MEDICA (Hradec Králové) 2008;51(4):223–228 223 linesterase (EqBuChE) against VX in female laboratory ment of Toxicology of the Faculty of Military Health Sciences rats. Due to the high toxicity of VX, the differences in LD50 (Hradec Kralove, Czech Republic) Their purities were ana- values for male and female rats are negligible (3, 15). Si- lyzed using HPLC technique. Benactyzine a trihexypheni- multaneously, the changes in the brain AChE activity fol- dyle were products of Leciva Prague (Czech Republic). lowing in vivo administration of these drugs were studied. Equine BuChE (original activity 20 000 mU/ml) was a kind Two different parts of the brain were used: the cerebellum gift from Dr. Bhupendra Doctor, Walter Reed Army In- – roughly representing AChE activity in the whole brain, stitute of Research, Washington, USA. All other chemicals and the pontomedullar area; AChE activity in this structu- of analytical purity were obtained commercially and used re is considered to be the most sensitive to OP and antido- without further purification. All substances were adminis- tal/prophylactic countermeasures (1, 3, 7, 19). tered i.m. (i.p.) at a volume of 0.1 ml/kg body weight. Material and Methods Animals Female Wistar rats, weighing from 200 to 220 g, were Chemicals purchased from BioTest (Konarovice, Czech Republic). VX (O-ethyl S-2-diisopropylaminoethyl methyl phos- The animals were maintained in an air-conditioned room phonothiolate) was obtained from the Military Technical (22° ± 2 °C and 50 ± 10% relative humidity, with light from Institute of Protection (Brno, Czech Republic). It was of 7 a.m. to 7 p.m.), and were allowed free access to standard minimally 95% purity and stored in glass ampullas (1 ml). chow and tap water. Housing of animals took place in the The solutions of the agents for experiments were prepared Central Vivarium of the Faculty of Military Health Sciences before use. HI-6 and tacrine were synthesized at the Depart- under veterinary control. All the experiments were perfor- med under permission and supervision of the Ethic Com- Tab. 1: Schematic representation of drug administration in mittee of the Faculty of Military Health Sciences, Hradec different groups used in the experiments. The doses are gi- Kralove. ven in the text. Prophylaxis and intoxication Designation Administration The general scheme of prophylaxis and intoxication was of group first second as follows: CONT SAL saline saline Administration of prophylactic agent (in control group CONT TAC tacrine saline saline) – first administration, and 20 min. later, adminis- CONT VX saline VX tration of VX (in control group saline) – second adminis- CONT H HI-6 saline tration. The animals were decapitated and the brains were CONT Tr trasentine saline removed 60 min. after the second administration or after CONT B benactyzine saline death. Groups of 10 animals were used. Designation of CONT PYR pyridostigmine saline groups and drugs administered are summarized in Tab. 1. H-VX HI-6 VX For the doses of drugs used – see below. B-VX benactyzine VX Tr-VX trasentine VX H+Tr-VX HI-6 + trasentine VX Doses of drugs used H+B-VX HI-6 + benactyzine VX The doses and timing of drug administration were used B+Tr-VX benactyzine + trasentine VX on the basis of our previous results with tacrine (2), reacti- vators including HI-6 (3, 15), pyridostigmine, benactyzine TAC-VX (1TAC) tacrine VX TAC+B-VX (2 ) tacrine + benactyzine VX and trihexyphenidyle (3, 23, 24), and EqBuChE (8, 12), TAC respectively. The doses (except VX) represent the doses TAC+H-VX (3TAC) tacrine + HI-6 VX approximately to be used for human prophylaxis (2, 3, 8,15, TAC+B+H-VX (4TAC) tacrine + benactyzine + HI-6 VX 23). They were as follows: TAC+B+Tr-VX(5TAC) tacrine + benactyzine VX + trasentine • Tacrine 10 mg/kg, i.m.; • HI-6 15 mg/kg, i.m.; PYR-VX (1PYR) pyridostigmine VX PYR+B-VX (2PYR) pyridostigmine + benactyzine VX • Benactyzine 9 mg/kg, i.m.; PYR+H-VX (3PYR) pyridostigmine + HI-6 VX • Trihexyphenidyle 6 mg/kg, i.m.; PYR+B+H-VX (4PYR) pyridostigmine + HI-6 VX • Pyridostigmine 1 mg/kg, i.m.; PYR+B+Tr-VX (5PYR) pyridostigmine + benactyzine VX • BuChE 250 mU/kg, i.p.; + trasentine • VX 28 μg/kg, i.m., i.e. 2xLD50 dose; TAC+B+Tr+H-VX (6TAC) tacrine + benactyzine VX • saline 0.1 ml/kg; all doses are related to body weight. + trasentine + HI-6 PYR+B+Tr+H-VX (6PYR) pyridostigmine + benactyzine VX Determination of AChE activity + trasentine + HI-6 After decapitation, the brain parts (pontomedullar area BuChE-VX EqBuChE VX containing i.a. ncl. gigantocellularis /PM/ and cerebellum) 224 were prepared and frozen. After thawing, tissue was homo- TAC). All animals survived in groups with administration genized (1:10, distilled water, Ultra-Turrax homogenizer, of HI-6 and two parasympatholytics or pyridostigmine Janke and Kunkel, Germany) and homogenates were used (CONT H, CONT B, CONT Tr, CONT PYR. Following for enzymatic analysis. saline administration and VX intoxication (CONT VX), all AChE activity was determined using the method of animals died within 20–55 min (Tab. 2). Ellman et al. (13) as described elsewhere (9). Acetylthio- In experimental groups, the mortality was different de- choline was used as a substrate (TRIS-HCl buffer pH 7.6). pending on the administration of prophylactic drugs. Admi- The results were expressed as μkat/g wet weight tissue, nistration of oxime HI-6 alone, benactyzine or trihexyphe- UVIKON 752 (Germany) spectrophotometer was used for nidyle (H-VX; B-VX; Tr-VX) had no high prophylactic effect determination of absorbancy at 412 nm. The activity was – 60 % of the animals in the group died (Tab. 2). Com- also expressed as a relative % of control values.
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