Anticholinesterase Poisons – Biological Effects Of New Antidotes

The Ministry of Science, Education and Sports of the Republic of Croatia (2002-2006)

Principal Investigator: Božica Radić

A toxic effects of anticholinesterases (organophosphorous compounds (OPs) with highly toxic nervous warfare agents and carbamates) is irreversible inhibition of hydrolytic enzymes: acethylcholinesterase (AChE), the enzyme of vital importance, and buthyrilcholinesterase (BuChE).

The physiological role of AChE is to hydrolyse the neurotransmitter acethylcholine released in the process of cholynergic transmission of nerve impulses. AChE inhibited by OPs and carbamates does not hydrolyse acethylcholine. The consequence is the blocking of nerve impulses in the central and peripheral nervous system. The therapy of anticholinesterase poisoning includes specific drugs, called antidotes (atropine, oximes etc.). As there is no universal therapy for anticholinesterase poisoning, research of new antidotes aims at finding better therapeutic solutions. We are investigating in vitro and in vivo abilities of new potential antidotes: pyridinium compounds and derivatives of tenocyclidine-adamantane. Terrorist activities in the world have shown that chemical warfare agents are the still a threat, and have given new impulse and importance to this type of research.

A part of this project is focused on investigation of the efficiency of new antidotes on inhibited AChE. The physiologic role of BuChE is unknown. Scarce literature data show that BuChE is involved in the metabolism of lipids.

Additionally this project proposes to investigate the effects of BuChE inhibition on changes in the concentrations of  lipids (cholesterol and triglycerides) and lipoproteins (HDL, LDL, IDL) in rat’s plasma, as well as the activity of some enzymes involved in the metabolism of lipoproteins (lipoprotein lipase, lecitin-cholesterol-acyl transferase). The results may have clinical application in the diagnosis of patients with hiperlipidemia. Research will be performed in vitro and in vivo on experimental animals (mice, rats).