DIFFERENTIAL REACTIVATION BY HI-6 IN-VIVO OF PARAOXON-INHIBITED RAT-BRAIN ACETYLCHOLINESTERASE MOLECULAR-FORMS

The effects of the cholinesterase reactivator HI-6, [1-(((4-(aminocarb onyl)-piridinio) methoxy)methyl-2-(hydroxy-imino)methyl pyridinium dic hloride], on paraoxon-inhibited brain acetylcholinesterase (AChE) and its molecular forms were studied in rats. Treatment with paraoxon (0.2 5 mg/kg s.c.) caused approx. 60% inhibition of total AChE from frontal cerebral cortex, while that including HI-6 (140 mg/kg i.m.) and atrop ine (50 mg/kg i.m.) reduced such inhibition to only 25%. Two molecular forms of the enzyme, 10S and 4S, corresponding to globular tetrameric (G(4)) and monomeric (G(J)), were detected by sucrose gradient sedime ntation. In paraoxon treated rats the G(4) form was inhibited by appro x. 65% while G(1) only by 35%. The G(4) form was considerably and sele ctively reactivated by HI-6 while the G(1) form was not reactivated at all. The data show that HI-6 penetrates the blood-brain barrier and r eactivates the molecular forms preferentially inhibited by paraoxon an d involved in synaptic neurotransmission.