Differential reactivation by HI-6 in vivo of paraoxon-inhibited rat brain acetylcholinesterase molecular forms

Abstract The effects of the cholinesterase reactivator HI-6, [1-(((4-(aminocarbonyl)-piridinio) methoxy)methyl-2-(hydroxy-imino)methyl pyridinium dichloride], on paraoxon-inhibited brain acetylcholinesterase (AChE) and its molecular forms were studied in rats. Treatment with paraoxon (0.25 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 atropine (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 1 ), were detected by sucrose gradient sedimentation. In paraoxon treated rats the G 4 form was inhibited by approx. 65% while G 1 only by 35%. The G 4 form was considerably and selectively 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 reactivates the molecular forms preferentially inhibited by paraoxon and involved in synaptic neurotransmission.