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-(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 (G4) and monomeric (G1), were detected by sucrose gradient sedimentation. In paraoxon treated rats the G4 form was inhibited by approx. 65% while G1 only by 35%. The G4 form was considerably and selectively reactivated by HI-6 while the G1 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.