Blood-brain barrier AChE reactivating oximes

Although the major research and development effort on oxime reactivators has focused on the positively charged pyridinium ring, the poor ability of the charged oximes to cross the blood-brain barrier (BBB) has prompted several studies on noncharged aliphatic oximes in an effort to increase reactivation of OP-inhibited AChE in the central nervous system. The most smdied noncharged oximes are mono isonitrosoacetone (MINA, 44) and diacetyl monoxime (DAM, 45) " . 

The ability of pralidoxime, obidoxime and methoxime to reactivate sarin-inhibited AChE in rat diaphragm and brain is relatively low although methoxime seems to be better reactivator of sarin-inhibited AChE in vivo than expected on the basis of its in vitro reactivation potency (23). H oximes (HI-6, HLp-7) are very efficacious reactivators of sarin-inhibited AChE especially in diaphragm (23). However, they also seem to be good reactivators of sarin-inhibited AChE in the central compartment in spite of their quaternary structure that limits their penetration across the blood-brain barrier. 

The reactivation of AChE allows ACh to be hydrolyzed in the normal way, and therefore normal cholinergic neuro-transmission will resume. It is usually considered that the beneficial effects of oximes in OP poi.soning arc confined to peripheral nicotinic sites and that CNS effects are clinically insignificant (Bismuth etaL, 1992), although there is evidence that PAM can cross the blood-brain barrier (Sakurada etaL, 2003). This means that the beneficial effects will mainly be on neuromuscular transmission, and that there will be little action on parasympathetic effects, such as bronchoirhea, bronchoconstriction, and rhinorrhea, or on CNS effects. 

The crucial question dealing with the reactivator s effect on the central nervous system was discussed in the past. Because of their quaternary structure, at intact BBB, the penetration of the reactivators is slow. In order to reach an effective concentration of the reactivator in CNS, its extremely high plasma concentration is necessary. On the other hand, some authors (E3, FI, H12) have suggested that the central reactivation effect exists. It is known from other results that the inhibition and reactivation of AChE in the brain is selective for different OP (B6, B7, B33) and following administration of the reactivators to nerve agent-intoxicated animals, reactivation of AChE in different parts of the brain was demonstrated (B19, B20, B24). The ability of oximes to penetrate the blood-brain barrier was confirmed by Sakurada et al. (SI). 

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