Blood-brain barrier reactivator penetration

De La Manche, I.S., Verge, D.E., Bouchaud, C., Coq, H., Sentenac-Roumanou, H. 1979. Penetration of oximes across the blood-brain barrier. A histochemical study of the cerebral cholinesterases reactivation. Experlentia 35 531-532. 

Two other oximes (49, 50) are very interesting when considering blood-brain barrier penetration. They have instead only the quaternary nitrogen, the tertiary nitrogen having no charge. Unfortunately, such structure modification decreased their reactivation potency (Oh et al., 2008). 

Ai-methylpyridinium-2-carbaldoxime (2-PAM = a Figure 36.30b) constitutes the most potent reactivator of acetylcholinesterase poisoned by organophosphorus acylation. However, due to its quaternary nitrogen, 2-PAM penetrates the biological membranes poorly and does not appreciably cross the blood-brain barrier. For this compound Bodor et designed an ingenious dihydropyridine-pyridinium salt type of redox delivery system. The active drug is administered as its 5,6-dihydropyridine derivative (Pro-2-PAM = b), which exists as a stable immonium salt c. The lipoidal b (pA"a = 6.32) easily penetrates the blood-brain barrier where it is oxidized to the active a. 

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 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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