Acetylcholinesterase blood-brain barrier

Released ACh is broken down by membrane-bound acetylcholinesterase, often called the true or specific cholinesterase to distinguish it from butyrylcholinesterase, a pseudo-or non-specific plasma cholinesterase. It is an extremely efficient enzyme with one molecule capable of dealing with something like 10000 molecules of ACh each second, which means a short life and rapid turnover (100 ps) for each molecule of ACh. It seems that about 50% of the choline freed by the hydrolysis of ACh is taken back into the nerve. There is a wide range of anticholinesterases which can be used to prolong and potentiate the action of ACh. Some of these, such as physostigmine, which can cross the blood-brain barrier to produce central effects and neostigmine, which does not readily... 

In dogs poisoned with soman (Intravenously at 30 pg/kg) and treated with I at 104 mg/kg (Intravenously 31/2 min after soman), the large dose of I stopped aging of Inhibited cholinesterase and reactivated 24.0% and 35.6% of the red-cell and diaphragm cholinesterase activities, respectively. It failed to reactivate brain cholinesterase. Indeed, the brain acetylcholinesterase activity after the treatment with 1 was lower than that just before the injection of I. The last finding indicates the inability of I to cross the blood-brain barrier in significant quantities. 

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. 

Tacrine (THA, Cognex, 3), velnacrine (4) and SM 10888 (5) are members of the 9-amino-1,2,3,4-tetrahydroacridine family [1]. They have one common pharmacological property, that of selective inhibition of acetylcholinesterase in the central nervous system. Compared with classical anticholinesterases used in the treatment of myasthenia gravis, tacrine easily crosses the blood-brain barrier. 

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