Entry of Oximes into the Brain: A Review

Abstract

The passage of hydrophilic drugs, such as oxime acetylcholinesterase reactivators, into the central nervous system is restricted by the blood-brain and the blood-cerebrospinal fluid barriers. The present review summarizes morphological and functional properties of the blood-brain barrier, blood-cerebrospinal fluid barrier and cerebrospinal fluid-brain interface and reviews the existing data on brain entry of oximes. Due to the virtual absence of transcytosis, lack of fenestrations and unique properties of tight junctions in brain endothelial cells, the blood-brain barrier only allows free diffusion of small lipophilic molecules. Various carriers transport hydrophilic compounds and extrude potentially toxic xenobiotics. The blood-cerebrospinal fluid barrier is formed by the choroid plexus epithelium, whose tight junctions are more permeable than those of brain endothelial cells. The major function of plexus epithelium cells is active transport of ions for the production of the cerebrospinal fluid. The cerebrospinal fluid-brain interface is not a biological barrier and allows free diffusion. However, in contrast to passage via the blood-brain barrier or the blood-cerebrospinal fluid barrier, direct penetration from the cerebrospinal fluid into the brain is very slow, since much longer distances have to be covered. A bulk flow of brain interstitial fluid and cerebrospinal fluid speeds up exchange between these two fluid compartments. Oximes, by reactivating acetylcholinesterase, are important adjunct therapeutics in organophosphate poisoning. They are very hydrophilic and therefore cannot diffuse freely into the central nervous system. Changes in brain acetylcholinesterase activity, oxime concentration and some biological effects elicited by oxime administration in the periphery indicate, however, that oximes can gain access to the brain to a certain degree, probably by carrier-mediated transport, reaching in the brain about 4-10% of their respective plasma levels. The clinical relevance of this effect is hotly debated. Possible strategies to improve brain penetration of oximes are discussed.

A Comparison of the Neuroprotective Efficacy of Individual Oximes (Hi-6, Trimedoxime, K203) and Their Mixtures (Hi-6 + Trimedoxime, Hi-6 + K203) in Cyclosarin-Poisoned Rats

“…Unfortunately, the neuroprotective efficacy of all currently available oximes as well as newly developed oximes is rather low, probably due to poor penetration through blood-brain barrier (BBB) and low reactivating efficacy in the CNS (8,22,37). Even the oxime HI-6 that is considered to be the best reactivator of cyclosarin-inhibited AChE (6,9,10,20,21) is not satisfactorily effective oxime for the elimination of cyclosarin-induced neurotoxic signs and symptoms due to low penetration through BBB and low reactivating efficacy in the CNS (6,22).…”

“…Even the oxime HI-6 that is considered to be the best reactivator of cyclosarin-inhibited AChE (6,9,10,20,21) is not satisfactorily effective oxime for the elimination of cyclosarin-induced neurotoxic signs and symptoms due to low penetration through BBB and low reactivating efficacy in the CNS (6,22). On the other hand, it is known that the oximes may also attentuate nerve agent-induced brain insult via different mechanisms other than AChE reactivation (35).…”

“…Nevertheless, our results demonstrate that the combination of the oxime HI-6 with trimedoxime or K203 did not bring any beneficial effect for the potency of single oximes (HI-6, trimedoxime, K203) to reduce acute neurotoxic effects of cyclosarin. The absence of an increase in the neuroprotective efficacy of chosen oxime mixtures compared to tested single oximes could be explained by a limited penetration of oximes through BBB (22) and limited reactivation of nerve agent-inhibited AChE in the brain (6,9).…”

Organophosphorus compounds as chemical warfare agents: a review

“…However, all of them have three great deficiencies: (i) the utilized oximes are generally quaternary ammonium ions and, as hydrophilic compounds, have many difficulties to cross the blood-brain barrier: their concentrations in the brain are only 1 to 10% of their plasma levels. [140][141][142] As a consequence, they can reactivate only a small fraction of the inhibited AChE in the CNS; (ii) oximes do not reactivate aged phosphyl-enzymes; and (iii) unlike atropine, oximes are not effective against all OPCs, having different activities for each one of them.…”

Acid Dissociation Constants and Molecular Descriptors of Some Xylene Linked Bispyridinium Oximes

“…Oximes, in first instance, due to their polar quaternary ammoniumbased chemical structure, are far from fulfilling the minimum conditions requested for BBB penetration at an efficient concentration level. Cerebral AChE reactivation is not necessarily illustrative of oxime protective effect [13]. The explanation for the synergistic therapeutic effects of oximes together with other antidotes, resides in the peripheral effects on respiratory muscles and the increase in oxygen supply, also having indirect effects on seizures in OP intoxication, but also on other effects not correlated with the tissue.…”