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Rat Model of Blood-brain Barrier Disruption to Allow Targeted Neurovascular Therapeutics

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Increasing oxime efficacy by blood-brain barrier modulation.

Marloes J A Joosen¹, Marcel J van der Schans, Christian G M van Dijk

¹TNO Earth, Environmental and Life Sciences, CBRN Protection, P.O. Box 45, 2280 AA Rijswijk, The Netherlands. Marloes.joosen@tno.nl

Toxicology Letters

|May 24, 2011

Summary

To improve nerve agent poisoning treatment, researchers found that blocking the P-glycoprotein (Pgp) transporter in the blood-brain barrier (BBB) significantly increased oxime drug levels in the brain, enhancing efficacy.

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Area of Science:

Neuroscience
Pharmacology
Toxicology

Background:

Nerve agent poisoning is a critical threat, and current treatments using oximes are limited by poor blood-brain barrier (BBB) penetration.
Oximes, crucial for reactivating inhibited enzymes, struggle to reach effective concentrations in the brain due to efflux transporters like P-glycoprotein (Pgp).

Purpose of the Study:

To investigate if inhibiting Pgp can enhance the brain penetration and efficacy of the oxime HI-6 in treating nerve agent poisoning.
To evaluate the therapeutic potential of modulating BBB transport for improved medical countermeasures against nerve agents.

Main Methods:

Quantitative brain microdialysis in rats to measure HI-6 levels in plasma and brain after co-administration with the Pgp inhibitor tariquidar.
A proof-of-concept study in rats assessing the protective effects of tariquidar, HI-6, and atropine against soman-induced seizures and convulsions.

Main Results:

Tariquidar administration resulted in a twofold increase in brain HI-6 levels within the first hour, with no significant change in plasma levels.
Rats pretreated with tariquidar, HI-6, and atropine were almost completely protected from soman-induced seizures and convulsions.
Acetylcholinesterase (AChE) activity in the brains of treated rats was double that of control rats.

Conclusions:

Inhibiting Pgp at the BBB with tariquidar effectively enhances oxime (HI-6) delivery to the brain.
Modulating BBB transport represents a promising strategy to improve the efficacy of oximes as medical countermeasures against nerve agent poisoning.
Tariquidar, a non-toxic Pgp inhibitor, shows significant value in enhancing oxime-based treatments.