SUMMARY
In this in vitro study, using the HPLC method, we determined the ability of acetylcholinesterase (AChE) reactivators, used clinically, to penetrate the blood-brain barrier (BBB). We evaluated pralidoxime, HI-6, obidoxime, trimedoxime and methoxime - reactivators varying in the position of the oxime group on the pyridinium ring and linker connecting the pyridinium rings. Our results indicated that pralidoxime, a monoquaternary AChE reactivator, was the oxime with the most penetration. Molecular weight seems to be the most important factor for passive transport through the BBB. From the structural perspective, the connecting linker also plays a key role in the ability of the reactivators to penetrate the CNS. In this case, the simple and short linker is favorable for permeation of these compounds. The location of the oxime group on the pyridine ring may also influence passive transport into the brain; the best position of the oxime group seems to be position four.
KEY WORDS
blood-brain barrier; CNS penetration; HI-6; obidoxime; HPLC; oxime
REFERENCES
Bajgar J: Organophosphates/nerve agent poisoning: mechanism of action, diagnosis, prophylaxis, and treatment. Adv Clin Chem 38:151-216, 2004.
Bajgar J, Jakl A, Hrdina V: The influence of obidoxime on acetylcholinesterase activity in different parts of the mouse brain following isopropylmethyl phosphonofluoridate intoxication. Eur J Pharmacol 19:199-202, 1972.
Bajgar J, Fusek J, Kuca K, Bartosova L, Jun D: Treatment of organophosphate intoxication using cholinesterase reactivators: facts and fiction. Mini Rev Med Chem 7:461-466, 2007a.
Bajgar J, Kuca K, Fusek J, Karasova J, Kassa J, Cabal J, Blaha V: Inhibition of blood cholinesterases following intoxication with VX and its derivatives. J Appl Toxicol 27:458-463, 2007b.
Bellawance MA, Blanchette M, Fortin D: Recent advances in blood-brain barrier disruption as a CNS delivery strategy. AAPS J 10:166-177, 2008.
Cassel G, Karlsson L, Waara L, Ang KW, Goransson-Nyberg A: Pharmacokinetics and effects of HI 6 in blood and brain of soman-intoxicated rats: a microdialysis study. Eur J Pharmacol 30:43-52, 1997.
Clark DE: Rapid calculation of polar molecular surface area and its application to the prediction of transport phenomena: Prediction of intestinal absorption potential. J Pharm Sci 88:807-814, 1999.
Eyer P: The role of oximes in the management of organophosphorus pesticide poisoning. Toxicol Rev 22:165-190, 2003.
Falb A, Erdmann WD: Penetration of 14C-obidoxime through the so-called blood-brain barrier of mice and rats. Arch Toxicol 24:123-132, 1969.
Goswany R, Chaudhuri A, Mahashur AA: Study of respiratory failure in organophosphate and carbamate poisoning. Heart Lung 23:466-472, 1994.
Gupta RC: Brain regional heterogeneity and toxicological mechanisms of organophosphates and carbamates. Toxicol Mech Methods 14:103-143, 2004.
Kalasz H, Szoko E, Tabi T, Petroianu GA, Lorke DE, Omar A, Alafifi S, Jasem A, Tekes K: Analysis of Pralidoxime in Serum, Brain and CSF of Rats. Med Chem 5:237-241, 2009.
Kassa J, Karasova J, Vasina L: The evaluation of neuroprotective efficacy of newly developed oximes (K 074, K 075) and currently available oximes (obidoxime, HI-6) in cyclosarin-poisoned rats. J Appl Toxicol 27:621-630, 2007.
Kassa J, Jun D, Karasova J, Bajgar J, Kuca K: A comparison of reactivating efficacy of newly developed oximes (K074, K075) and currently available oximes (obidoxime, HI-6) in soman, cyclosarin and tabun-poisoned rats. Chem Biol Interact 175:425-427, 2008.
Kubin L, Fenik V: Pontine cholinergic mechanisms and their impact on respiratory regulation. Respir Physiol Neurobiol 143:235-249, 2004.
Kuca K, Kassa J: Oximes-induced reactivation of rat brain acetylcholinesterase inhibited by VX agent. Hum Exp Toxicol 23:167-171, 2004.
Kuca K, Jun D, Musilek K: Structural requirements for acetylcholinesterase reactivators. Mini Rev Med Chem 6:269-277, 2006.
Kuca K, Jun D, Bajgar J: Currently used cholinesterase reactivators against nerve agent intoxication: Comparison of their effectivity in vitro. Drug Chem Toxicol 30:31-40, 2007.
Kuca K, Stodulka P, Hrabinova M, Hanusova P, Jun D, Dolezal B: Preparation of oxime HI-6 (dichloride and dimethanesulphonate)-antidote against nerve agents. Def Sci J 58:399-404, 2008.
Kuca K, Musilek K, Jun D, Pohanka M, Zdarova Karasova J, Novotny L, Musilova L: Could oxime HI-6 really be considered as "broad-spectrum" antidote? J Appl Biomed 7:143-149, 2009.
Lorke DE, Hasan MY, Nurulain SM, Sheen R, Kuca K, Petroianu GA: Entry of two new asymmetric bispiridium oximes (K-27 and K-48) into the rat brain: comparison with obidoxime. J Appl Toxicol 27:482-490, 2007.
Lorke DE, Kalasz K, Petroianu GA, Tekesz K: Entry of oximes into the brain: A review. Curr Med Chem 15:743-753, 2008.
Musilek K, Lipka L, Racakova V, Kuca K, Jun D, Dohnal V, Dolezal M: New methods in synthesis of acetylcholinesterase reactivators and evaluation of their potency to reactivate cyclosarin-inhibited AChE. Chem Pap 60:48-51, 2006.
Musilek K, Kuca K, Jun D, Dolezal M: In vitro reactivation potency of bispyridinium (E)-but-2-ene linked acetylcholinesterase reactivators against tabun-inhibited acetylcholinesterase. J Appl Biomed 5:25-30, 2007.
Palm K, Luthman K, Ungell AL, Strandlung G, Beigi F, Lundahl P: Evaluation of dynamic polar molecular surface area as predictor of drug absorption: comparison with other computational and experimental predictors. J Med Chem 41:5382-5392, 1998.
Petroianu GA, Lorke DE, Hasan YM, Adem A, Sheen R, Nurulain SM, Kalasz H: Paraoxon has only a minimal effect on pralidoxime brain concentration in rats. J Appl Toxicol 27:350-357, 2007.
Sakurada K, Matsubara K, Shimizu K, Shiono H, Seto Y, Tsuge K, Yoshino M, Sakai I, Mukoyama H, Takatori T: Pralidoxime iodide (2-PAM) penetrates across the blood brain barrier. Neurochem Res 28:1401-1407, 2003.
Sungur M, Guven M: Intensive care management of organophosphate insecticide poisoning. Crit Care 5:211-215, 2001.
Yoon HCh, Kim SJ, Shin BS, Lee KCh, Yoo SD: Rapid screening of blood-brain barrier penetration of drugs using the immobilized artificial memebrane phosphatidylchline column chromatography. J Biomol Screen 11:13-20, 2006.
Zdarova Karasova J, Kassa J, Jung Y-S, Musilek K, Pohanka M, Kuca K: Effect of Several new and currently available oxime cholinesterase reactivators on tabun-intoxicated rats. Int J Mol Sci 9:2243-2252, 2008.
Zdarova Karasova J, Bajgar J, Novotny L, Kuca K: Is a high dose of Huperzine A really suitable for pretreatment against high doses of soman? J Appl Biomed 7:93-99, 2009.
Zdarova Karasova J, Stodulka P, Pohanka M, Kuca K (2010): In vitro screening of blood-brain barrier penetration of monoquaternary acetylcholinesterase reactivators. Anal Lett - In press. DOI 10.1080/00032710903502082.
Zhu C, Jiang L, Chen TM, Hwang KK: A comparative study of artificial membrane permeability assay for high throughput profiling of drug absorption potential. Eur J Med Chem 37:399-407, 2002.
|
CITED
Berger J. The age of biomedicine: current trends in traditional subjects. J Appl Biomed. 9: 57-61, 2011.
Zdarova Karasova J, Zemek F, Bajgar J, Vasatova M, Prochazka P, Novotny L, Kuca K. Partition of bispyridinium oximes (trimedoxime and K074) administered in therapeutic doses into different parts of the rat brain. J Pharm Biomed Anal. 54: 1082-1087, 2011.
Zdarova Karasova J, Pohanka M, Musilek K, Zemek F, Kuca K. Passive diffusion of acetylcholinesterase oxime reactivators through the blood-brain barrier: Influence of molecular structure. Toxicol in Vitro. 24: 1838-1844, 2010.
Zdarova Karasova J, Kassa J, Pohanka M, Musilek K, Kuca K. Potency of HI-6 to Reactivate Cyclosarin, Soman and Tabun Inhibited Acetylcholinesterase - In Vivo Study. Lett Drug Des Discovery. 7: 516-520, 2010.
Zdarova Karasova J, Stodulka P, Pohanka M, Kuca K. In vitro screening of blood-brain barrier penetration of monoquaternary acetylcholinesterase reactivators. Anal Lett. 43: 1516-1524, 2010.
|
