Bile acid derivatives as blood-brain barrier modifiers
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1
University of Novi Sad, Department of Pharmacology, Toxicology and Clinical Pharmacology, Medical Faculty, Russia
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2
University of Novi Sad, Faculty of Science, Russia
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3
University of Novi Sad, Faculty of Agriculture, Russia
The Blood-Brain Barrier (BBB) is composed by the endothelial cell lining of the brain capillaries linked by tight junctions, basement membrane, pericytes and astroglial foot processes. The BBB limits the entry of many molecules into the brain and is active in exporting molecules if they penetrate in it. Apart from the physicochemical properties of drugs like charge, lipophylicity and molecular weight, an important role is played by drug transporters. The understanding of the modification of the BBB and the interplay between its functional parts is crucial for central nervous system (CNS) activity, side effects and toxicity of different drugs and other xenobiotics as well as endogenous substrates (1,2,3). The lack of proper animal and in vitro models which can resemble human BBB makes it difficult to translate findings to humans.
Bile acids are amphiphilic steroids which have been studied as therapeutic agents as well as enhancers of permeability through different biological membranes (4). There are some studies on the influence of natural bile acids on the BBB but very few were performed with synthetic bile acids. Unconjugated cholic, deoxycholic and chenodeoxycholic acids were shown to be present in the cytoplasmic fraction of rat brain, suggesting that bile acids may play a significant role in CNS function (5). There are more than 500 bile acid analogues which are potential drugs and permeation modifiers. In order to test the efficacy of the semisynthetic bile acid derivatives, the sodium salt of 3α,7α- dihydroxy-12-oxo-5β-cholanate (MKC-Na) and the methyl ester of 3α,7α-dihydroxy-12- oxo-5β-cholanate (MKC-Me), as BBB-permeation modifiers, we studied their effect on quinine uptake into the central nervous system in rats. In our studies we have shown the potentiation of the analgesic effect of morphine given in combination with MKC-Na (6,7). MKC-Na is less toxic than natural bile acid salts, neither solubilizing plasma membranes nor opening tight junctions. We also showed in our previous paper that MKC-Na displays different physicochemical and biological properties as compared with natural bile salts. It does not show strong membrane-solubilizing properties, but modulates mechanical properties of phospholipid monolayers, intercalates the cell membrane and affects membrane fluidity, which may enhance passive diffusion and indirectly affect transporters (8).
Experiments were carried out using Wistar rats in accordance with the National Institutes of Health Guide. Thirty minutes before injecting quinine to the right a. axillaris, the animals of the test group were given s.c. a solution of MKC-Na in a dose of 2 mg/kg; the second group received s.c. MKC-Me in a dose of 2 mg/kg; the control animals received s.c. a saline solution. Animals of all groups were given quinine at a dose of 25 mg/kg by a retrograde bolus injection to the right a. axillaris. Before decapitation the brain was washed with 5 ml of saline solution injected to the left heart ventricle. The animals were decapitated 30, 60, 150, and 240 s after quinine injection. The cranial bones were resected and the brain tissue divided into: cerebrum, brain stem, and cerebellum. After weighing, the particular brain parts were homogenized in a 4-fold volume of distilled water. The quinine was extracted from the homogenates and analyzed by the method of Cram’er and Isaksson.
Given with MKC-Na, quinine uptake by the cerebrum was increased 2.3 times, by brain stem 1.5 times, and by cerebellum 1.7 times, in comparison to the control. On the contrary, given with MKC-Me, quinine uptake by the cerebrum was decreased to 0.41, by brain stem to 0.39, and by cerebellum to 0.32, in comparison to the control.
Effect of MKC-Na and MKC-Me on quinine uptake in the CNS in the rat. Each value represents the mean±SD (n=6)
References
1. Urquhart B.L. and Kim RB (2009) Eur J Clin Pharmacol 65: 1063-1070
2. Shalev H. et al. (2009) Cardiovasc Psych Neurology 2009: 1-7
3. Kusuhara H. and Sugiyama Y. (2001) DDT 6: 150-156
4. Mikov M. and Fawcet P. (eds) (2007) Bile acids, MedisetPublisher Geneva
5. Mano N. et al. (2004) J Lipid Res 45: 295-300
6. Kuhajda I. et al (2009) Eur J Drug Metab Pharmacokin 34: 73-78
7. Mikov M. et al (2004) Pol J Pharmacol 56: 367-371
8. Yang l. et al (2009) Mol Pharmaceutics 6: 448-456
Conference:
Pharmacology and Toxicology of the Blood-Brain Barrier: State of the Art, Needs for Future Research and Expected Benefits for the EU, Brussels, Belgium, 11 Feb - 12 Feb, 2010.
Presentation Type:
Oral Presentation
Topic:
Presentations
Citation:
Mikov
M,
V
V,
S
G,
K
K,
S
K and
V
J
(2010). Bile acid derivatives as blood-brain barrier modifiers.
Front. Pharmacol.
Conference Abstract:
Pharmacology and Toxicology of the Blood-Brain Barrier: State of the Art, Needs for Future Research and Expected Benefits for the EU.
doi: 10.3389/conf.fphar.2010.02.00009
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Received:
23 Feb 2010;
Published Online:
23 Feb 2010.
*
Correspondence:
Momir Mikov, University of Novi Sad, Department of Pharmacology, Toxicology and Clinical Pharmacology, Medical Faculty, Novi Sad, Russia, mikovmomir@gmail.com