Blood–Brain Barrier Unlocked

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N. Goldstein^1,2*, R. Goldstein¹, D. Terterov³, A. A. Kamensky¹, G. I. Kovalev⁴, Yu. A. Zolotarev⁵, G. N. Avakyan⁶, and S. Terterov⁷

¹Department of Human and Animal Physiology, Biological Faculty, Lomonosov Moscow State University, 119991 Moscow, Russia; E-mail: dr.naum.goldstein@googlemail.com; roman.goldstein@gmail.com; Kamensky@5.Human.bio.msu.ru

²Senior Experten Service (SES), Buschstrasse 2, 53113 Bonn, Germany

³Discipline of Surgery, Faculty of Medicine, Memorial University of Newfoundland, Health Sciences Centre, 300 Prince Philip Drive, St. John’s, NL A1B 3V6, Canada; E-mail: dterterov@mun.ca

⁴Zakusov Institute of Pharmacology, Russian Academy of Medical Sciences, ul. Baltiiskaya 8, 125315 Moscow, Russia; E-mail: kovalev_g@m9com.ru

⁵Institute of Molecular Genetics, Russian Academy of Sciences, pl. Kurchatova 2, 123182 Moscow, Russia; E-mail: zolya@img.ras.ru

⁶Department of Neurology and Neurosurgery, Russian State Medical University, ul. Ostrovityanova 1, 117997 Moscow, Russia; E-mail: gavakyan@yandex.ru

⁷Department of Neurosurgery, University of California Los Angeles, 18-228 Semel, Box 957039, Los Angeles, CA, 90095-7039, USA; E-mail: STerterov@mednet.ucla.edu

^* To whom correspondence should be addressed.

Received January 15, 2012; Revision received January 23, 2012

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The brain is protected by a physiological blood–brain barrier (BBB) against toxins and some metabolites circulating in the blood. At the same time, the BBB limits penetration into the brain of many neuroactive drugs. Efficient ways to increase BBB permeability for delivery of drugs of different chemical nature into the brain are unknown. This work deals with delivery into the brain of 10^–2 M dopamine, a substance that does not penetrate the BBB under normal circumstances. It was studied in two independent experiments: (i) penetration of ³H-labeled dopamine from its mixture with 10^–5 M H₂O₂ into hypothalamus and striatum structures of intact rat brain, and (ii) effect of unlabeled dopamine from a mixture with H₂O₂ on the rat motor activity in a haloperidol catalepsy model. It was shown that (i) at the third minute after nasal application of the dopamine + H₂O₂ mixture, the dopamine level increases 45-fold in the hypothalamus and almost 30-fold in the striatum and (ii) motility of animals in the catalepsy haloperidol model is recovered 90 sec after intranasal introduction of dopamine. No such effects were observed after replacement of H₂O₂ by 0.9% NaCl solution. Thus, it was shown on the example of dopamine that its introduction into the nasal cavity simultaneously with H₂O₂ provides for rapid delivery of the drug into the brain. These results expand our knowledge concerning the biological role of exoROS in modulating BBB permeability and may contribute to the development of a new therapeutic strategy for neurological diseases.

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KEY WORDS: blood–brain barrier, reactive oxygen species, hydrogen peroxide, ³H-labeled dopamine, haloperidol induced catalepsy

DOI: 10.1134/S000629791205001X

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