Neuroprotective and cerebrovascular effects of endogenous N-Arachidonoyl-GABA and its putative Cox-2 metabolite – GABA conjugate with Prostaglandin E2

Narine R. Mirzoyan; Nelly G. Khostikyan; Vahe S. Meliksetyan; Arpine A. Hakobyan; Tamara S. Gan’shina; Melanya G. Baghdasaryan; Anna M. Arakelyan; Anna V. Gnezdilova; Elena V. Kurza; Natalia M. Gretskaya; Vladimir V. Bezuglov; Lusine Danielyan; Ruben S. Mirzoyan

doi:10.3897/rrpharmacology.7.70974

Authors

Narine R. Mirzoyan Yerevan State Medical University after M. Heratsi https://orcid.org/0000-0001-5570-488X
Nelly G. Khostikyan Yerevan State Medical University after M. Heratsi
Vahe S. Meliksetyan Yerevan State Medical University after M. Heratsi
Arpine A. Hakobyan Yerevan State Medical University after M. Heratsi
Tamara S. Gan’shina V.V. Zakusov Research Institute of Pharmacology https://orcid.org/0000-0003-0442-1761
Melanya G. Baghdasaryan Yerevan State Medical University after M. Heratsi
Anna M. Arakelyan Yerevan State Medical University after M. Heratsi
Anna V. Gnezdilova V.V. Zakusov Research Institute of Pharmacology https://orcid.org/0000-0002-8439-2683
Elena V. Kurza V.V. Zakusov Research Institute of Pharmacology https://orcid.org/0000-0002-5394-5839
Natalia M. Gretskaya Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of Russian Academy of Sciences
Vladimir V. Bezuglov Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of Russian Academy of Sciences https://orcid.org/0000-0001-8439-8607
Lusine Danielyan University Hospital of Tuebingen https://orcid.org/0000-0003-4130-8477
Ruben S. Mirzoyan V.V. Zakusov Research Institute of Pharmacology https://orcid.org/0000-0002-7542-8904

DOI:

https://doi.org/10.3897/rrpharmacology.7.70974

Abstract

Introduction: The aim of the study was to compare the neuroprotective and cerebrovascular effects of bioactive, endogenous lipid – N-arachidonoyl-GABA (AA-GABA) and GABA conjugate with prostaglandin E2 (PGE2-GABA) by evaluation of a morphological state of rat brain tissue and lipofuscin levels under the condition of permanent focal brain ischemia, as well as cerebral circulation under the condition of global transient ischemia.

Materials and methods: The study has been implemented using the models of the left middle cerebral artery occlusion (MCAO) and global transient ischemia of the brain. A morphological examination of the brain tissue, a registration of local blood flow by laser flowmeter, and quantitative measurement of lipofuscin by fluorescence spectroscopy were used.

Results and discussion: AA-GABA and the putative COX-2 metabolite PGE2-GABA showed significant neuroprotective and cerebrovascular effects in rat models of global and focal cerebral ischemia. In the MCAOmodel, AA-GABA and PGE2-GABA at a dose of 2 mg/kg/day administered i.p. for 6 or 12 days led to: 1) significant restoration of neurons and glial cells with intracellular regeneration of cytoplasmic and nuclear structures, 2) decrease in brain tissue edema; 3) attenuated thrombosis and stasis, and 4) absence of large necrotic foci in rat brain tissue. AA-GABA and PGE2-GABA at the same dose prevented excessive accumulation of lipofuscin in both brain hemispheres in rats with MCAO. All the studied compounds increase cerebral blood circulation in rats subjected to global transient ischemia. However, the cerebrovascular effect of PGE2-GABA was superior to the activity of AA-GABA and all other tested compounds. AA-GABA and PGE2-GABA, unlike PGE2 and nimodipine, increase the cerebral blood flow in rats with global transient brain ischemia and have no influence on the intact animals. Apparently, the GABAergic vascular system of the brain is involved in the mechanisms of the neuroprotective action of AA-GABA and PGE2-GABA.

Conclusion: For the first time, we demonstrated the ability of AA-GABAand its putative metabolite COX-2 PGE2-GABA to improve cerebral circulation, attenuate structural damage and lipofuscin accumulation during cerebral ischemia. The natural origin of AA-GABA, which possesses neuroprotective and cerebrovascular activity, as well as anti-aggregatory activity, allows considering AA-GABA as one of the endogenous protective factors in ischemic brain lesions.

Keywords:

PGE2-GABA, AA-GABA, nimodipine, ethylmethylhydroxypyridine succinate (mexidol), focal permanent ischemia, global transient ischemia, brain tissue, lipofuscin, cerebral blood flow, bicuculline, GABAA-receptors

Author Contribution

Narine R. Mirzoyan, Yerevan State Medical University after M. Heratsi

Doctor Habil. of Medical Sciences, Professor, Head, Clinical Pharmacology Department, e-mail: nanamirzoyan@gmail.com, ORCID ID https://orcid.org/0000-0001-5570-488X. The author had a leading role in planning and conducting the experiments to study the neuroprotective activity of the substances, analyzing the data and the literature, and writing the article.

Nelly G. Khostikyan, Yerevan State Medical University after M. Heratsi

Doctor Habil. of Medical Sciences, Professor, Former Head, Department of pathological anatomy and Clinical Morphology. The author participated in planning the experiments to study the neuroprotective activity of the substances, analyzing the literature, and interpreting the data.

Vahe S. Meliksetyan, Yerevan State Medical University after M. Heratsi

Former Lecturer, Clinical Pharmacology Department. The author participated in planning the experiments to study the neuroprotective activity of the substances, analyzing the literature, and interpreting the data.

Arpine A. Hakobyan, Yerevan State Medical University after M. Heratsi

Lecturer, Clinical Pharmacology Department, e-mail: arpine.h@rambler.ru.The author participated in studying the neuroprotective activity of the substances, analyzing the literature, and interpreting the data.

Tamara S. Gan’shina, V.V. Zakusov Research Institute of Pharmacology

Doctor Habil. of Biological Sciences, Professor, Lead Researcher, Laboratory of Pharmacology of Cerebrovascular Disorders, e-mail: toma2902@mail.ru,ORCID ID https://orcid.org/0000-0003-0442-1761. The author participated in planning the experiments to study the cerebrovascular activity of the substances, analyzing the literature, interpreting the data, and reviewing the manuscript.

Melanya G. Baghdasaryan, Yerevan State Medical University after M. Heratsi

PhD in Medical Sciences, Associate Professor, Clinical Pharmacology Department, e-mail: melanyabag@gmail.com. The author participated in planning the experiments to study the neuroprotective activity of the substances, analyzing the literature, and interpreting the data.

Anna M. Arakelyan, Yerevan State Medical University after M. Heratsi

Lecturer, Clinical Pharmacology Department, e-mail: arakelyan-machkalyan@gmail.com. The author participated in studying the neuroprotective activity of the substances, analyzing the literature, and interpreting the data.

Anna V. Gnezdilova, V.V. Zakusov Research Institute of Pharmacology

PhD in Biological Sciences, Senior Researcher, Laboratory of Pharmacology of Cerebrovascular Disorders, e-mail: the_luxory@mail.ru, ORCID ID https://orcid.org/0000-0002-8439-2683. The author participated in planning the experiments to study the cerebrovascular activity of the substances, analyzing the literature, and interpreting the data.

Elena V. Kurza, V.V. Zakusov Research Institute of Pharmacology

PhD in Biological Sciences, Researcher, Laboratory of Pharmacology of Cerebrovascular Disorders, e-mail: duxlink@yandex.ru, ORCID ID https://orcid.org/0000-0002-5394-5839. The author participated in planning the experiments to study the cerebrovascular activity of the substances, analyzing the literature, and interpreting the data.

Natalia M. Gretskaya, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of Russian Academy of Sciences

Doctor Habil. of Chemical Sciences, Senior Research Worker, Laboratory of Oxylipins, e-mail: natalia.gretskaya@gmail.com. The author had a role in the compound synthesis, analyzing the data and the literature, and reviewing the manuscript.

Vladimir V. Bezuglov, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of Russian Academy of Sciences

Doctor Habil. of Chemical Sciences, Professor, Head, Laboratory of Oxylipins, e-mail: vvbez@ibch.ru, ORCID ID https://orcid.org/0000-0001-8439-8607. The author had a role in conceptualization, analyzing the data and the literature, and reviewing the manuscript.

Lusine Danielyan, University Hospital of Tuebingen

Doctor Habil. of Medical Sciences, Assistant Professor, Head of Laboratory, Vice Director of the Department of Clinical Pharmacology. e-mail: lusine.danielyan@med-uni-tebingen.de, ORCID ID https://orcid.org/0000-0003-4130-8477. The author contributed to the analysis of the literature, data interpretation and article reviewing.

Ruben S. Mirzoyan, V.V. Zakusov Research Institute of Pharmacology

Doctor Habil. of Medical Sciences, Professor, Head, Laboratory of Pharmacology of Cerebrovascular Disorders, e-mail: cerebropharm@mail.ru, ORCID ID https://orcid.org/0000-0002-7542-8904. The author had a leading role in conceptualization, planning the experiments to study the cerebrovascular activity of the substances, analyzing the data and the literature, and writing the article.