NEUROIMMUNOMODULATORY INFLUENCE OF SPLEEN LYMPHOCYTES MODIFIED WITH SYNTHETIC BENZODIAZEPINE RECEPTOR LIGAND IN EXPERIMENTAL ALCOHOLISM
DOI: 10.22138/2500-0918-2025-22-4-419-433 (In Russ)
I.V. Savkin, E.V. Markova
Scientific Research Institute of Clinical immunology, Siberian Branch,
Academy of Medical Sciences of Russia, Novosibirsk, Russian Federation
Abstract. Prolonged use of ethanol leads to a violation of the functional phenotype of lymphocytes, which is an essential link in the pathogenesis of alcoholism. GABA/Benzodiazepine receptor complex (GABA/BDR) is a molecular target of ethanol on cells, potentiating the effects of alcohol. We first have demonstrated that the original compound ortho-fluorobenzonal (o-FB), a synthetic BDR ligand, has immunomodulatory properties and is able to restore in vitro lymphocyte activity in long-term alcoholized mice. The aim of the work was to study the neuroimmunomodulatory effect of spleen lymphocytes modified in vitro with o-FB in the long-term alcoholized syngeneic recipient. Materials and methods. The study was performed on long-term alcoholized male mice (CBAxC57BL/6) F1 aged 10-11 months (10% ethanol solution for 6 months as the only source of fluid), which were used as donors and recipients of spleen lymphocytes. These cells were modified in vitro with o-FB. After systemic administration of these cells, the recipients' behavioral patterns characteristic of alcoholism and indicators of the functional activity of the immune and nervous systems were evaluated. Results. It was found that after intravenous administration of in vitro o-FB-modified splenic lymphocytes in long-term alcoholized syngeneic recipients a decrease in alcohol motivation, stimulation of motor and exploratory activities in the «Open Field» test was recorded. At the same time, in certain brain structures, a modulation of the quantitative content of a number of cytokines is observed towards a decrease in a number of pro-inflammatory ones (IL-1β, IL-6, TNF-α and IFN-γ) and an increase in IL-10, a cytokine with anti-inflammatory activity. Changes in the cytokine profile in the brain were accompanied by an increase in BDNF levels in the hippocampus. The immunomodulatory effect of o-FB-modified lymphocytes was manifested in the stimulation of humoral and cellular immune responses, assessed by the relative number of antibody-forming spleen cells and the level of delayed-type hypersensitivity reaction, respectively. as well as in increasing spontaneous and mitogen-induced proliferative activity of splenocytes. Conclusion. o-FB-modified splenic lymphocytes in the body of a syngeneic long-term alcoholized recipient have a pronounced neuroimmunomodulatory effect, correcting behavioral patterns characteristic of alcoholism, inhibiting neuroinflammation and positively influencing neuroplasticity, which is an experimental justification for the prospects of immunotherapy of alcoholism based on autologous immunocompetent cells modified ex vivo with synthetic BDR ligands.of alcoholism using autologous immune cells modified ex vivo with synthetic BDR ligands.
Keywords: long-term alcoholized mice, ortho-fluorobenzonal, spleen lymphocytes, immune response, cytokines, brain neurotrophic factor, behavior
There is no conflict of interest.
Contact details of the corresponding author:
Ivan V. Savkin
i.v.savkin2020@yandex.ru
Recieved 25.04.2025
For citation: Savkin I.V., E.V. Markova E.V. Neuroimmunomodulatory influence of spleen lymphocytes modified with synthetic benzodiazepine receptor ligand in experimental alcoholism. [Online] Vestn. Ural. Med. Akad. Nauki. = Journal of Ural Medical Academic Science. 2025, Vol. 22, no. 4, pp. 419–433. DOI: 10.22138/2500-0918-2025-22-4-419-433 (In Russ)
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Authors
Ivan V. Savkin
Researcher of Neuroimmunology Laboratory
i.v.savkin2020@yandex.ru
Evgeniya V. Markova
MD, PhD, D.Sc., Chief Researcher and Head of Neuroimmunology Laboratory
evgeniya_markova@mail.ru
Federal State Budgetary Scientific Institution “Research Institute of Fundamental
and Clinical Immunology”
Novosibirsk, Russian Federation