EFFECT OF IN VITRO CAFFEINE-MODULATED IMMUNE CELLS ON THE INFLAMMATORY RESPONSE IN TRAUMATIC BRAIN INJURY



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Abstract

Abstract

Introduction. The inflammatory response, developing in response to brain injury, plays a crucial role in the pathogenesis of traumatic brain injury (TBI). This response contributes to resolving the consequences of brain damage while simultaneously being a leading cause of post-traumatic complications. The development of therapeutic approaches to modulate inflammation in TBI is a relevant task today. Caffeine possesses pronounced immunomodulatory properties, affecting both innate and adaptive immune responses. Previously, the potential to stimulate neurogenesis, neuroplasticity processes, and reduce neuroinflammation using spleen immune cells modulated in vitro with caffeine has been demonstrated in a depression-like state. Objective. To investigate the effect of splenocytes modulated in vitro with caffeine on the development of the inflammatory response in a laser-induced TBI model in Danio rerio. Materials and Methods. The studies were conducted on adult Danio rerio fish. Levels of IL-1β in the brain and peripheral cortisol were determined using ELISA. Assessment of Hif-1α levels was performed using IHC on cryosections of the telencephalon. RNAseq was performed, followed by analysis of the differential expression of genes (DEG) involved in controlling neuroinflammation (il1b and vegfaa). Results. Intravenous administration of syngeneic splenocytes modulated in vitro with caffeine on day 1 post-TBI did not significantly affect the level of IL-1β or the expression of its gene, il1b, in fish with TBI. However, an increase in peripheral cortisol levels was observed, followed by its reduction to the levels of intact individuals by day 3. On day 3 post-injury, the expression of the il1b gene, as well as the production of the IL-1β cytokine, decreased compared to day 1 levels. This was accompanied by decreased levels of Hif-1α and reduced expression of the vegfaa gene. Conclusion. The study demonstrates the modulatory effect of immunocompetent cells pre-cultured with caffeine on neuroinflammation following TBI. This effect manifested as a limitation of the inflammatory response by day 3, attributed to reduced levels of IL-1β, cortisol, Hif-1α, and decreased vegfaa expression. The obtained results provide an experimental rationale for the potential of this therapeutic approach in modulating the inflammatory response in TBI.

About the authors

Evgeny Vladislavovich Nekhoroshev

Novosibirsk State University, Novosibirsk, Novosibirsk, Russia;
Federal State Budgetary Scientific Institution «Scientific Research Institute of Neurosciences and Medicine», Novosibirsk, Russia

Email: e.nekhoroshev@g.nsu.ru
ORCID iD: 0009-0005-4108-4305
ResearcherId: MVU-1766-2025

Postgraduate student NSU, laboratory research assistant at the Laboratory of Experimental Models of Neuropsychiatric Disorders

Russian Federation, 630090, Russia, Novosibirsk, st. Pirogova, 1; 630117, Russia, Novosibirsk, st. Timakova, 4

Shenghao Wang

Novosibirsk State University, Novosibirsk, Novosibirsk, Russia

Email: 1357044664@qq.com
ORCID iD: 0009-0000-4631-9074
ResearcherId: MXL-1655-2025

Postgraduate student NSU, Department of Natural Sciences

China, 630090, Russia, Novosibirsk, st. Pirogova, 1.

Evgeniya Valeryevna Markova

Federal State Budgetary Scientific Institution «Research Institute of Fundamental and Clinical Immunology», Novosibirsk, Russia

Email: evgeniya_markova@mail.ru
ORCID iD: 0000-0002-9746-3751
SPIN-code: 8439-7310
Scopus Author ID: 58177556400
ResearcherId: AAK-5322- 2021

MD, PhD, D.Sc., Chief researcher and Head of Neuroimmunology Laboratory

Russian Federation, 630099, Russia, Novosibirsk, st. Yadrintsevskaya, 14

Maxim Alexandrovich Kleshchev

Federal State Budgetary Scientific Institution «Research Institute of Fundamental and Clinical Immunology», Novosibirsk, Russia

Email: max82cll@ngs.ru
ORCID iD: 0000-0002-7537-2525
SPIN-code: 6718-0770
Scopus Author ID: 35177700900
ResearcherId: I-5469-2016

PhD, Senior researcher of the Laboratory of Experimental Models of Neuropsychiatric Disorders

Russian Federation, 630117,Russia, Novosibirsk, st. Timakova, 4.

Ivan Vladimirovich Savkin

Federal State Budgetary Scientific Institution «Research Institute of Fundamental and Clinical Immunology», Novosibirsk, Russia

Email: i.v.savkin2020@yandex.ru
ORCID iD: 0000-0002-1065-9234
SPIN-code: 8344-4247
Scopus Author ID: 6507473764
ResearcherId: HSG-1191-023

Researcher of Neuroimmunology Laboratory

Russian Federation, 630099, Russia, Novosibirsk, st. Yadrintsevskaya, 14.

Evgeny Vladimirovich Serenko

Federal State Budgetary Scientific Institution «Research Institute of Fundamental and Clinical Immunology», Novosibirsk, Russia

Email: serenko.evgeniy@mail.ru
ORCID iD: 0000-0001-7807-3603
SPIN-code: 3197-7109
Scopus Author ID: 57325420800

Junior researcher of Neuroimmunology Laboratory

Russian Federation, 630099, Russia, Novosibirsk, st. Yadrintsevskaya, 14.

Maria Alexandrovna Knyazheva

Federal State Budgetary Scientific Institution «Research Institute of Fundamental and Clinical Immunology», Novosibirsk, Russia

Email: lira357knyazheva@yandex.ru
ORCID iD: 0000-0002-2537-8232
SPIN-code: 8913-3798
Scopus Author ID: 57221404169
ResearcherId: HSG-3258-2023

PhD, Junior researcher of Neuroimmunology Laboratory

Russian Federation, 630099, Russia, Novosibirsk, st. Yadrintsevskaya, 14.

Anna Aleksanovna Akopyan

Novosibirsk State University, Novosibirsk, Novosibirsk, Russia

Email: annaaleksanovna@mail.ru
SPIN-code: 7002-3079
Scopus Author ID: 57194284785

PhD, Senior researcher of the Laboratory of Neurobiological Mechanisms of Neurodegenerative Processes

Russian Federation, 630117, Russia, Novosibirsk, st. Timakova, 4

Tamara Gennadievna Amstislavskaya

Novosibirsk State University, Novosibirsk, Novosibirsk, Russia;
Federal State Budgetary Scientific Institution «Scientific Research Institute of Neurosciences and Medicine», Novosibirsk, Russia

Author for correspondence.
Email: amstislavskayatg@neuronm.ru
ORCID iD: 0000-0002-2656-8687
Scopus Author ID: 6601959852
ResearcherId: K-4149-2018

PhD, D.Sc. (Biol), Associate professor of the Department of Neurosciences IMPZ, NSU; Chief researcher and Head of the Laboratory of Experimental Models of Neuropsychiatric Disorders SRINM

Russian Federation, 630090, Russia, Novosibirsk, st. Pirogova, 1; 630117, Russia, Novosibirsk, st.Timakova, 4

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Copyright (c) Nekhoroshev E.V., Wang S., Markova E.V., Kleshchev M.A., Savkin I.V., Serenko E.V., Knyazheva M.A., Akopyan A.A., Amstislavskaya T.G.

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