Astroglial connexin 43 is a novel therapeutic target for chronic multiple sclerosis model

Ezgi Ozdemir Takase; Ryo Yamasaki; Satoshi Nagata; Mitsuru Watanabe; Katsuhisa Masaki; Hiroo Yamaguchi; Jun-Ichi Kira; Hideyuki Takeuchi; Noriko Isobe

doi:10.1038/s41598-024-61508-2

Astroglial connexin 43 is a novel therapeutic target for chronic multiple sclerosis model

Sci Rep. 2024 May 13;14(1):10877. doi: 10.1038/s41598-024-61508-2.

Authors

Affiliations

¹ Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
² Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. yamasaki.ryo.510@m.kyushu-u.ac.jp.
³ School of Physical Therapy, Faculty of Rehabilitation, Reiwa Health Sciences University, Fukuoka, Japan.
⁴ Translational Neuroscience Center, Graduate School of Medicine, and School of Pharmacy at Fukuoka, International University of Health and Welfare, Ookawa, Japan.
⁵ Department of Neurology, Brain and Nerve Center, Fukuoka Central Hospital, Fukuoka, Japan.
⁶ Department of Neurology and Stroke Medicine, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan. htake@yokohama-cu.ac.jp.
⁷ Department of Neurology, Graduate School of Medicine, International University of Health and Welfare, Narita, Japan. htake@yokohama-cu.ac.jp.
⁸ Center for Intractable Neurological Diseases and Dementia, International University of Health and Welfare Atami Hospital, Atami, Japan. htake@yokohama-cu.ac.jp.

Abstract

In chronic stages of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalitis (EAE), connexin (Cx)43 gap junction channel proteins are overexpressed because of astrogliosis. To elucidate the role of increased Cx43, the central nervous system (CNS)-permeable Cx blocker INI-0602 was therapeutically administered. C57BL6 mice with chronic EAE initiated by MOG_35-55 received INI-0602 (40 mg/kg) or saline intraperitoneally every other day from days post-immunization (dpi) 17-50. Primary astroglia were employed to observe calcein efflux responses. In INI-0602-treated mice, EAE clinical signs improved significantly in the chronic phase, with reduced demyelination and decreased CD3⁺ T cells, Iba-1⁺ and F4/80⁺ microglia/macrophages, and C3⁺GFAP⁺ reactive astroglia infiltration in spinal cord lesions. Flow cytometry analysis of CD4⁺ T cells from CNS tissues revealed significantly reduced Th17 and Th17/Th1 cells (dpi 24) and Th1 cells (dpi 50). Multiplex array of cerebrospinal fluid showed significantly suppressed IL-6 and significantly increased IL-10 on dpi 24 in INI-0602-treated mice, and significantly suppressed IFN-γ and MCP-1 on dpi 50 in the same group. In vitro INI-0602 treatment inhibited ATP-induced calcium propagations of Cx43^+/+ astroglial cells to similar levels of those of Cx43^-/- cells. Astroglial Cx43 hemichannels represent a novel therapeutic target for chronic EAE and MS.

Keywords: Astroglia; Connexin 43; Experimental autoimmune encephalomyelitis; Gap junction; Hemichannel; Microglia; Multiple sclerosis.

MeSH terms

Animals
Astrocytes* / drug effects
Astrocytes* / metabolism
Astrocytes* / pathology
Connexin 43* / metabolism
Disease Models, Animal*
Encephalomyelitis, Autoimmune, Experimental* / drug therapy
Encephalomyelitis, Autoimmune, Experimental* / metabolism
Encephalomyelitis, Autoimmune, Experimental* / pathology
Female
Mice
Mice, Inbred C57BL*
Multiple Sclerosis* / drug therapy
Multiple Sclerosis* / metabolism
Multiple Sclerosis* / pathology

Substances

Connexin 43
GJA1 protein, mouse

Abstract

MeSH terms

Substances

Grants and funding