Deletion of voltage-gated calcium channels in astrocytes decreases neuroinflammation and demyelination in a murine model of multiple sclerosis.

Autor: Denaroso GE; Institute for Myelin and Glia Exploration, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, The State University of New York, University at Buffalo, NYS Center of Excellence, 701 Ellicott St., Buffalo, NY, 14203, USA., Smith Z; Institute for Myelin and Glia Exploration, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, The State University of New York, University at Buffalo, NYS Center of Excellence, 701 Ellicott St., Buffalo, NY, 14203, USA., Angeliu CG; Institute for Myelin and Glia Exploration, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, The State University of New York, University at Buffalo, NYS Center of Excellence, 701 Ellicott St., Buffalo, NY, 14203, USA., Cheli VT; Institute for Myelin and Glia Exploration, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, The State University of New York, University at Buffalo, NYS Center of Excellence, 701 Ellicott St., Buffalo, NY, 14203, USA., Wang C; Institute for Myelin and Glia Exploration, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, The State University of New York, University at Buffalo, NYS Center of Excellence, 701 Ellicott St., Buffalo, NY, 14203, USA., Paez PM; Institute for Myelin and Glia Exploration, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, The State University of New York, University at Buffalo, NYS Center of Excellence, 701 Ellicott St., Buffalo, NY, 14203, USA. ppaez@buffalo.edu.
Jazyk: angličtina
Zdroj: Journal of neuroinflammation [J Neuroinflammation] 2023 Nov 14; Vol. 20 (1), pp. 263. Date of Electronic Publication: 2023 Nov 14.
DOI: 10.1186/s12974-023-02948-x
Abstrakt: The experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis was used in combination with a Cav1.2 conditional knock-out mouse (Cav1.2 KO ) to study the role of astrocytic voltage-gated Ca ++ channels in autoimmune CNS inflammation and demyelination. Cav1.2 channels were specifically ablated in Glast-1-positive astrocytes by means of the Cre-lox system before EAE induction. After immunization, motor activity was assessed daily, and a clinical score was given based on the severity of EAE symptoms. Cav1.2 deletion in astrocytes significantly reduced the severity of the disease. While no changes were found in the day of onset and peak disease severity, EAE mean clinical score was lower in Cav1.2 KO animals during the chronic phase of the disease. This corresponded to better performance on the rotarod and increased motor activity in Cav1.2 KO mice. Furthermore, decreased numbers of reactive astrocytes, activated microglia, and infiltrating lymphocytes were found in the lumbar section of the spinal cord of Cav1.2 KO mice 40 days after immunization. The degree of myelin protein loss and size of demyelinated lesions were also attenuated in Cav1.2 KO spinal cords. Similar results were found in EAE animals treated with nimodipine, a Cav1.2 Ca ++ channel inhibitor with high affinity to the CNS. Mice injected with nimodipine during the acute and chronic phases of the disease exhibited lower numbers of reactive astrocytes, activated microglial, and infiltrating immune cells, as well as fewer demyelinated lesions in the spinal cord. These changes were correlated with improved clinical scores and motor performance. In summary, these data suggest that antagonizing Cav1.2 channels in astrocytes during EAE alleviates neuroinflammation and protects the spinal cord from autoimmune demyelination.
(© 2023. The Author(s).)
Databáze: MEDLINE
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