Suppression of neuroinflammation by an allosteric agonist and positive allosteric modulator of the α7 nicotinic acetylcholine receptor GAT107

Autor: Adi Vaknin-Dembinsky, Tehila Mizrachi, Oshrit Marsha, Talma Brenner, Karen Brusin, Yael Ben-David, Ganesh A. Thakur, Millet Treinin
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Encephalomyelitis
Autoimmune
Experimental
Allosteric modulator
alpha7 Nicotinic Acetylcholine Receptor
medicine.medical_treatment
T cell
Immunology
Cell Culture Techniques
Pharmacology
Myelin oligodendrocyte glycoprotein
Multiple sclerosis
Mice
Cellular and Molecular Neuroscience
Immune system
medicine
Animals
Humans
α7 Nicotinic acetylcholine receptor
RC346-429
Neuroinflammation
Inflammation
Sulfonamides
B cells
biology
Chemistry
Research
General Neuroscience
Immune cholinergic system
Experimental autoimmune encephalomyelitis
Selective allosteric agonist for α7 nAChR
medicine.disease
Central nervous system inflammation
Mice
Inbred C57BL
Disease Models
Animal
Cytokine
medicine.anatomical_structure
Spinal Cord
Neurology
Quinolines
biology.protein
Cytokines
Cholinergic
Female
Neurology. Diseases of the nervous system
Zdroj: Journal of Neuroinflammation, Vol 18, Iss 1, Pp 1-14 (2021)
Journal of Neuroinflammation
ISSN: 1742-2094
Popis: Background The α7 nicotinic acetylcholine receptor (α7 nAChR) negatively regulates the synthesis and release of pro-inflammatory cytokines by immune cells. Our previous studies showed that in encephalitogenic T cells, α7 nAChR expression is upregulated and that activation of the cholinergic system can attenuate experimental autoimmune encephalomyelitis (EAE). GAT107 is an allosteric agonist and positive allosteric modulator (ago-PAM) of α7 nAChR that can produce persistent activation of this receptor. Therefore, in the present study, we investigated the effect of GAT107 on neuroinflammation in EAE, the animal model used for the study of multiple sclerosis (MS) via α7 nAChR, and the inflammatory pathways involved. Methods EAE was induced by administration of myelin oligodendrocyte glycoprotein (MOG35–55) in C57BL/6 mice. EAE mice were treated with the ago-PAM GAT107 or a placebo for 9 days, starting from the day of EAE induction. Clinical assessment and immunological evaluation of immune cells and cytokine production was performed. Results Following activation of the α7 nAChR by GAT107 during EAE, disease severity was significantly reduced by 70% and was correlated with a reduction in the extent of neuroinflammation in the CNS. The treatment reduced encephalitogenic T cell proliferation and the production of pro-inflammatory cytokines, as well as increased the production of the anti-inflammatory cytokine IL-10. Furthermore, the expression of immune cell markers was altered by GAT107 treatment, which induced a significant reduction in macrophages, dendritic cells, and B cells, as well as a reduction in anti-MOG35–55 antibodies. Additionally, GAT107 was found to directly activate α7 nAChR in murine macrophage RAW264.7 cells and in human PBMCs derived from MS patients and healthy donors. Conclusions Our results show that GAT107 can be a useful molecule for harnessing the cholinergic anti-inflammatory pathway for long-lasting and wide-ranging modulation and downregulation of neuroinflammation in EAE.
Databáze: OpenAIRE
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