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http://hdl.handle.net/10603/522591
Title: | Characterization of oral and subcutaneous efficacy of GMFBI 1 in the suppression of Experimental Autoimmune Encephalomyelitis progression |
Researcher: | Sunitha Subhramanian |
Guide(s): | Krishnakumar Menon and Gopi Mohan C |
Keywords: | Life Sciences Molecular Biology and Genetics; Pharmacokinetics; Multiple Sclerosis |
University: | Amrita Vishwa Vidyapeetham University |
Completed Date: | 2023 |
Abstract: | In the emerging significance of research on gut-brain control of multiple sclerosis (MS), therapeutic targeting of gut-brain inflammation modulation at a fundamental level is more enlivening, wherein the immunomodulator glia maturation factor-and#946; (GMF-and#946;) plays an important role in proinflammation mediation. Activation of GMF-and#946; leads to GMF-and#946;-Ser-83 phosphorylation which results in proinflammation and augments experimental autoimmune encephalomyelitis (EAE). Remarkably, there were no EAE symptoms in GMF-and#946;-/- mice. Consequently, our group recognized 1H-Indazole4-yl-methanol (GMFBI.1) inhibitor which prevented GMF-and#946;-Ser-83 phosphorylation in EAE suppression. Moreover, to ascertain the role of gut GMF-and#946; in EAE suppression and the impact of gut-brain implication in neurodegenerative diseases, we amended the gut bioavailability of GMFBI.1 as a parameter of EAE suppression. Primarily, we pinpointed Miglyol 812N as an appropriate biocompatible GMFBI.1 carrier in contrast to other FDA approved carriers screened using in silico molecular docking. GMFBI.1 Miglyol 812N formulation enhanced the retention/brain penetration of the inhibitor. Consequently, administration of GMFBI.1-Miglyol 812N at varying doses by subcutaneous/oral routes resulted in differential GMFBI.1 bioavailability in both gut and brain determined by pharmacokinetic approach indicating the effect of local GMFBI.1 inhibitor bioavailability in EAE reversal. Insufficient gut GMFBI.1 bioavailability caused incomplete EAE reversal despite having adequate GMFBI.1 inhibitor in the systemic circulation to hamper brain GMF-and#946; activity. On the other hand, adequate GMFBI.1 gut bioavailability led to absolute EAE reversal. The extent of GMF-and#946;-Ser-83 phosphorylation/GM-CSF expressions in the enteric glial cells and the partial/full recovery from EAE is linked to GMFBI.1 compound bioavailability. In addition, up-regulation of Treg cells within the periphery following GMFBI.1 p.o. treatment abrogated EAE clinical progression. Necessarily, dual targeting of GMF-and#946; in both.. |
Pagination: | ix, 134 |
URI: | http://hdl.handle.net/10603/522591 |
Appears in Departments: | Amrita Centre for Nanosciences and Molecular Medicine |
Files in This Item:
File | Description | Size | Format | |
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01_title.pdf | Attached File | 226.19 kB | Adobe PDF | View/Open |
02_preliminary page.pdf | 709.5 kB | Adobe PDF | View/Open | |
03_contents.pdf | 230.97 kB | Adobe PDF | View/Open | |
04_abstract.pdf | 179.95 kB | Adobe PDF | View/Open | |
05_chapter 1.pdf | 7.63 MB | Adobe PDF | View/Open | |
06_chapter 2.pdf | 3.49 MB | Adobe PDF | View/Open | |
07_chapter 3.pdf | 14.18 MB | Adobe PDF | View/Open | |
08_chapter 4.pdf | 312.62 kB | Adobe PDF | View/Open | |
09_chapter 5.pdf | 1.55 MB | Adobe PDF | View/Open | |
10_annexure.pdf | 402.21 kB | Adobe PDF | View/Open | |
80_recommendation.pdf | 1.77 MB | Adobe PDF | View/Open |
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