الفهرس | Only 14 pages are availabe for public view |
Abstract The heterogeneous nature of multiple sclerosis (MS) and the unavailability of a therapy addressing its intricate network and reversing the disease state, is yet an area that needs to be elucidated. The emergence of glucagon like peptide-1 analogue, liraglutide, as an intriguing neuroprotective candidate raised the interest to investigate its potential effects against a mouse model of MS along with the possible underlying mechanisms. Demyelination was induced in C57Bl/6 mice by cuprizone (400 mg/kg/day p.o.) for 5 weeks. Animals received liraglutide (100 µg/kg/day i.p.), or dorsomorphin, an AMPK inhibitor, (2.5 mg/Kg/day i.p.) 30 minutes before liraglutide dose, for 4 weeks (starting from second week). Liraglutide improved the behavioral and motor profiles in cuprizone-treated mice as demonstrated by open field, rotarod and grip strength tests. Moreover, liraglutide induced remyelination through stimulating oligodendrocyte progenitor cells differentiation via Olig2 transcription activation, as reflected by increased myelin basic protein expression and myelinated nerve fiber percentage. Histopathological and immunohistochemical examination of Iba1 + microglia emphasized these findings. Liraglutide effects were manifested via elevating the levels of p-AMPK and SIRT-1 proteins, in addition to the autophagy proteins Beclin-1 and LC3-B. Interestingly, liraglutide halted cellular damage as manifested by reduced HMGB1 protein and subsequently TLR-4 downregulation, coupled with a decrease in NF-κB level. Furthermore, liraglutide caused suppression of NLRP3 transcription and its apoptotic downstream cascade caspase-1 as well as IL-1β. Dorsomorphin pre-administration indicated a possible interplay between AMPK/SIRT-1 and NLRP3 inflammasome activation as it partially reversed liraglutide-induced effects. In conclusion, liraglutide exerted a significant neuroprotection against cuprizone-induced demyelination via anti- Abstract inflammatory, autophagic flux activation, NLRP3 inflammasome suppression, and anti-apoptotic mechanisms, which are possibly mediated, at least partially, via AMPK/SIRT-1, autophagy, and TLR4/ NF-κB/NLRP3 signaling |