الفهرس 
The potential neuroprotective effect of a GLP-1 analogue in experimentally induced multiple sclerosis PO.3.4.3
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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