| dc.description.abstract | Multiple sclerosis (MS) is a neuroinflammatory, autoimmune, chronic and disabling
disease that affects the central nervous system due to an autoimmune response
against myelin proteins, along with the formation of inflammatory infiltrate,
demyelination, excitotoxicity, astrogliosis and neurodegeneration. Astrocytes are the
most abundant cell type in the mammalian central nervous system (CNS) and, upon
injury, they become reactive. Activation of metabotropic glutamate receptor subtype 5
(mGluR5) has been shown to be neuroprotective upon glutamate insult and can
inhibit pro-inflammatory microglial signaling in vitro, as well as induce microglial and
astrocytic BDNF expression in a murine model of MS. Currently, there are no
therapeutic approache that could mitigate both MS-related neuroinflamation and
neurogeneration. In the present study, we aimed to establish a pro-inflammatory
stimulus with cytokines associated with MS pathology and astrocytic reactivity, tumor
necrosis factor alpha (TNF -α), interleukin 1 beta (IL-1β) and granulocyte and
macrophage colony stimulating factor (GM-CSF) and to evaluate the effect of the
positive modulator (PAM) of mGluR551, VU0409551, in stimulated astrocytes derived
from human induced pluripotency cells (hiPSCs). We observed an increase in the
expression of TNF-α and IL-1β 24 hours following TNF-α and IL-1β stimulation.
VU0409551 was found to increase the expression of IL-6, regardless of TNF-α and
IL-1β stimulation. Furthermore, a marginal effect of treatment with 1μM of
VU0409551 was observed in the prevention of the elevation of IL-1β expression
induced by the pro-inflammatory stimulus with TNF-α and IL-1β over 24h. The results
indicate that TNF-α, IL-1β and VU0409551 treatment does not change the
expression of the other evaluated targets IL-10, GNR, BDNF, EAAT1, and does not
modify glutamate levels in astrocyte conditioned media. Therefore, the assumed anti-
inflammatory effect of VU0409551 was not confirmed by the results in this study. | |
