O tratamento com VU0409551, um modulador alostérico positivo do mGluR5, melhora sinais clínicos, parâmetros imunológicos e moleculares em um modelo murino da esclerose múltipla

Abstract

Multiple Sclerosis (MS) is a neurodegenerative, autoimmune, inflammatory, and demyelinating disease. It is the leading cause of disability in young adults, and its symptoms vary depending on the region of the central nervous system affected. Disease-modifying drugs used to treat MS often have serious side effects, are unable to cure the disease, and fail to halt its relapse-independent progression. The type 5 metabotropic glutamate receptor (mGluR5) has been identified as a potential therapeutic target for neurodegenerative and neuroinflammatory diseases. Therefore, the aim of this study is to evaluate the effects of treatment with VU0409551, a positive allosteric modulator (PAM) of mGluR5, on behavioral parameters related to anxiety and depression, as well as pathophysiological, immunological and molecular parameters, in the EAE model. Positive allosteric modulation of mGluR5 through treatment with VU0409551 in EAE animals was able to: I) improve clinical score and prevent the model's characteristic weight loss; II) reduce anxiety-like behaviors by increasing the number of entries into the light area in the light-dark box test, and by increasing both time spent and entries in the open arm in the elevated plus maze test; III) modulate the peripheral immune response by preventing the increase of IL-17 and Th1 cells in the spleen; IV) downregulate immune-related pathways that are upregulated when EAE is induced; V) reduce the gene expression of diseaseassociated oligodendrocyte markers such as Serpina3n and H2D1; VI) normalize the increased number of astrocytes in the cortex; VII) prevent the increase of microglia and the influx of monocytes into the CNS. These findings reinforce the role of mGluR5 as a potential therapeutic target for neuroinflammatory and neurodegenerative diseases, as the use of the mGluR5 PAM, VU0409551, demonstrates protective and immunomodulatory effects.