Diazepam Impairs Innate and Adaptive Immune Responses and Ameliorates Experimental Autoimmune Encephalomyelitis

FALCÓN, CRISTIAN R.; LÓPEZ, PABLO HÉCTOR HORACIO; CERVI, LAURA; HURST, NICOLÁS FERNÁNDEZ; ZURITA, ADOLFO; MONFERRAN, CLARA G.; VIVINETTO, ANA LAURA; GATTI, GERARDO; ROTH, GERMAN A.

Frontiers in Immunology

Frontiers

Lugar: Berlin; Año: 2021 vol. 12

Currently there is increasing attention on the modulatory effects of benzodiazepines on theimmune system. Here, we evaluate how Diazepam (DZ) affects both innate and adaptiveimmunity. We observed that treatment with DZ and Lipopolysaccharide (LPS) onmacrophages or dendritic cells (DCs) induced a defective secretion of IL-12, TNF-a, IL-6and a lesser expression of classical activation markers as NO production and CD40 incomparison with LPS condition. More importantly, mice pre-treated with DZ and thenchallenged to LPS induced-septic shock showed reduced death. The DZ treatment shiftedthe LPS-induced pro-inflammatory cytokine production of peritoneal cells (PCs) to an anti-inflammatory profile commanded by IL-10. In agreement with this, DZ treatment preventedLPS-induced DC ability to initiate allogeneic Th1 and Th17 responses in vitro whencompared with LPS-matured DC. Since these inflammatory responses are the key in thedevelopment of the experimental autoimmune encephalomyelitis (EAE), we treated EAEmice preventively with DZ. Mice that received DZ showed amelioration of clinical signs andimmunological parameters of the disease. Additionally, DZ reduced the release of IFN-gand IL-17 by splenocytes from untreated sick mice in vitro. For this reason, we decided totreat diseased mice therapeutically with DZ when they reached the clinical score of 1. Mostimportantly, this treatment ameliorated clinical signs, reduced the MOG-specificinflammatory cytokine production and prevented axonal damage. Altogether, theseresults indicate that DZ is a potent immunomodulator capable of controlling undesiredinnate and adaptive immune responses, both at the beginning of these responses and alsoonce they have started.