CROSSTALK BETWEEN GLUCOCORTICOID AND HISTAMINERGIC SIGNALING SYSTEMS IN NEUROINFLAMMATORY CONTEXTS.

ZAPPIA D; BEAUQUIS J; GRANJA-GALEANO G; FERNANDEZ N; SARAVIA F; FITZSIMONS C; MONCZOR F

Mar del Plata

Congreso; Reunión Anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2018

Sociedad Argentina de Investigación Clínica

The relationship between neuroinflammation and neurodegenerative disease has been extensively documented, pointing to glial cells as crucial players in neuroinflammation. We have shown before a crosstalk between histamine H1 receptor (H1R) and glucocorticoid receptor (GR) signaling that could have specific impact on (neuro)inflammatory conditions. The objective of the present work was to evaluate this signaling interaction in a neuroinflammatory context. In a first stage, we used the BV2 murine glial cell line. Using this system, we aimed to set an in vitro neuroinflammatory model by treating the cells with 1μg/μl of lipopolysaccharide (LPS) and evaluating the induction of the inducible nitric oxide synthase (iNOS) gene expression. Pretreatment with 1nM of the synthetic glucocorticoid dexamethasone (DEX) reduced LPS-induced iNOS response to 50%, while co-incubation with the antihistamines chlorpheniramine and diphenhydramine enhanced DEX-induced iNOS reduction to 65 and 90%. To extend these results to a human glial cell model, we used hiPSC-derived astrocytes. In this system we modeled neuroinflammation using synthetic beta-amyloid oligomers (Aβ). Treatment with 1μM of Aβ resulted in an induction of TNF-α gene expression. Pretreatment with 10nM DEX showed a significant reduction of TNF-α response to Aβ. Co-incubation with 10μM of the antihistamines mepyramine and triprolidine resulted in a 2 and 3-fold enhancement of DEX effect respectively. This enhancement was not induced by a different antihistamine, chlorpheniramine. We conclude there is a ligand specific interaction between H1R signaling and GR transcriptional activity that can have pharmacological impact on neuroinflammatory contexts where glial cells play a central role.