Crosstalk between glucocorticoid and histaminergic signaling systems in neuroinflammatory contexts

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

Mar del Plata

Congreso; LXIII Reunión Anual de la Sociedad Argentina de Investigación Clínica (SAIC), LXVI Reunión Anual de la SAI, Reunión Anual de la Sociedad Argentina de Fisiología (SAFIS); 2018

Sociedad Argentina de Investigación Clínica (SAIC)

The relationship between neuroinflammation andneurodegenerative disease has been extensively documented, pointing to glialcells as crucial players in neuroinflammation. We haveshown before a crosstalk between histamineH1 receptor (H1R) and glucocorticoid receptor (GR) signaling that could have specific impact on (neuro)inflammatoryconditions. The objective of the present work was to evaluatethis signaling interaction in a neuroinflammatory context. In a first stage, we used the BV2 murineglial cell line. Using this system, we aimed to set an in vitroneuroinflammatory model by treating the cells with 1µg/µl of lipopolysaccharide (LPS) and evaluating theinduction of the inducible nitric oxide synthase (iNOS) gene expression. Pretreatmentwith 1nM of the synthetic glucocorticoid dexamethasone (DEX) reduced LPS-inducediNOS response to 50%, while co-incubation with the antihistamines chlorpheniramineand diphenhydramine enhanced DEX-induced iNOS reduction to 65 and 90%. To extendthese results to a human glial cell model, we used hiPSC-derived astrocytes. Inthis 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 toAβ. Co-incubation with 10µM of the antihistamines mepyramine and triprolidineresulted in a 2 and 3-fold enhancement of DEX effect respectively. Thisenhancement was not induced by a different antihistamine, chlorpheniramine. Weconclude there is a ligand specific interaction between H1R signaling and GR transcriptionalactivity that can have pharmacological impact on neuroinflammatory contextswhere glial cells play a central role.