Compound A, a selective glucocorticoid receptor agonist, inhibits immunoinflammatory diabetes, induced by multiple low doses of streptozotocin in mice
2014
Authors:
Saksida, TamaraVujičić, Milica
Nikolić, Ivana
Stojanović, Ivana D.
Haegeman, G.
Stošić-Grujičić, Stanislava
Document Type:
Article (Published version)
,
© 2014 The British Pharmacological Society
Metadata
Show full item recordAbstract:
Background and PurposeType 1 diabetes is a multifactorial inflammatory
disease that develops as a result of deregulated immune responses,
causing progressive autoimmune destruction of insulin-producing beta
cells of pancreas. 2-((4-acetoxyphenyl)-2-chloro-N-methyl) ethylammonium
chloride, compound A (CpdA), is a selective glucocorticoid receptor (GR)
agonist that displays strong anti-inflammatory and immunomodulatory
activities. We investigated the therapeutic effectiveness of CpdA in a
pharmacological model of type 1 diabetes in mice.
Experimental ApproachThe utility of CpdA in diabetes prevention was
evaluated in vivo through its prophylactic administration to male
C57BL/6 mice that received multiple low doses of streptozotocin for
immunoinflammatory diabetes induction. The effect of CpdA on disease
development was studied by measuring blood glucose and insulin level,
histopathological examination, determination of the nature of
infiltrating cells, pro- and anti-inflammatory cytokine production, and
signalling pathways.
Key ResultsProphylactic in vivo therapy with CpdA conferred protection
against development of immunoinflammatory diabetes in mice by dampening
the M1/Th1/Th17 immune response and switching it towards an
anti-inflammatory M2/Th2/Treg profile, thus preserving beta cell
function.
Conclusions and ImplicationsAnti-diabetic properties of CpdA are
mediated through modulation of immune cell-mediated pathways, but
without triggering adverse events. These findings provide basic
information for the therapeutic use of selective GR agonists in the
amelioration of islet-directed autoimmunity.
Source:
British Journal of Pharmacology, 2014, 171, 24, SI, 5898-5909Funding / projects:
- Molecular mechanisms of physiological and pharmacological control of inflammation and cancer (RS-MESTD-Basic Research (BR or ON)-173013)
DOI: 10.1111/bph.12892
ISSN: 1476-5381