Title:Triamcinolone Acetonide Inhibits p38MAPK Activation and Neuronal Apoptosis in Early Diabetic Retinopathy
VOLUME: 13 ISSUE: 6
Author(s):X. Zhang, D. Lai, S. Bao, B.D. Hambly and M.C. Gillies
Affiliation:Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University; Beijing Ophthalmology & Visual Sciences Key Lab, 100730 P.R. China.
Keywords:Apoptosis, diabetic macular edema, diabetic retinopathy, neuro-protection, protein phosphorylation,
triamcinolone acetonide.
Abstract:Objective: Intravitreal glucocorticoids and anti-vascular endothelial growth factor (VEGF) therapies
are novel strategies for the treatment of advanced diabetic retinopathy, a condition with inflammatory and
neuropathic elements. In contrast with anti-VEGF therapy, glucocorticoids may also exert neuroprotective
effects. How glucocorticoids protect retinal neurons is unknown. The aims of the study are to investigate the
anti-apoptotic actions of glucocorticoids on diabetic retinal neurons, and characterize the signalling pathways
involved.
Research Design and Methods: The regulation of gene expression of the four p38 mitogen-activated protein
kinase (MAPK) isoforms (α, β, δ and γ) and the glucocorticoid receptor (GR) in the retinas was evaluated using
quantitative RT-PCR, Western blot and immunohistochemistry. Phosphorylation of all isoforms p38MAPK
(Thr180/Tyr182) and GR (S-211) was further evaluated. Apoptosis was confirmed by immunolocalization of
active CASPASE-3 and the subsequent cleavage of poly (ADP-ribose) polymerase (PARP) following
intravitreal injection of triamcinolone acetonide (IVTA), in an early diabetic rat model (26 days after induction of
diabetes).
Results: IVTA significantly down-regulated mRNA expression of Caspase 3. Activation of CASPASE-3, the
subsequent cleavage of PARP-1 and phosphorylation of p38MAPK induced by diabetes were attenuated by
IVTA treatment, concomitantly with activation by phosphorylation of the glucocorticoid receptor (GR S-211).
Conclusions: IVTA activates the GR and exerts neural protective effects on retinal neurons. Inhibition of the
p38MAPK pathway and activation of GR play a critical anti-apoptotic role in retinal neurons of diabetes
following IVTA treatment. Both the anti-inflammatory and anti-apoptotic effects of glucocorticoids may be
mediated through inhibition of the p38MAPK pathway in diabetic retinopathy.
