title: Triamcinolone acetonide inhibits p38MAPK activation and neuronal apoptosis in early diabetic retinopathy.
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.
  
  
  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.
authors.affiliation: Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University; Beijing Ophthalmology & Visual Sciences Key Lab, P.R. China. mmzxy@yahoo.com
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: D
authors.initials: D
authors.lastname: Lai
authors.forename: S
authors.initials: S
authors.lastname: Bao
authors.forename: B D
authors.initials: BD
authors.lastname: Hambly
authors.forename: M C
authors.initials: MC
authors.lastname: Gillies
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D015153:Blotting, Western; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D003930:Diabetic Retinopathy / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D007150:Immunohistochemistry; D058449:Intravitreal Injections; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D012160:Retina / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D014222:Triamcinolone Acetonide / Q000494:pharmacology* / Q000627:therapeutic use; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; D014222:Triamcinolone Acetonide