title: Effects of p38 MAPK inhibition on early stages of diabetic retinopathy and sensory nerve function.
abstract: Purpose. p38 mitogen-activated protein kinase (MAPK) is known to play a regulatory role in inflammatory processes in disease. Inflammation has been linked also to the development of diabetic retinopathy in rodents. This study was conducted to evaluate the effect of a p38 MAPK inhibitor on the development of early stages of diabetic retinopathy in rats. Methods. Streptozotocin-diabetic rats were assigned to two groups-treated with the p38 MAPK inhibitor PHA666859 (Pfizer, New York, NY) and untreated-and compared with age-matched nondiabetic control animals. Results. At 2 months of diabetes, insulin-deficient diabetic control rats exhibited significant increases in retinal superoxide, nitric oxide (NO), cyclooxygenase (COX)-2, and leukostasis within retinal microvessels. All these abnormalities were significantly inhibited by the p38 MAPK inhibitor (25 mg/kgBW/d). At 10 months of diabetes, significant increases in the number of degenerate (acellular) capillaries and pericyte ghosts were measured in control diabetic rats versus those in nondiabetic control animals, and pharmacologic inhibition of p38 MAPK significantly inhibited all these abnormalities (all P < 0.05). This therapy also had beneficial effects outside the eye in diabetes, as evidenced by the inhibition of a diabetes-induced hypersensitivity of peripheral nerves to light touch (tactile allodynia). Conclusions. p38 MAPK plays an important role in diabetes-induced inflammation in the retina, and inhibition of p38 MAPK offers a novel therapeutic approach to inhibiting the development of early stages of diabetic retinopathy and other complications of diabetes.
authors.affiliation: Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Du
authors.forename: Jie
authors.initials: J
authors.lastname: Tang
authors.forename: Guangyuan
authors.initials: G
authors.lastname: Li
authors.forename: Guanyuan
authors.initials: G
authors.lastname: Li
authors.forename: Liliana
authors.initials: L
authors.lastname: Berti-Mattera
authors.forename: Chieh Allen
authors.initials: CA
authors.lastname: Lee
authors.forename: Darian
authors.initials: D
authors.lastname: Bartkowski
authors.forename: David
authors.initials: D
authors.lastname: Gale
authors.forename: Joe
authors.initials: J
authors.lastname: Monahan
authors.forename: Michael R
authors.initials: MR
authors.lastname: Niesman
authors.forename: Gordon
authors.initials: G
authors.lastname: Alton
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Kern
mesh_terms: D000818:Animals; D015153:Blotting, Western; D051546:Cyclooxygenase 2; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000517:prevention & control; D003930:Diabetic Retinopathy / Q000201:enzymology / Q000517:prevention & control*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006930:Hyperalgesia / Q000188:drug therapy*; D018921:Leukostasis / Q000188:drug therapy; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D020286:Pericytes / Q000187:drug effects / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D012171:Retinal Vessels / Q000473:pathology; D011984:Sensory Receptor Cells / Q000187:drug effects*; D013481:Superoxides / Q000378:metabolism; D014110:Touch; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; C548896:PHA 666859; D011720:Pyrazoles; D011743:Pyrimidines; D013481:Superoxides; D009569:Nitric Oxide; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D048051:p38 Mitogen-Activated Protein Kinases