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.