Stimulation of nerve growth-factor and substance P expression in the iris-trigeminal axis of diabetic rats--involvement of oxidative stress and effects of aldose reductase inhibition.
In rats with streptozotocin-induced diabetes, we measured increased (by 61%; P < 0.05) mRNA for nerve growth factor (NGF) in the iris together with increased (by 82%; P < 0.05) mRNA for preprotachykinin (the substance P precursor) in the trigeminal ganglion, suggesting that increased NGF was driving increased substance P gene expression. In other diabetic rats, these changes were prevented by treatment with either an antioxidant (butylated hydroxytoluene; 1% by diet) or an aldose reductase inhibitor (ARI) (sorbinil; 25 mg/kg/day p.o.) and the sorbinil treatment was associated with significant inhibition of polyol pathway intermediates in both lens and sciatic nerve. This suggests that polyol pathway activity in the lens may translate to oxidative stress-driving stimulation of NGF gene expression in the iris. The change is selective for NFG, because expression of the analogous neurotrophin, neurotrophin-3 (NT-3), was unaltered in the same irises. These changes suggest that oxidative stress and/or inflammation can drive up NGF expression in diabetes--a mechanism that might participate in iritis.
Fernyhough
P
P
Department of Pharmacology, Queen Mary and Westfield College, London, UK.
Brewster
W J
WJ
Fernandes
K
K
Diemel
L T
LT
Tomlinson
D R
DR
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002352:Carrier Proteins / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D048289:Imidazolidines; D007498:Iris / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D009005:Monosaccharides / Q000378:metabolism; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D011108:Polymers / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020917:Receptor, trkA; D012584:Sciatic Nerve / Q000378:metabolism; D013373:Substance P / Q000378:metabolism*; D015320:Tachykinins / Q000235:genetics; D012668:Trigeminal Ganglion / Q000378:metabolism*
D001786:Blood Glucose; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D007093:Imidazoles; D048289:Imidazolidines; D008565:Membrane Proteins; D009005:Monosaccharides; D009414:Nerve Growth Factors; D011108:Polymers; D011498:Protein Precursors; D012333:RNA, Messenger; D015320:Tachykinins; C024617:polyol; C044206:preprotachykinin; D013373:Substance P; D000449:Aldehyde Reductase; D020917:Receptor, trkA; C026411:sorbinil