Attenuation of diabetic retinopathy by enhanced inhibition of MMP-2 and MMP-9 using aspirin and minocycline in streptozotocin-diabetic rats.
Interruptions of Matrix Metalloproteinase-2 (MMP-2) and Matrix Metalloproteinase-9 (MMP-9) have been shown to reduce the ensuing threatening risk factors of vascular complications of diabetes by alteration in Extracellular Matrix (ECM). We hypothesized that minocycline induced MMP-2 and MMP-9 inhibition can be enhanced by aspirin, a non-selective COX and tPA inhibitor and this combination can reduce progression of diabetic retinopathy. Diabetes was induced in male Wistar rats by streptozotocin (55 mg/kg i.p.). Four weeks after diabetes induction rats were treated with minocycline (50 mg/kg, p.o.) per se, aspirin (50 mg/kg, p.o.) per se, or minocycline in combination with aspirin for a period of four weeks. At the end of eighth week rats were anesthetized and electroretinograms were recorded. B-wave latency, B-wave amplitude and retinal permeability were measured. Histology was done and retinal thickness was measured. Zymography was carried out for MMP-2 and MMP-9 level determinations. B-wave amplitude was significantly decreased while B- wave latency was significantly increased in diabetic group when compared with normo-glycemic rats. Treatment with combination of minocycline and aspirin significantly reversed B-wave amplitude and latency compared with vehicle-treated diabetic controls. Blood retinal permeability and retinal thickness were also significantly attenuated by the treatment of minocycline in combination with aspirin. Results of the present study suggest that MMP-2 and MMP-9 inhibition in presence of COX inhibitor prevents the development of experimental diabetic retinopathy in rats and can be a potential approach for the treatment.
Bhatt
Lokesh Kumar
LK
Department of Pharmacology, School of Pharmacy and Technology Management, NMIMS University, Vile Parle (W) Mumbai, 400 056, India.
Addepalli
Veeranjaneyulu
V
J Genet. 2009 Dec;88(4):495-515
20090210
Expert Opin Investig Drugs. 2004 Oct;13(10):1275-93
15461557
FASEB J. 1992 Aug;6(11):2905-14
1644256
N Engl J Med. 1987 Mar 5;316(10):599-606
3027558
FASEB J. 1990 Apr 1;4(6):1577-90
2180767
Rev Endocr Metab Disord. 2008 Dec;9(4):315-27
18654858
Invest Ophthalmol Vis Sci. 2003 May;44(5):2163-70
12714657
Diabetologia. 1976 Aug;12(4):367-74
134921
Acta Ophthalmol Scand. 2002 Jun;80(3):305-9
12059871
Clin Cancer Res. 2003 Feb;9(2):551-4
12576417
Circ Res. 2001 Jun 22;88(12):1291-8
11420306
Invest Ophthalmol Vis Sci. 2008 Feb;49(2):732-42
18235022
Arch Ophthalmol. 1961 Sep;66:366-78
13694291
Graefes Arch Clin Exp Ophthalmol. 2007 Sep;245(9):1335-45
17265029
Graefes Arch Clin Exp Ophthalmol. 2009 May;247(5):699-706
19084986
Diabet Med. 2008 May;25(5):536-42
18346159
Arch Ophthalmol. 1999 Apr;117(4):498-503
10206578
Arch Ophthalmol. 1990 Mar;108(3):372-5
2310337
FASEB J. 1991 May;5(8):2145-54
1850705
Proc Natl Acad Sci U S A. 1989 Jul;86(13):5141-5
2740348
Exp Eye Res. 1980 Apr;30(4):401-10
7449869
Diabetes. 1979 Jan;28(1):16-9
759246
Bioessays. 1992 Jul;14(7):455-63
1445287
FASEB J. 1998 Sep;12(12):1075-95
9737711
Invest Ophthalmol Vis Sci. 1999 Mar;40(3):809-13
10067990
Diabetes. 2006 Sep;55(9):2401-11
16936187
Acta Pharmacol Sin. 2003 Jun;24(6):534-8
12791179
J Glaucoma. 2000 Apr;9(2):163-8
10782626
Angiology. 2005 Mar-Apr;56(2):173-89
15793607
Curr Pharm Des. 2007;13(26):2699-712
17897014
Surv Ophthalmol. 2002 Dec;47 Suppl 2:S253-62
12507627
BMC Health Serv Res. 2008 Jul 28;8:159
18655733
J Biol Chem. 2000 Mar 17;275(11):8051-61
10713126
Lab Invest. 2005 May;85(5):597-607
15711567
Biochem Biophys Res Commun. 2004 May 28;318(2):594-600
15120641
Ophthalmology. 2008 Nov;115(11):1869-75
18584872
Med Res Rev. 2003 Mar;23(2):117-45
12500286
Invest Ophthalmol Vis Sci. 2001 Mar;42(3):789-94
11222542