Reduction of experimental laser-induced choroidal neovascularization by orally administered BPHA, a selective metalloproteinase inhibitor.
BACKGROUND
N-Biphenyl sulfonyl-phenylalanine hydroxamic acid (BPHA), a synthetic, selective matrix metalloproteinase (MMP)-2, -9, -14 inhibitor, has been reported to show significant antiangiogenic activity without unpleasant adverse effects. After film in situ zymography (FIZ) and conventional zymography were performed to detect MMP in experimental choroidal neovascularizations (CNVs), we studied the reducible effect of BPHA on CNVs.


METHODS
Using FIZ, the gelatinolytic activity of MMPand BPHA-reduction on gelatinolysis were examined in diode-laser-induced CNV lesions in a total of 22 male Brown Norway rats. The MMP subtypes were studied in the CNV lesions of three rats using conventional zymography. Vehicle solution only or 25-, 50-, or 100 mg/kg-body-weight of BPHA was administered orally twice daily for 14 days after the laser photocoagulation in 18 rats, respectively. Fluorescein angiograms were taken, and the late hyperfluorescence of CNVs was given scores by three researchers using four grades. The thickness of CNV lesions was studied histologically.


RESULTS
In laser-induced CNVs, the gelatinolytic activity of MMP and reduction of gelatinolysis by BPHA were observed on FIZ, and MMP-2 and proMMP-2 were identified by conventional zymography. The scores given to the late dye leakage and staining on angiograms were lower in the BPHA-treated groups ( p<0.01) than in the controls, and the effect appeared to be dose-dependent. Similarly, the CNV lesions in the BPHA-treated groups were less thick than in the controls ( p<0.01).


CONCLUSIONS
MMP-2 played a role in laser-induced CNV development, and administration of BPHA reduced the experimental CNVs.
Kohri
Takashi
T
Department of Ophthalmology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, 545-8585, Osaka City, Japan. kohri@med.osaka-cu.ac.jp
Moriwaki
Mitsuyasu
M
Nakajima
Masatoshi
M
Tabuchi
Hitoshi
H
Shiraki
Kunihiko
K
D000284:Administration, Oral; D000818:Animals; D020256:Choroidal Neovascularization / Q000175:diagnosis / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D004792:Enzyme Precursors / Q000378:metabolism; D005451:Fluorescein Angiography; D018093:Gelatinases / Q000378:metabolism / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000037:antagonists & inhibitors; D007150:Immunohistochemistry; D007834:Lasers; D008297:Male; D008666:Metalloendopeptidases / Q000378:metabolism; D045726:Metalloproteases / Q000037:antagonists & inhibitors*; D011833:Radiation Injuries, Experimental / Q000150:complications; D051381:Rats; D011914:Rats, Inbred BN; D015430:Weight Gain
D004791:Enzyme Inhibitors; D004792:Enzyme Precursors; D006877:Hydroxamic Acids; C400001:N-biphenylsulfonylphenylalanine hydroxamic acid; D045726:Metalloproteases; D018093:Gelatinases; D008666:Metalloendopeptidases; C069860:progelatinase