Effect Of Metalloproteinase Inhibitor Research Articles

Cardioprotective Effects of Metalloproteinase Inhibitor 1-({4-[(4-Chlorobenzoyl)amino]phenyl}sulfonyl-L-Proline in Modeled Acute Myocardial Infarction.

Cardioprotective effect of 1-({4 [(4 chlorobenzoyl)amino]phenyl}sulfonyl-L-proline (compound AL-828) was studied in rats with modeled acute myocardial infarction. The test compound was administered intragastrically in a dose of 30 mg/kg/day for 3 days prior to infarction modeling. Metalloproteinase inhibitor antibiotic doxycycline served as the reference drug and was administered in a dose of 40 mg/kg/day by the same schedule. It was shown that AL-828 similar to doxycycline significantly reduced the intensity of myocardial remodeling and maintained the inotropic function of the myocardium in the acute phase of myocardial infarction. By the 20th minute of ischemia, the end-systolic dimension of the left ventricle in control animals increased from 1.98±0.12 to 3.84±0.16 mm, while in animals treated with AL-828, this increase was significantly (p=0.007) less pronounced (from 1.84±0.07 and 2.87±0.21 mm, respectively). The ejection fraction characterizing the inotropic status of the left ventricle in animals treated with AL-828 was significantly higher (p=0.02). By its cardioprotective activity, AL-828 was not inferior to the reference drug doxycycline. It can be assumed that the cardioprotective activity of compound AL-828 is related to suppression of MMP-9 expression and/or inhibition of its activity as was previously demonstrated by us.

Effect of Metalloproteinase Inhibitors on Bond Strength of a Self-etching Adhesive on Erosively Demineralized Dentin.

To analyze the influence of epigallocatechin-3-gallate (EGCG) and chlorhexidine (CHX) on adhesive-dentin bond strength of a self-etch adhesive to sound dentin (SD) and eroded dentin (ED). Thirty-six middle-dentin samples were assigned to six groups (n = 6) according to pretreatment (DW: distilled water, control; 0.1% EGCG; or 2% CHX) and erosive challenge (presence or absence). Specimens were subjected to 2-h acquired pellicle formation, then half of them were exposed to 1% citric acid three times a day for five days. SD and ED were treated with the tested solutions for 60 s, and then Clearfil SE Bond was applied before resin composite buildup. Bonded teeth were longitudinally sectioned into sticks and half were immediately tested, while the remaining specimens were tested after six months. The mode of fracture was examined and the microtensile bond strength (µTBS) measured. Statistical analysis was performed with ANOVA and Bonferroni tests. At both time periods, regardless of the dentin substrate, EGCG groups did not show bond strengths that were significantly different from those obtained with DW (p > 0.05), while CHX generated lower values than did DW (p < 0.05). On SD, there was a bond strength reduction only in the CHX groups after six months. However, for ED, the bond strength significantly decreased in all groups. CHX negatively affected both dentin substrates, while the pretreatment with EGCG did not affect µTBS over time on SD. µTBS may be influenced by the substrate over time and EGCG can be used as an alternative to CHX to maintain the bond strength of self-etching adhesives.

Effect of Metalloproteinase Inhibitors on the Microtensile Bond Strength of Composite Resin to Er:YAG Laser-Irradiated Dentin.

This study evaluated the effect of matrix metalloproteinase (MMP) inhibitors - 2% (CHX) and sodium fluoride (NaF) (5000 ppm) - on microtensile bond strength (μTBS) of composite resin to Er:YAG laser-irradiated dentin after chemical degradation of the bond interface. The occlusal surface of forty sound human molars was removed exposing the dentin surface (n=10), which was polished, irradiated with Er:YAG laser, acid etched and dried. Twenty specimens were rewetted with 2% CHX (control group) and 20 were rewetted with NaF (5000 ppm). The adhesive system was applied and a 4-mm-high plateau of light-cured composite resin was built up. Resin-dentin sticks were obtained with a rectangular cross-sectional area (0.8-1 mm2) and were either stored in water at 37 ?#61616;C for 24 h or submitted to chemical degradation. For chemical degradation, they were immersed in 10% NaOCl aqueous solution for 5 h and rinsed in water for 1 h. The sticks were submitted to microtensile test in a mechanical testing machine at 0.5 mm/min until failure. Fracture pattern was analyzed using SEM. μTBS values were calculated in MPa and submitted to analysis of variance ANOVA (α=0.05). The variance analysis showed that the 'MMP inhibitor' and 'degradation' factors (p=0.214 and p=0.093, respectively) and interaction between the factors were not statistically significant (p=0.143). Mixed failure predominated in all groups. In conclusion, the 2% CHX and NaF 5000 ppm presented similar μTBS of composite resin to laser-irradiated dentin before and after chemical degradation.

Effect of Metalloproteinase Inhibitor on Early Postinfarction Remodeling in the Most Acute Phase of Myocardial Infarction

Echocardiography in control narcotized rats (n=12) revealed that acute single-stage ligation of coronary artery induced a rapid and significant decrease in systolic function of the heart, which attained minimum to postischemic minutes 10-20 and then gradually restored during 60 min after coronary occlusion. Matrix proteinase inhibitor doxycycline (40 mg/kg/day intragastrically for 3 days prior to the experiment) prevented dramatic impairment of systolic function in the left ventricle during first 20 min of ischemia and then all the indices characterizing the state of pumping function of the left ventricle in the experimental (doxycycline) group (n=9) surpassed the control. Thus, matrix proteinase inhibitor doxycycline prevented early postischemic remodeling of the heart during the most acute phase of experimental myocardial infarction.

Effects of a metalloproteinase inhibitor on osteochondral angiogenesis, chondropathy and pain behavior in a rat model of osteoarthritis

SummaryObjectiveTo investigate the effects of a matrix metalloproteinase (MMP) inhibitor on joint pathology and pain behavior in the rat meniscal transection (MNX) model of osteoarthritis (OA) and evaluate which aspects of structural disease modification contribute to symptom improvement.MethodsOA pathology was induced in male Lewis rats, by transecting the medial collateral ligament with (MNX) or without (SHAM) a full thickness cut through the meniscus. MNX animals were orally administered an equipotent MMP 2, 8, 9, 12, 13 inhibitor (0.25, 1 and 5 mg/kg/day) or vehicle from day 1. Chondropathy, osteophytosis, osteochondral vascularity were assessed from toluidine blue stained coronal sections of the total knee joint and weight-bearing asymmetry by incapacitance. Group differences were evaluated using 1-way analysis of variance (ANOVA) and associations as Spearman's correlation coefficients.ResultsTreatment with the MMP inhibitor reduced weight-bearing asymmetry from day 14 onwards, and attenuated chondropathy (both P < 0.05). Osteochondral vascularity was elevated in MNX compared with SHAM-operated animals (P < 0.001) and reduced, dose-dependently, by MMP inhibitor treatment (r = −0.89, P < 0.05). Reduced osteochondral vascularity and chondropathy were associated with the amelioration of weight-bearing asymmetry (both P < 0.05).ConclusionHere we show that treatment with a MMP inhibitor reduces joint damage, osteochondral angiogenesis and behavioral evidence of pain. The association between osteochondral angiogenesis and pain behavior may be explained by perivascular nerve growth or stimulation of subchondral nerves following loss of osteochondral integrity. Our data suggest that targeting angiogenesis may have utility in the treatment of pain associated with structural damage in OA.

Effects of metalloproteinase inhibitors on leukotriene A 4 hydrolase in human airway epithelial cells

Human neutrophil leukotriene A 4 (LTA 4) hydrolase is a zinc-containing metalloproteinase with aminopeptidase activity and can be inhibited by some metalloproteinase inhibitors. Human airway epithelial cells also contain an LTA 4 hydrolase enzyme that has some novel properties, suggesting that this enzyme may be functionally and structurally unique. Thus, we questioned whether the epithelial enzyme could also be inhibited by metalloproteinase inhibitors. Transformed human airway epithelial cells were studied either intact or disrupted. Of the metalloproteinase inhibitors examined, only captopril, bestatin, and fosinoprilat had appreciable inhibitory activity for LTA 4 hydrolase in disrupted epithelial cells. Concentration-inhibition curves to captopril, bestatin, and fosinoprilat revealed ic 50 values of 430 μM, 7 μM, and 1 mM, respectively, for disrupted-cell LTA 4 hydrolase activity. In contrast to its effects on neutrophils, 1,10- O-phenanthroline had no significant effect on disrupted epithelial cell hydrolase activity and had only minimal effects when this activity was partially purified (179-fold). LTA 4 hydrolase concentration-inhibition curves examined in intact cells with captopril, bestatin, and 1,10- O-phenanthroline revealed ic 50 values of 63, 70, and 920 μM, respectively. Aminopeptidase activity in disrupted epithelial cells was inhibited by amastatin, bestatin, and 1,10- O-phenanthroline ( ic 50 values of 500 nM, 1 μM, and 17 μM, respectively), but not by captopril at the highest concentration tested, 10 mM. These findings are in contrast to prior studies in neutrophils. When neutrophils were stimulated with A23187 after treatment with captopril, transcellular synthesis of LTB 4 was inhibited more effectively than direct synthesis of leukotriene B 4 (LTB 4) (43.8 ± 2.5 vs 18.5 ± 4.7%; N = 8, P < 0.02). We conclude that LTA 4 hydrolase activity of human airway epithelial cells is inhibited by some metalloproteinase inhibitors, but that the profile of inhibition is distinct from that for the neutrophil enzyme. These data provide additional information that LTA 4 hydrolase in the epithelial cell is a novel enzyme, distinct from that found in the neutrophil.