Sphingosine-1-Phosphate (S1P) decreases outflow facility by reducing effective filtration area for aqueous humor outflow in bovine eyes

SECTION: Physiology/Pharmacology

Purpose: The cause of decreased aqueous outflow facility (C) in the conventional outflow pathway of primary open-angle glaucoma remains unknown. Sphingosine-1-phosphate (S1P), a lysophospholipid, was previously reported to decrease C in perfused porcine and human eyes. However, the morphological correlations to this decrease remain unclear. We hypothesize that decreased C by S1P is due to a decrease in effective filtration area (EFA), which results from increased connectivity between the juxtacanalicular connective tissue (JCT) and inner wall (IW) of aqueous plexus (AP) in bovine eyes.
Methods: Freshly enucleated bovine eyes were perfused at 15mmHg to establish a stable baseline C. One eye of each pair (N=7) was then perfused with 5μM S1P and the contralateral eye with GPBS for 2 hours. All eyes were perfused with a fixed volume of fluorescent microspheres (0.002%, 0.5μm) to trace the outflow pattern. Eyes were perfusion-fixed.
Trabecular meshwork of eyes (N=4) were frontally sectioned for confocal microscopy. Total length (TL) and filtration length (FL) of AP were measured to calculate percent effective filtration length (PEFL=FL/TL). The tissue was further processed for light microscopy. JCT/IW separation (SL) was measured and calculated for percent separation length (PSL=SL/TL). Two-tailed Student's t-test was used for statistical analysis.
Results: C was significantly increased in both S1P (p=0.04) and control (p=0.002) groups compared to baseline. Although both groups exhibited washout effect, C was significantly lower in the S1P group (1.93±0.44μl/min/mmHg) compared to the control group (3.60±1.07μl/min/mmHg, p=0.005). A significantly lesser amount of tracer was observed along the JCT/IW region of S1P treated eyes, corresponding to a 62.63% decrease in PEFL compared to controls (p=0.001). A significant positive correlation was found between PEFL and the percent increase in C. Interestingly, no significant difference was found in PSL between the control (25.64±6.32%) and S1P (22.57±3.34%) groups.
Conclusions: Our results are consistent with our hypothesis that decreased C by S1P is due to a significant decrease in EFA in bovine eyes. However, the morphologic correlation was not related to increased connectivity between the JCT and IW. Further morphologic examination will be needed to understand what structural changes account for decreased EFA by S1P.

Targeting aging: Geroprotective drug metformin reduces risk of adult-onset open-angle glaucoma

SECTION: Glaucoma

Purpose: Caloric-restriction (CR) and CR-mimetic drugs have geroprotective effects that delay or reduce Psome risks of aging. This study tested the hypothesis that the CR-mimetic drug metformin can reduce the risk of developing the late-onset trait open-angle glaucoma (OAG).
Methods: We analyzed nine years of longitudinal data from a large US health claims database (2001-2009). Diabetics, aged 40 and above with no pre-existing OAG, were monitored for incident OAG. The key predictor was exposure to metformin. A Cox proportional hazard model tested the effect of metformin on the hazard of developing OAG, adjusting for sociodemographic factors, glycemic control (HbA1c level), other diabetes medications, and other ocular and systemic conditions. The University of Michigan Institutional Review Board deemed use of this anonymized database to be exempt.
Results: Of 150,016 diabetics, 5,893 (3.9%) developed incident OAG. Use of >1,110 cumulative grams of metformin over two years was associated with a 25% reduction in relative risk of developing OAG (HR=0.75; 95% CI=0.59-0.95; p=0.017) compared with no metformin use. Every 1 gram increase in metformin was associated with a 0.01% reduced hazard of developing OAG (p=0.001). Thus someone receiving a normal dose of metformin (2 grams per day) over two years would show a 13% reduction in absolute risk of OAG relative to someone not taking metformin. When we stratified by baseline OAG risk and HbA1c level, the greatest absolute metformin-induced risk reduction was seen for those with the highest baseline risk and the highest HbA1c levels. Although HbA1c levels were associated with increased risk of OAG (HR=1.08; 95% CI=1.03-1.13; p=0.003), other hypoglycemic drugs did not reduce risk of OAG, and OAG risk-reduction in response to metformin occurred when HbA1c levels were taken into account.
Conclusions: Metformin use was associated with reduced risk of OAG. This OAG risk reduction was dose-dependent and independent of glycemic control; other diabetes medications did not confer a similar risk reduction. Thus, systems beyond glycemic control, such as neurogenesis, longevity pathways, and/or reduced inflammation may be involved in metformin-induced OAG risk-reduction. If confirmed by prospective clinical trials, these findings would offer novel treatments for this sight-threatening disease and perhaps other diseases of aging too.