Lipoprotein-associated phospholipase A2 (Lp-PLA2) as a therapeutic target to prevent retinal vasopermeability during diabetes

Lipoprotein-associated phospholipase A2 (Lp-PLA2) hydrolyses oxidized low-density lipoproteins into proinflammatory products, which can have detrimental effects on vascular function. As a specific inhibitor of Lp-PLA2, darapladib has been shown to be protective against atherogenesis and vascular leakage in diabetic and hypercholesterolemic animal models. This study has investigated whether Lp-PLA2 and its major enzymatic product, lysophosphatidylcholine (LPC), are involved in blood-retinal barrier (BRB) damage during diabetic retinopathy. We assessed BRB protection in diabetic rats through use of species-specific analogs of darapladib. Systemic Lp-PLA2 inhibition using SB-435495 at 10 mg/kg (i.p.) effectively suppressed BRB breakdown in streptozotocin-diabetic Brown Norway rats. This inhibitory effect was comparable to intravitreal VEGF neutralization, and the protection against BRB dysfunction was additive when both targets were inhibited simultaneously. Mechanistic studies in primary brain and retinal microvascular endothelial cells, as well as occluded rat pial microvessels, showed that luminal but not abluminal LPC potently induced permeability, and that this required signaling by the VEGF receptor 2 (VEGFR2). Taken together, this study demonstrates that Lp-PLA2 inhibition can effectively prevent diabetes-mediated BRB dysfunction and that LPC impacts on the retinal vascular endothelium to induce vasopermeability via VEGFR2. Thus, Lp-PLA2 may be a useful therapeutic target for patients with diabetic macular edema (DME), perhaps in combination with currently administered anti-VEGF agents.

New Observations of Balmer Continuum Flux in Solar Flares:Instrument Description and First Results

Increase in the Balmer continuum radiation during solar flares was predicted by various authors, but has never been firmly confirmed observationally using ground-based slit spectrographs. Here we describe a new post-focal instrument, the image selector, with which the Balmer continuum flux can be measured from the whole flare area, in analogy to successful detections of flaring dMe stars. The system was developed and put into operation at the horizontal solar telescope HSFA2 of the Ondřejov Observatory. We measure the total flux by a fast spectrometer from a limited but well-defined region on the solar disk. Using a system of diaphragms, the disturbing contribution of a bright solar disk can be eliminated as much as possible. Light curves of the measured flux in the spectral range 350 – 440 nm are processed, together with the Hα images of the flaring area delimited by the appropriate diaphragm. The spectral flux data are flat-fielded, calibrated, and processed to be compared with model predictions. Our analysis of the data proves that the described device is sufficiently sensitive to detect variations in the Balmer continuum during solar flares. Assuming that the Balmer-continuum kernels have at least a similar size as those visible in Hα, we find the flux increase in the Balmer continuum to reach 230 – 550 % of the quiet continuum during the observed X-class flare. We also found temporal changes in the Balmer continuum flux starting well before the onset of the flare in Hα.