Novel Neuroprotective Strategies in Ischemic Retinal Lesions

Retinal ischemia can be effectively modeled by permanent bilateral common carotid artery occlusion, which leads to chronic hypoperfusion-induced degeneration in the entire rat retina. The complex pathways leading to retinal cell death offer a complex approach of neuroprotective strategies. In the present review we summarize recent findings with different neuroprotective candidate molecules. We describe the protective effects of intravitreal treatment with: (i) urocortin 2; (ii) a mitochondrial ATP-sensitive K+ channel opener, diazoxide; (iii) a neurotrophic factor, pituitary adenylate cyclase activating polypeptide; and (iv) a novel poly(ADP-ribose) polymerase inhibitor (HO3089). The retinoprotective effects are demonstrated with morphological description and effects on apoptotic pathways using molecular biological techniques

Comparative pharmacokinetics and pharmacodynamics of the advanced Retinol-Binding Protein 4 antagonist in dog and cynomolgus monkey.

Accumulation of lipofuscin bisretinoids in the retina contributes to pathogenesis of macular degeneration. Retinol-Binding Protein 4 (RBP4) antagonists reduce serum retinol concentrations thus partially reducing retinol delivery to the retina which decreases bisretinoid synthesis. BPN-14136 is a novel RBP4 antagonist with good in vitro potency and selectivity and optimal rodent pharmacokinetic (PK) and pharmacodynamic (PD) characteristics. To select a non-rodent species for regulatory toxicology studies, we conducted PK and PD evaluation of BPN-14136 in dogs and non-human primates (NHP). PK properties were determined following oral and intravenous administration of BPN-14136 in beagle dogs and cynomolgus monkeys. Dynamics of plasma RBP4 reduction in response to compound administration was used as a PD marker. BPN-14136 exhibited favorable PK profile in both species. Dose-normalized exposure was significantly higher in NHP than in dog. Baseline concentrations of RBP4 were considerably lower in dog than in NHP, reflecting the atypical reliance of canids on non-RBP4 mechanisms of retinoid trafficking. Oral administration of BPN-14136 to NHP induced a strong 99% serum RBP4 reduction. Dynamics of RBP4 lowering in both species correlated with compound exposure. Despite adequate PK and PD characteristics of BPN-14136 in dog, reliance of canids on non-RBP4 mechanisms of retinoid trafficking precludes evaluation of on-target toxicities for RBP4 antagonists in this species. Strong RBP4 lowering combined with good PK attributes and high BPN-14136 exposure achieved in NHP, along with the biology of retinoid trafficking that is similar to that of humans, support the choice of NHP as a non-rodent safety species

Identification of Transthyretin Tetramer Kinetic Stabilizers That Are Capable of Inhibiting the Retinol-Dependent Retinol Binding Protein 4-Transthyretin Interaction

Dissociation of transthyretin (TTR) tetramers may lead to misfolding and aggregation of pro-amyloidogenic monomers, which underlies TTR amyloidosis (ATTR) pathophysiology. ATTR is a progressive disease resulting from the deposition of toxic fibrils in tissues that predominantly presents clinically as amyloid cardiomyopathy and peripheral polyneuropathy. Ligands that bind to and kinetically stabilize TTR tetramers prohibit their dissociation and may prevent ATTR onset. Drawing from clinically investigated AG10, we designed a constrained congener (18a) that exhibits excellent TTR tetramer binding potency, prevents TTR aggregation in a gel-based assay, and possesses desirable pharmacokinetics in mice. Additionally, 18a significantly lowers murine serum retinol-binding protein 4 (RBP4) levels despite a lack of binding at that protein’s all-trans-retinol site. We hypothesize that kinetic stabilization of TTR tetramers via 18a is allosterically hindering all-trans-retinol-dependent RBP4-TTR tertiary complex formation and that the compound could present ancillary therapeutic utility for indications treated with RBP4 antagonists, such as macular degeneration.<br /

Quercetin increases the efficacy of glioblastoma treatment compared to standard chemoradiotherapy by the suppression of PI-3-kinase-Akt pathway

The goal of the present study was to compare the efficacy of treatment with irradiation (IR), temozolomide, and quercetin, alone, or in combinations, on 2 glioblastoma cell lines, DBTRG-05 and U-251. Cell viability assay, flow cytometry analysis, colony formation assay, and Western blot analysis were used to compare the effects of treatment on the 2 cell lines. The greatest reduction in cell viability and colony formation was observed when cells were treated with a combination of the agents including quercetin. The treatment of cells with the combination of IR and quercetin was equal to the efficiency of the combination of IR and temozolomide in decreasing cell viability as well as colony formation. Quercetin alone, or in combination with IR, increased the cleavage of caspase-3 and PARP-1 showing an activated apoptosis and significantly reduced the level of phospho-Akt. Moreover, these treatments increased the levels of phospho-ERK, phospho-JNK, phospho-p38, and phospho-RAF1. Our data indicate that the supplementation of standard therapy with quercetin increases efficacy of treatment of experimental glioblastoma through synergism in the induction of apoptosis via the cleavage of caspase-3 and PARP-1 and by the suppression of the actitivation of Akt pathway

Bicyclic [3.3.0]-Octahydrocyclopenta[<i>c</i>]pyrrolo Antagonists of Retinol Binding Protein 4: Potential Treatment of Atrophic Age-Related Macular Degeneration and Stargardt Disease

Antagonists of retinol-binding protein 4 (RBP4) impede ocular uptake of serum all-<i>trans</i> retinol (<b>1</b>) and have been shown to reduce cytotoxic bisretinoid formation in the retinal pigment epithelium (RPE), which is associated with the pathogenesis of both dry age-related macular degeneration (AMD) and Stargardt disease. Thus, these agents show promise as a potential pharmacotherapy by which to stem further neurodegeneration and concomitant vision loss associated with geographic atrophy of the macula. We previously disclosed the discovery of a novel series of nonretinoid RBP4 antagonists, represented by bicyclic [3.3.0]-octahydro­cyclopenta­[<i>c</i>]­pyrrolo analogue <b>4</b>. We describe herein the utilization of a pyrimidine-4-carboxylic acid fragment as a suitable isostere for the anthranilic acid appendage of <b>4</b>, which led to the discovery of standout antagonist <b>33</b>. Analogue <b>33</b> possesses exquisite <i>in vitro</i> RBP4 binding affinity and favorable drug-like characteristics and was found to reduce circulating plasma RBP4 levels <i>in vivo</i> in a robust manner (>90%)

Effects of PACAP on the circadian changes of signaling pathways in chicken pinealocytes

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Design, Synthesis, and Evaluation of Nonretinoid Retinol Binding Protein 4 Antagonists for the Potential Treatment of Atrophic Age-Related Macular Degeneration and Stargardt Disease

Accumulation of lipofuscin in the retina is associated with pathogenesis of atrophic age-related macular degeneration and Stargardt disease. Lipofuscin bisretinoids (exemplified by <i>N</i>-retinylidene-<i>N</i>-retinylethanolamine) seem to mediate lipofuscin toxicity. Synthesis of lipofuscin bisretinoids depends on the influx of retinol from serum to the retina. Compounds antagonizing the retinol-dependent interaction of retinol-binding protein 4 (RBP4) with transthyretin in the serum would reduce serum RBP4 and retinol and inhibit bisretinoid formation. We recently showed that A1120 (<b>3</b>), a potent carboxylic acid based RBP4 antagonist, can significantly reduce lipofuscin bisretinoid formation in the retinas of <i>Abca4</i>^{<i>–/–</i>} mice. As part of the NIH Blueprint Neurotherapeutics Network project we undertook the in vitro exploration to identify novel conformationally flexible and constrained RBP4 antagonists with improved potency and metabolic stability. We also demonstrate that upon acute and chronic dosing in rats, <b>43</b>, a potent cyclopentyl fused pyrrolidine antagonist, reduced circulating plasma RBP4 protein levels by approximately 60%