oxadiazoles and Glaucoma

We investigated the feasibility and efficacy of using a specific sphingosine 1-phosphate (S1P1) receptor agonist, CYM-5442, to slow or block retinal ganglion cell (RGC) loss in endothelin-1 (ET-1) induced RGC loss. A single intravitreal injection of ET-1 (20pmol/ul), a potent vasoactive peptide that produces retinal vessels vasoconstriction, was used to induce and characterize RGC-specific cell death. CYM-5442 (1 mgr/kg) or vehicle was administered intraperitoneally for five consecutive days after ET-1-induced RGC loss. The functional extent of RGC loss injury was evaluated with pattern visual evoked potentials (VEP) and electroretinography. RGCs and retinal nerve fiber layer (RNFL) thickness were assessed in vivo using optical coherence tomography and ex vivo using Brn3a immunohistochemistry in flat-mounted retinas. ET-1 caused significant RGC loss and function loss one week after intravitreal injection. VEP showed preserved visual function after CYM-5442 administration compared to vehicle-treated animals (11.95 ± 0.86 μV vs 3.47 ± 1.20 μV, n = 12) (p < 0.05). RNFL was significantly thicker in the CYM treated-animals compared to the vehicle (93.62 ± 3.22 μm vs 77.72 ± 0.35 μm, n = 12) (p < 0.05). Furthermore, Brn3a immunohistochemistry validated this observation, showing significantly higher RGCs numbers in CYM treated rats than in the vehicle group (76,540 ± 303 vs 52,426 ± 1,932 cells/retina, n = 9) (p = 0.05). CYM-5442 administration was associated with significant retinal cleaved caspase-3 deactivation, indicating reduced apoptotic levels. The results of the present study further demonstrate the important role of S1P1 receptor agonists to lessen intravitreal ET-1 induced RGC loss.

Topics: Animals; Disease Models, Animal; Electroretinography; Endothelin-1; Evoked Potentials, Visual; Feasibility Studies; Glaucoma; Immunohistochemistry; Indans; Intravitreal Injections; Ischemia; Nerve Fibers; Neuroprotective Agents; Optic Nerve Diseases; Oxadiazoles; Rats; Rats, Wistar; Receptors, Lysosphingolipid; Retinal Diseases; Retinal Ganglion Cells; Transcription Factor Brn-3A

A small series of water-soluble NO-donor furoxans bearing a basic center at the 4-position, having a wide lipophilic-hydrophilic balance range, and endowed with different NO-release capacities, were synthesized and characterized. Selected members were studied for their IOP-lowering activity in the transient ocular hypertensive rabbit model at 1% dose. The most effective IOP-lowering products were compounds 3 and 7, whose activity 60min after administration was similar to that of Timolol. Notably, 7 was characterized by a long-lasting action. The IOP-lowering activity in this series of products appeared to be modulated by the lipophilic-hydrophilic balance rather than by the NO-donor capacity.

Topics: Animals; Antihypertensive Agents; Disease Models, Animal; Glaucoma; Intraocular Pressure; Nitric Oxide; Ocular Hypertension; Oxadiazoles; Rabbits; Solubility; Timolol

A series of furazan and furoxan sulfonamides were prepared and studied for their ability to inhibit human carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, hCA II, hCA IX, and hCA XII. The simple methyl substituted products 3-5 were potent inhibitors. Differing structural modifications of these leads had differing effects on potency and selectivity. In particular, products in which the sulfonamide group is separated from the hetero ring by a phenylene bridge retained high potency only on the hCA XII isoform. The sulfonamides 3-5 exerted intraocular pressure (IOP) lowering effects in vivo in hypertensive rabbits more efficiently than dorzolamide. Some other products (39-42), although less effective in vitro hCA II/XII inhibitors, also effectively lowered IOP in two different animal models of glaucoma.

Topics: Acrylic Resins; Animals; Antineoplastic Agents; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Disease Models, Animal; Glaucoma; Humans; Male; Oxadiazoles; Protein Isoforms; Rabbits; Sulfonamides

Several neurotoxins are known which destroy some specific retinal component or other link in the visual pathway. We have employed such reagents to induce blindness in chicks, in order to explore the role of vision in the development of light-induced avian glaucoma (LIAG) and/or lid-suture myopia (LSM). Chicks made pharmacologically blind with formoguanamine failed to develop LSM. Under LIAG conditions, increased eye weight and global enlargement did not occur, but the characteristic anterior segment changes were seen. Thus LIAG globe enlargement, and LSM axial lengthening, appear to be vision-driven, but anterior segment changes are probably separately controlled. The retinal neurotoxin kainic acid rendered chicks behaviorally blind in the eye into which it was injected intravitrially, but this failed to prevent LIAG changes in either anterior segment or growth of the globe. Chicks reared under LSM conditions, and treated with kainic acid were not different from untreated controls, in that they developed globe enlargement in spite of their pharmacologically-induced blindness. Preliminary trials with quisqualic acid, another retinal neurotoxin, indicate that this agent, like kainic acid, cannot prevent LIAG eye enlargement. Several quis-treated eyes developed phthisis bulbi however, and thus could not be included among those assessed for eye weight and dimensional measurements.

Topics: Animals; Blindness; Chickens; Cornea; Disease Models, Animal; Glaucoma; Kainic Acid; Light; Myopia; Organ Size; Oxadiazoles; Quisqualic Acid; Retina; Triazines; Vision, Ocular