Neuroprotective properties of a synthetic docosanoid, unoprostone isopropyl: clinical benefits in the treatment of glaucoma.
The characteristic loss of visual field due to glaucoma is directly associated with retinal ganglion cell (RGC) death. The process of RGC death is thought to be biphasic, starting with a primary injury, followed by a slow secondary degeneration. Retinal ischemia may establish the cellular conditions that create a fatal biochemical cascade; hypoxia, followed by high excitotoxic levels of glutamate cause pathologically elevated levels of intracellular calcium resulting in neuronal cell death via apoptosis or necrosis. Impaired ocular perfusion, primarily due to abnormal autoregulation and/or vasoconstriction caused by endothelin-1, probably contributes to the ischemic milieu. Neuroprotection, the preservation of neurons that were either not damaged or only slightly damaged during the primary insult, has become important for the clinician when considering treatment options. Unoprostone, the first synthetic docosanoid, has been demonstrated to exhibit neuroprotective properties. In an ischemic animal model, unoprostone protected RGCs in a dose-dependent manner. Unoprostone inhibits glutamate stimulation and opens maxi-K channels, which are potassium channels that reach an activation threshold only during depolarization and/or at high intracellular Ca2+ concentrations. The resultant large efflux of K+ hyperpolarizes the cell, thereby closing voltage-gated Ca2+ channels and limiting neuronal damage by decreasing influx of intracellular Ca2+. Unoprostone has also been shown to protect rat photoreceptors from constant light-induced damage. Lastly, unoprostone has vasorelaxant properties, evidenced by increased choroidal blood flow and inhibition of vasoconstrictors such as endothelin-1. These findings indicate that a substantial clinical benefit of unoprostone is neuroprotection of RGCs.
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Sam Rothberg Glaucoma Center, Goldschlager Eye Institute, Sackler School of Medicine, Tel-Aviv University, Tel-Hashomer 52621, Israel.
D000818:Animals; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use*; D005901:Glaucoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats; D012160:Retina / Q000473:pathology
D018696:Neuroprotective Agents; C072630:isopropyl unoprostone; D015237:Dinoprost