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Unoprostone isopropyl is an ocular hypotensive that was originally produced as a prostaglandin F2alpha analogue and is eventually recognized as a synthetic docosanoid. The compound is recently suggested to have potent neuroprotective ability in the retina. The purpose of this study is to test whether and how the biologically active metabolites of unoprostone isopropyl rescue retinal neuro-glial progenitor cells from apoptosis.R28 cells were deprived of serum for 24 hr with or without varying concentrations of unoprostone metabolite M1 or M2 or vehicle in the presence or absence of specific inhibitors against several types of signal transduction proteins. Immunocytochemistry against activated caspase-3 with Hoechst nuclear staining was performed.Up to 15%of R28 cells became pyknotic and activated caspase-3 immunoreactive after 24-hr serum withdrawal. M1, but not M2, significantly reduced apoptotic cells in a dose-dependent fashion with a maximal effect at 100 microM (p.0001). LY294002, the phosphatidylinositol 3-OH kinase (PI3K) inhibitor, and KT5823, the protein kinase G (PKG) inhibitor, reversed the antiapoptotic effect of M1.The unoprostone metabolite M1 protects retinal neuro-glial progenitor R28 cells from apoptosis induced by serum deprivation via the PI3K and PKG pathways.

To evaluate the effect, and the duration of the effect, of topically administrated travoprost and unoprostone on optic nerve head (ONH) circulation in Dutch rabbits.First, travoprost (0.004% solution) or unoprostone (0.12% solution) was unilaterally instilled once, or once daily (travoprost) or twice daily (unoprostone) for 7 days in Dutch rabbits. The ONH tissue blood velocity (NB(ONH)) was measured using the laser speckle method at 30 and 60 min after a single instillation of travoprost or unoprostone, and before and at 1, 6, and 12 hr (travoprost or unoprostone) and 24 hr (travoprost only) after the last instillation of the aforementioned 7-day instillation regimen. Second, similar experiments were conducted with indomethacin (5 mg/kg) pretreatment.Both travoprost and unoprostone significantly increased NB(ONH) only in the treated eyes after a single instillation (p = 0.011 to 0.038); this effect was abolished by indomethacin pretreatment. In the 7-day instillation regimen, NB(ONH) was increased by 11%, 40%, 17%, 16%, and 12% only in the treated eyes just before and at 1, 6, 12, and 24 hr after the final instillation of travoprost, respectively, and increased by 10%, 25%, 13%, and 14% only in the treated eyes just before and at 1, 6, 12 hr after the final instillation of the unoprostone, respectively.Topical travoprost or unoprostone significantly increased the ONH blood velocity with a single instillation and the effect persisted for 24 hr after a 7-day instillation. The effects of these drugs against retinal and ONH circulation are probably associated with the production of endogenous prostaglandins.

To clarify the vasodilatory mechanism of unoprostone isopropyl (unoprostone), a PG F2alpha related compound used for treatment of glaucoma, we have investigated the effect of this drug and its metabolites on isolated rabbit ciliary artery in vitro.Under the dissecting microscope, ciliary arteries were prepared from albino rabbit eyes and mounted in a myograph system. The effects of unoprostone isopropyl and other agents were investigated using isometric tension recording methods.Unoprostone induced a dose-dependent relaxation in ciliary arteries that were pre-contracted with high-K solution, 10 microM histamine or 10 microM PG F2alpha. Neither unoprostone metabolite M1 or M2 had a relaxant effect on the precontracted vessels. Relaxation was unaffected by inhibition of adenylyl cyclase with SQ 22536, guanylyl cyclase with ODQ, or maxi-K channels with iberiotoxin. Pretreatment with unoprostone did not affect histamine-induced transient contractions in Ca2+ -free solution. However, SKF96365, a general Ca2+ channel blocker, evoked relaxation similar to unoprostone with respect to amplitude and rate of onset.Unoprostone, but not its metabolites M1 and M2, relaxed pre-contracted rabbit ciliary artery. The mechanism of vascular smooth muscle relaxation by unoprostone differs from that of IOP reduction and does not depend on adenylyl cyclase, guanylyl cyclase, or maxi-K channels. Relaxation may be mediated by inhibition of Ca2+ entry, possibly through capacitative Ca2+ channels.