Latanoprost exerts neuroprotective activity in vitro and in vivo.
Prostaglandins may influence cyclo-oxygenase (COX-2) and nitric oxide (NO) synthase activity, thus interfering with ischemia-induced neurotoxic processes. The prostaglandin synthetic derivative, latanoprost was tested in different in vivo and in vitro models of neuronal damage in order to study its influence on these processes. Ischemia was induced in rats by bilateral occlusion of the carotid arteries for 30 min. Latanoprost (0.01 mg x kg(-1)per die, i.p. for 3 days) or the ionotropic glutamate receptors antagonist, MK-801 (0.1 mg x kg(-1)per die, i.p. for 3 days) were equal in preventing lactate accumulation in retinal tissue of animals subjected to acute ischemia. Similar results were obtained in animals with retinal ischemia induced by increasing intraocular pressure to 120 mm Hg for 45 min. PGF2alpha, PGE2, latanoprost and acid of latanoprost (PhXA85) reduced the release of LDH from primary cultures of human retinal cells in vitro subjected to glutamate (10 microM) or hypoxia/re-oxygenation exposure. This effect was observed only at concentrations of 1-0.01 microM for PGF2alpha and PGE2, and of 0.1-0.001 microM for latanoprost (0.01 microM-0.1 nM for PhXA85). The COX-2 activity in cultured retinal cells exposed to glutamate was measured as PGE2 production when latanoprost was applied compared to arachidonic acid (AA) at different molar concentrations. The COX-2 activity was reduced by arachidonic acid (0.1-0.01 microM) as well as by latanoprost (0.1-0.001 microM) and PhXA85 (0.01-0.001 microM) in retinal cells exposed to glutamate. Inhibition of inducible NO synthase was also found with the same drug concentrations. These results suggest that latanoprost exerts a neuroprotective activity in vitro and in vivo. This effect seems to be present only at low concentrations of the drug. A negative feedback on neuronal COX-2 activity may be possibly involved.
Drago
F
F
Department of Experimental and Clinical Pharmacology, University of Catania Medical School, Catania, Italy. fdrago@tin.it
Valzelli
S
S
Emmi
I
I
Marino
A
A
Scalia
C C
CC
Marino
V
V
D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018698:Glutamic Acid / Q000009:adverse effects; D006801:Humans; D007511:Ischemia / Q000188:drug therapy*; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D000077338:Latanoprost; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011461:Prostaglandins F, Synthetic / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000033:anatomy & histology*; D013053:Spectrophotometry
D018696:Neuroprotective Agents; D011461:Prostaglandins F, Synthetic; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D000077338:Latanoprost; D007770:L-Lactate Dehydrogenase; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D011451:Prostaglandin-Endoperoxide Synthases