Latanoprost rescues retinal neuro-glial cells from apoptosis by inhibiting caspase-3, which is mediated by p44/p42 mitogen-activated protein kinase

Abstract

The purpose of this study was to investigate whether latanoprost, a prostaglandin F2alpha analogue, has a direct anti-apoptotic effect both in retinal neuro-glial cells in culture and in diabetic retina. R28 cells, immortalized retinal neuroglial progenitor cells, were induced apoptosis by 24h serum deprivation. Serum withdrawal made up to 15% of R28 cells pyknotic and activated caspase-3 immunoreactive, and latanoprost acid suppressed apoptosis with dose dependency at an optimum concentration of 1.0 microM (P<0.001). UO126, a mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase kinase (MEK) 1 and 2 inhibitor reversed this effect. Streptozotocin induced one- or three-month diabetic rats received balanced-salt-solution (BSS) in the left eye and latanoprost eye drops in the right for 5 days. Retinal wholemount was subjected to terminal dUTP nick end labeling (TUNEL) staining, whereas eyeballs were enucleated for cleaved caspase-3 immunofluorescence. Retinal homogenates were probed for phospho- or total p44/p42 MAPK and Akt. One- and three-month diabetic retina had 30.2+/-15.3 and 23.6+/-9.0 TUNEL positive cells per 0.5 cm(2), respectively, whereas control retina had few TUNEL positive cells. Latanoprost instillation significantly reduced these cells (10.0+/-3.1 and 11.3+/-3.1 cells per 0.5 cm(2) for 1M and 3M, respectively, P<0.01), whereas BSS did not. Latanoprost also significantly reduced cleaved caspase-3 immunoreactive cells in ganglion cell and inner nuclear layers (P<0.05). Latanoprost increased phosphorylated to total protein ratio of p44/p42 MAPK (P<0.05), but not of Akt. Taken together, the present findings suggest that latanoprost rescues retinal neurons and/or glial cells from apoptosis, which is probably mediated by p44/p42 MAPK through caspase-3 inhibition.

Comparison of the Protective Effects of Prostaglandin Analogues in the Ischemia and Reperfusion Model of Rabbit Eyes

“…Nakanishi et al showed that latanoprost rescued cells from apoptosis, secondary to serum deprivation, by inhibiting caspase-3, probably mediated by the mitogenactivated protein kinase pathway coupled to FP receptors in a dose-dependent manner [26]. In our study, we detected a significant alteration in the NaCl treated group compared to the control group.…”

“…During I/R, apoptosis plays a major role because oxygenderived reactive species (ROS) are known to trigger apoptosis [37,38]. Several studies have shown that application of exogenous free radical scavengers [3,9] and topically applied medications including PGA may reduce I/R-induced damage to the retina [2,20,26,29].…”

Direct Inhibition of N-Methyl-D-Aspartate (NMDA)-Receptor Function by Antiglaucomatous β-Antagonists

“…Although we observed that latanoprost had little inhibitory effects on NMDA receptors, this drug has been demonstrated to be neuroprotective against NMDAinduced RGC damage (13). This discrepancy could be because, as suggested by Nakanishi et al (14), latanoprost may act on proapoptotic signals downstream from NMDA receptors.…”

“…On the other hand, timolol, a nonselective β-antagonist, shows only weak inhibition of glutamate-induced Ca 2+ influx and little effect on cell death (9 -11). Recently, latanoprost, a prostaglandin F 2α analogue, has been demonstrated to exert a protective effect against RGC damage induced by NMDA (13), which seems to be related to the another report that shows an inhibitory effect of latanoprost on caspase-3 activation (14).…”

Pharmacotherapy of Glaucoma

“…The neuroprotective effect of latanoprost seems to be at least partially mediated by the pro-survival p44/p42 mitogen-activated protein kinase (MAPK). 84,85 In contrast, bimatoprost seems to prevent from RGC loss via the Akt pathway. Stimulation of the FP receptor by bimatoprost leads to activation of the PI3K/Akt pathway, which not only has a prosurvival effect but also initiates the proapoptotic Raf/MEK/ERK pathway.…”