Neuroprotective Effect of Ocular Hypotensive Drugs: Latanoprost/Timolol in Combination Are More Effective than Each as Monotherapy in RGC-5

Abstract

The combination of timolol and latanoprost, which are ocular hypotensive agents, has a greater ocular hypotensive effect than each as monotherapy. However, the protective effect of the combination is not well understood. In the present study, we investigated whether latanoprost/timolol in combination has an additive or synergistic cytoprotective effect on neuro retinal cells (RGC-5). To investigate the protective effects of timolol/latanoprost in combination, cultured RGC-5 were treated with various concentrations of these two agents, singly or together, after which the cells were exposed to oxidative stress, serum deprivation, or endoplasmic reticulum (ER) stress in vitro. Cells were also treated with an Akt inhibitor, LY294002, to examine the mechanism of the protective effect. Latanoprost, timolol, and the two in combination reduced cell death induced by oxidative stress, serum deprivation, or ER stress. The latanoprost/timolol combination reduced cell death to a greater extent than monotherapy with latanoprost or timolol on serum deprivation only, and LY294002 inhibited the protective effect of their combination. These findings suggest that timolol/latanoprost in combination have a protective effect against serum deprivation only by activation of Akt signaling. Furthermore, this combination has not only an ocular hypotensive effect but also a neuroprotective effect.Key words glaucoma; latanoprost; neuroprotective effect; phosphatidyl inositol 3-kinase (PI3K); Akt; timolol Glaucoma is a progressive neurodegenerative disease affecting over 60 million people worldwide and predicted to affect more than 80 million people by 2020. 1) Glaucoma is also the second most common cause of irreversible blindness. An increase in intraocular pressure (IOP) contributes to the pathogenesis of glaucoma.2) Treatment of glaucoma is focused on decreasing IOP, because IOP is one of the most important risk factors for disease progression.3) Glaucoma drugs that reduce IOP include beta blockers, carbonic anhydrase inhibitors, prostaglandin analogs, sympathomimetics, and miotics. Retinal ganglion cells are highly sensitive to increased IOP, and retinal ganglion cell damage is caused by several types of cell stress. 4,5) For example, retinal ganglion cell death in glaucoma is not only related to oxidative stress, but also to endoplasmic reticulum (ER) stress and ischemic stress. 6,7) Moreover, a previous report suggested that this retinal ganglion cell death is mediated by phosphatidyl inositol 3-kinase (PI3K)/Akt pathway, and the inhibition of PI3K/Akt pathway promoted retinal ganglion cell survival in rat optic nerve injury model. 8) Many patients with glaucoma have normal IOP. Therefore, it is important to not only decrease IOP, but also to protect retinal cells during glaucoma therapy.Prostaglandin analogs, such as latanoprost, are the major therapy that reduces IOP by stimulating drainage of the aqueous humor. Latanoprost is a prostaglandin F2α analog and is effective at reducing IOP when used alone. 9) Additionally, latanoprost p...

Effect of Timolol on Optineurin Aggregation in Transformed Induced Pluripotent Stem Cells Derived From Patient With Familial Glaucoma

“…It has been reported that timolol has neuroprotective effects, 21,22 and our results showed that timolol increased the number of ATH5-positive RGCs and decreased TUNEL-positive RGCs in the E50K-iPSCs-RGCs #1 (Figs. 3K-N) and E50K-iPSCs-RGCs #2 ( Supplementary Fig.…”

“…We examined whether timolol might be a therapeutic agent for OPTNE50K-NTG because of the increase of DBH in E50K-iPSCs-RGCs #1 and the earlier evidence that timolol has neuroprotective effects. 21,22 First, we examined whether timolol can reduce OPTNE50K aggregation. BX795 was used as a positive control because it is a TBK1 inhibitor that is known to reduce OPTN aggregation.…”

Prostaglandin analogues: past, present, and future

“…Необходимо упомянуть, что помимо гипотензивного эффекта аналоги простагландинов также, возможно, обладают и независимым от снижения ВГД нейропротективным эффектом [89], который был наиболее убедительно продемонстрирован в новых исследованиях латанопроста [90] и может быть ещё более выражен при использовании латанопроста в составе фиксированной комбинации с тимололом [30]. Эти исследования представляют одно из перспективных направлений научного поиска в области борьбы с глаукомой в ближайшем будущем.…”