Latanoprost Promotes Neurite Outgrowth in Differentiated RGC-5 Cells via the PI3K-Akt-mTOR Signaling Pathway

Abstract

Latanoprost, a synthetic derivative of the natural prostaglandin F(2a) (PGF(2a)), is a powerful antiglaucoma agent with ocular hypotensive and neuroprotective effects. However, the neuroregenerative effect and signaling pathway of latanoprost in retinal ganglion cells (RGCs) are still unknown. The purpose of this study is to investigate the regenerative effect of latanoprost in differentiated RGC-5 cells and its underlying mechanisms. Cell viability was determined by Cell Counting Kit-8 (CCK-8) assay and neurite length was examined by ArrayScan HCS Reader and Neurite outgrowth BioApplication. Expressions of Akt phosphorylation (p-Akt) and mammalian target of rapamycin phosphorylation (p-mTOR) were investigated by Western blot analysis. The results indicated that 0.1 μM latanoprost (at a clinically therapeutic concentration) significantly increased cell viability as compared with control. Meanwhile, 0.1 μM latanoprost resulted in the obvious promotion of neurite outgrowth similar to ciliary neurotrophic factor (CNTF) and simultaneously increased the levels of p-Akt and p-mTOR expression. The effects of latanoprost were blocked by the Prostaglandin F receptor (FP receptor) inhibitor AL8810, the phosphoinositide 3-kinase (PI3K) inhibitor LY294002 and the mTOR inhibitor rapamycin. This study presents novel in vitro evidence that latanoprost could promote neurite outgrowth through an FP receptor-mediated modulation of the PI3K-Akt-mTOR signaling pathway. This finding may provide insight into a better understanding of a new mechanism of latanoprost for glaucoma therapy and into the physiological-modulating activities of prostaglandins.

Neurite outgrowth mediated by the heat shock protein Hsp90α: a novel target for the antipsychotic drug aripiprazole

“…19, 21, 22, 23, 40, 41, 42, 43, 44, 45, 46, 47 We examined the effects of specific inhibitors for these molecules on neurite outgrowth. The PLC-γ inhibitor, U73122 (1.0 μℳ), PI3K inhibitor, LY294002 (10 μℳ), mTOR inhibitor (rapamycin; 5.0 μℳ), p38 MAPK inhibitor, SB203580 (10.0 μℳ), JNK inhibitor, SP600125 (10 μℳ) and Akt inhibitor (1.0 μℳ) significantly blocked aripiprazole's potentiation of NGF-induced neurite outgrowth (Figure 3).…”

Long Non-Coding RNA-MALAT1 Mediates Retinal Ganglion Cell Apoptosis Through the PI3K/Akt Signaling Pathway in Rats with Glaucoma

“…Nakazawa et al created an ischemic model of optic nerve injury with optic nerve crush and found that PI3K/Akt pathway activation produces a neuroprotective effect against retinal and optic nerve injury [39]. Moreover, the P13K/Akt signaling pathway can contribute to the neurite outgrowth of differentiated RGCs [40]. Therefore, this pathway is needed to inhibit the occurrence of apoptosis and promote axonal regeneration in both glaucoma and optic neuropathy [41, 42].…”

Secondary neuroprotective effects of hypotensive drugs and potential mechanisms of action

“…Additionally, this same study found that COX-2 activity was reduced by both arachidonic acid and latanoprost in RGCs exposed to excess glutamate and that inhibition of inducible nitric oxide synthase occurred with the same drug concentrations. Latanoprost may also exhibit a direct anti-apoptotic effect via neurite outgrowth and caspase-3 inhibition, mediated by p44/p42 mitogen-activated protein kinase [98,99]. There are several other hypotheses regarding secondary neuroprotective mechanisms for prostaglandin analogs, including effects on ocular and ONH hemodynamics [100,101].…”