Nipradilol Promotes Axon Regeneration Through S-Nitrosylation of PTEN in Retinal Ganglion Cells

Abstract

Nipradilol (Nip) is registered as an anti-glaucoma agent. More recently, a protective effect of Nip has been demonstrated in retinal ganglion cells (RGCs) mediated by S-nitrosylation of antioxidative-related Keap1 protein due to its nitric oxide (NO)-donating effect. It also has been reported that Nip promoted axon outgrowth in cat RGCs. However, the detailed mechanism remains unclear. NO physiologically regulates numerous cellular responses through S-nitrosylation of protein at cysteine residues. It has been reported that phosphatase and tensin homologue deleted on chromosome 10 (PTEN) deletion strongly showed axon regeneration after optic nerve injury. PTEN inactivation by S-nitrosylation results in the accumulation of phosphatidylinositol (3, 4, 5) triphosphate (PIP3) and the activation of Akt/mammalian target of rapamycin (mTOR) signaling. The ribosomal S6 kinase 1 (S6K) which can monitor as phospho-S6 (pS6) is one of major target of mTOR. In this study, we investigated the possibility that Nip can promote axon outgrowth in RGCs by Akt/mTOR signaling thorough S-nitrosylation of PTEN.

Medical Treatment of Primary Canine Glaucoma

“…87,90,93,94 Because the preponderance of current antiglaucoma medications target AH production and uveoscleral outflow, there remains an enormous therapeutic potential for compounds, such as NO, that exert direct effects on the conventional pathway. Furthermore, numerous additional studies hint at the profound effects NO may have on regulating intraocular inflammation, 95 chorioretinal and optic nerve head blood flow, 96,97 AH formation, 98,99 and episcleral vascular resistance 100 as well as limiting RGC degeneration in models of glaucoma and ischemia. [101][102][103] Although eNOS and nNOS expression have been noted in human trabecular meshwork tissue, [104][105][106] there are no studies to the authors' knowledge that demonstrate ocular expression and localization under normal physiologic conditions of the NOS isoforms in domestic animal species (eg, dogs, cats, and horses).…”

Nitric Oxide (NO): An Emerging Target for the Treatment of Glaucoma

“…110 Nipradilol also caused S-nitrosylation and inhibition of phosphatase and tensin homologue deleted on chromosome 10 (PTEN), leading to increased protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling, a pathway for axon regeneration. 111 Overall, the literature on the role of NO in optic neuropathy is suggestive of a dual action, with low levels exhibiting neuroprotective effects and high levels (from induction of iNOS and/or upregulation of nNOS) mediating neurodegenerative effects. In the case of topical NO therapy, data is lacking; however, studies using nipradilol demonstrate that this particular NO donor reaches the retina at levels that can mediate neuroprotective effects.…”

Nitric Oxide Contributes to Retinal Ganglion Cell Survival Through Protein S-Nitrosylation After Optic Nerve Injury

“…It has been known that PTEN is inactivated by S-nitrosylation and then activates phosphoinositide 3-kinase (PI3K) and its downstream pathway [39]. We showed a correlation between Akt/mTOR activities and optic nerve regeneration through S-nitrosylation of PTEN in RGCs [80] (Fig. 6.3).…”