Axonal Protection by Netarsudil, a ROCK Inhibitor, Is Linked to an AMPK-Autophagy Pathway in TNF-Induced Optic Nerve Degeneration

Kitaoka, Yasushi; Sase, Kana; Tsukahara, Chihiro; Fujita, Naoki; Arizono, Ibuki; Kogo, Jiro; Tokuda, Naoto; Takagi, Hitoshi

doi:10.1167/iovs.63.1.4

Cited by 12 publications

(8 citation statements)

References 33 publications

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“…Although a direct association between NR and AMPK has not been explored in neurons, it is noteworthy that Nampt ameliorated acute ischemic stroke during neuronal injury by upregulated AMPK [ 38 ]. We recently found that p-AMPK exists in optic nerve axons [ 27 ], and the present study found that oral NR administration enhanced the axonal immunoreactivity of p-AMPK. This is consistent with the current immunoblotting findings, implying that oral NR administration upregulates p-AMPK in optic nerve axons.…”

Section: Discussionsupporting

confidence: 70%

“…Our previous study demonstrated that intravitreal injection of NR attenuated axonal degeneration via the SIRT1-autophagy pathway in the TNF-induced optic nerve damage model [ 36 ]. In this TNF-induced optic nerve degeneration model, we recently found that netarsudil, a ROCK inhibitor, upregulated the p-AMPK protein level in the optic nerve and ameliorated axonal loss [ 27 ]. In the current study, oral NR administration clearly increased p-AMPK levels in the optic nerve in glaucomatous as well as control eyes.…”

Section: Discussionmentioning

confidence: 99%

“…Because one-time oral NR administration leads to p-AMPK elevation at 24 h, it is reasonable to speculate that daily oral NR administration leads to p-AMPK elevation during oral administration. One possible underlying mechanism of the upregulation of p-AMPK and protection from ocular hypertension is that upregulation of p-AMPK may lead to autophagy activation, because AMPK activator A769662 exerted axonal protection with autophagy activation in TNF-induced optic nerve damage [ 27 ]. In other neurons, NR upregulated the expression of key proteins of lipid droplet dynamics, PLIN1 and CIDEC, in the cochlea [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

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Axonal Protection by Oral Nicotinamide Riboside Treatment with Upregulated AMPK Phosphorylation in a Rat Glaucomatous Degeneration Model

Arizono,

Fujita,

Tsukahara

et al. 2023

CIMB

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Nicotinamide riboside (NR), a precursor of nicotinamide adenine dinucleotide (NAD+), has been studied to support human health against metabolic stress, cardiovascular disease, and neurodegenerative disease. In the present study, we investigated the effects of oral NR on axonal damage in a rat ocular hypertension model. Intraocular pressure (IOP) elevation was induced by laser irradiation and then the rats received oral NR of 1000 mg/kg/day daily. IOP elevation was seen 7, 14, and 21 days after laser irradiation compared with the controls. We confirmed that oral NR administration significantly increased NAD+ levels in the retina. After 3-week oral administration of NR, morphometric analysis of optic nerve cross-sections showed that the number of axons was protected compared with that in the untreated ocular hypertension group. Oral NR administration significantly prevented retinal ganglion cell (RGC) fiber loss in retinal flat mounts, as shown by neurofilament immunostaining. Immunoblotting samples from the optic nerves showed that oral NR administration augmented the phosphorylated adenosine monophosphate-activated protein kinase (p-AMPK) level in rats with and without ocular hypertension induction. Immunohistochemical analysis showed that some p-AMPK-immunopositive fibers were colocalized with neurofilament immunoreactivity in the control group, and oral NR administration enhanced p-AMPK immunopositivity. Our findings suggest that oral NR administration protects against glaucomatous RGC axonal degeneration with the possible upregulation of p-AMPK.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Axonal Protection by Oral Nicotinamide Riboside Treatment with Upregulated AMPK Phosphorylation in a Rat Glaucomatous Degeneration Model

Arizono,

Fujita,

Tsukahara

et al. 2023

CIMB

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“…A recent study has demonstrated that ripasudil upregulates p-AMPK in bovine corneal endothelial cells [ 28 ]. We have recently found that the ROCK inhibitor netarsudil increased p-AMPK in the optic nerve with upregulation of autophagy [ 29 ]. Very recent studies have also shown a close relationship between ROCK inhibition and AMPK activation in several different cells [ 30 , 31 ], suggesting that ROCK inhibitors may act as upstream effectors of AMPK.…”

Section: Discussionmentioning

confidence: 99%

“…Treatment with the AMPK activator A769662 increased Thr-172 phosphorylation of AMPK, resulting in stimulated PGC-1α-directed mitochondrial biogenesis and autophagy induction [ 34 ]. Treatment with A769662 exerted axonal protection associated with AMPK activation and autophagy induction in TNF-induced optic nerve degeneration [ 29 ]. A very recent study showed that A769662 protected UVA-induced retinal pigmented epithelial cells [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Axonal protection by combination of ripasudil and brimonidine with upregulation of p-AMPK in TNF-induced optic nerve degeneration

Otsubo,

Sase,

Tsukahara

et al. 2024

Int Ophthalmol

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Purpose The ROCK inhibitor ripasudil hydrochloride hydrate was shown to have axonal protective effects in TNF-induced optic nerve degeneration. The α2-adrenoreceptor agonist brimonidine was also shown to exert axonal protection. The current study aimed to elucidate whether additive axonal protection was achieved by the simultaneous injection of ripasudil and brimonidine and examine the association with AMPK activation. Methods Intravitreal administration was performed in the following groups: PBS, TNF, or TNF with ripasudil, with brimonidine, or with a combination of ripasudil and brimonidine. Axon numbers were counted to evaluate the effects against axon loss. Immunoblot analysis was performed to examine phosphorylated AMPK expression in optic nerves, and immunohistochemical analysis was performed to evaluate the expression levels of p-AMPK and neurofilament in the optic nerve. Results Both ripasudil alone or brimonidine alone resulted in significant neuroprotection against TNF-induced axon loss. The combination of ripasudil and brimonidine showed additive protective effects. Combined ripasudil and brimonidine plus TNF significantly upregulated p-AMPK levels in the optic nerve compared with the TNF groups. Immunohistochemical analysis revealed that p-AMPK is present in axons and enhanced by combination therapy. Conclusion The combination of ripasudil and brimonidine may have additive protective effects compared with single-agent treatment alone. These protective effects may be at least partially associated with AMPK activation.

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Phase 3 Clinical Trial Comparing the Safety and Efficacy of Netarsudil to Ripasudil in Patients with Primary Open-Angle Glaucoma or Ocular Hypertension: Japan Rho Kinase Elevated Intraocular Pressure Treatment Trial (J-ROCKET)

Araie,

Sugiyama,

Aso

et al. 2023

Adv Ther

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Introduction A clinical trial evaluated ocular hypotensive efficacy and safety of netarsudil 0.02% once daily (QD) relative to ripasudil 0.4% twice daily (BID). Methods This was a single-masked, randomized, phase 3, superiority study. Japanese patients were randomized to either the netarsudil 0.02% group or the ripasudil 0.4% group in a 1:1 ratio and treated for 4 weeks. The primary efficacy variable was mean diurnal intraocular pressure (IOP) (average of diurnal time points at 09:00, 11:00, and 16:00) at Week 4. Results A total of 245 patients were included in the primary analysis. At Week 4, least squares (LS) mean of diurnal IOP adjusted for baseline was 15.96 and 17.71 mmHg in the netarsudil 0.02% and ripasudil 0.4% groups, respectively, demonstrating the superiority of netarsudil 0.02% QD over ripasudil 0.4% BID by a margin of − 1.74 mmHg ( p < 0.0001). Mean reduction from baseline in mean diurnal IOP at Week 4 was 4.65 and 2.98 mmHg, respectively. Adverse events (AEs) occurred less frequently in netarsudil 0.02% than in ripasudil 0.4%, with the incidence of ocular AEs being 59.8% and 66.7%, respectively. The most frequently reported AE was conjunctival hyperemia in both groups, with an incidence of 54.9% and 62.6%, respectively. No serious eye-related AEs were reported. Conclusion Netarsudil ophthalmic solution 0.02% dosed QD (p.m.) was well tolerated and more effective in reducing IOP than ripasudil ophthalmic solution 0.4% dosed BID. Netarsudil 0.02% QD may become an important option for the treatment of Japanese patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT). Trial registration ClinicalTrials.gov identifier, NCT04620135. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-023-02550-w.

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Axonal Protection by Netarsudil, a ROCK Inhibitor, Is Linked to an AMPK-Autophagy Pathway in TNF-Induced Optic Nerve Degeneration

Cited by 12 publications

References 33 publications

Axonal Protection by Oral Nicotinamide Riboside Treatment with Upregulated AMPK Phosphorylation in a Rat Glaucomatous Degeneration Model

Axonal Protection by Oral Nicotinamide Riboside Treatment with Upregulated AMPK Phosphorylation in a Rat Glaucomatous Degeneration Model

Axonal protection by combination of ripasudil and brimonidine with upregulation of p-AMPK in TNF-induced optic nerve degeneration

Phase 3 Clinical Trial Comparing the Safety and Efficacy of Netarsudil to Ripasudil in Patients with Primary Open-Angle Glaucoma or Ocular Hypertension: Japan Rho Kinase Elevated Intraocular Pressure Treatment Trial (J-ROCKET)

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