Topical Ripasudil Suppresses Retinal Ganglion Cell Death in a Mouse Model of Normal Tension Glaucoma

Akaiwa, Kei; Namekata, Kazuhiko; Azuchi, Yuriko; Sano, Hiroki; Guo, Xiaoli; Kimura, Atsuko; Harada, Chikako; Mitamura, Yoshinori; Harada, Takayuki

doi:10.1167/iovs.17-23276

Cited by 20 publications

(29 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As already mentioned, the remaining fraction of released fasudil will most likely be eliminated via the retina. Besides their neuroprotective effects on retinal ganglion cells [19], ROCK inhibitors are under investigation for the treatment of several vitreoretinal diseases [67]. This could be very beneficial for some glaucoma patients because the prevalence of comorbid retinal disease is higher in patients with primary open-angle glaucoma (15.7%) [68].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Fasudil Loaded PLGA Microspheres as Potential Intravitreal Depot Formulation for Glaucoma Therapy

et al. 2020

View full text Add to dashboard Cite

Rho-associated protein kinase (ROCK) inhibitors allow for causative glaucoma therapy. Unfortunately, topically applied ROCK inhibitors suffer from high incidence of hyperemia and low intraocular bioavailability. Therefore, we propose the use of poly (lactide-co-glycolide) (PLGA) microspheres as a depot formulation for intravitreal injection to supply outflow tissues with the ROCK inhibitor fasudil over a prolonged time. Fasudil-loaded microspheres were prepared by double emulsion solvent evaporation technique. The chemical integrity of released fasudil was confirmed by mass spectrometry. The biological activity was measured in cell-based assays using trabecular meshwork cells (TM cells), Schlemm’s canal cells (SC cells), fibroblasts and adult retinal pigment epithelium cells (ARPE-19). Cellular response to fasudil after its diffusion through vitreous humor was investigated by electric cell-substrate impedance sensing. Microspheres ranged in size from 3 to 67 µm. The release of fasudil from microspheres was controllable and sustained for up to 45 days. Released fasudil reduced actin stress fibers in TM cells, SC cells and fibroblasts. Decreased collagen gel contraction provoked by fasudil was detected in TM cells (~2.4-fold), SC cells (~1.4-fold) and fibroblasts (~1.3-fold). In addition, fasudil readily diffused through vitreous humor reaching its target compartment and eliciting effects on TM cells. No negative effects on ARPE-19 cells were observed. Since fasudil readily diffuses through the vitreous humor, we suggest that an intravitreal drug depot of ROCK inhibitors could significantly improve current glaucoma therapy particularly for patients with comorbid retinal diseases.

show abstract

Section: Discussionmentioning

confidence: 99%

“…The great advantages of this strategy are that there is no ocular surface exposure and the portion of the drug that reaches the retina may be beneficial. In fact, ROCK inhibitors have been demonstrated to have neuroprotective effects on cells of the retina [19].…”

Section: Introductionmentioning

confidence: 99%

Fasudil Loaded PLGA Microspheres as Potential Intravitreal Depot Formulation for Glaucoma Therapy

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Excitatory amino-acid carrier 1 (EAAC1; EAAT3) is another type of glutamate transporter and it is mainly localized to RGCs in the retina. In EAAC1 KO mouse retinas, high levels of oxidative stress markers are observed compared with wild-type mice; and in cultured RGCs from EAAC1 KO mice, susceptibility to H 2 O 2 insults is higher compared with wild-type RGCs [16,28,29]. Like GLAST KO mice, EAAC1 KO mice reproduce some aspects of sporadic, age-dependent NTG pathology and make a good mouse model of NTG [16].…”

Section: Glutamate Transporter Deficient Micementioning

confidence: 99%

“…Moreover, in human glaucoma progressive retinal degeneration occurs slowly over years, but in GLAST/EAAC1 KO mice, it starts at 3~5 weeks of age, and in GLAST heterozygous mice, it occurs more slowly (1~4 months) and the effect of a drug can be studied over a year [16,32]. Regardless of such limitations, GLAST/EAAC1 KO mice all develop NTG-like phenotypes in a consistent time-course without affecting non-RGCs in the retina [16,29] and have been useful for providing potential therapeutic targets. We demonstrated the therapeutic effects of decreasing oxidative stress in these mice and we recently reported that some widely prescribed drugs suppressed RGC death in these mice without altering IOP.…”

Section: Glutamate Transporter Deficient Micementioning

confidence: 99%

Suppression of Oxidative Stress as Potential Therapeutic Approach for Normal Tension Glaucoma

et al. 2020

Self Cite

View full text Add to dashboard Cite

Glaucoma is a neurodegenerative disease of the eye, which involves degeneration of retinal ganglion cells (RGCs): the output neurons of the retina to the brain, which with their axons comprise the optic nerve. Recent studies have shown the possible involvement of oxidative stress in the pathogenesis of glaucoma, especially in the subtype of normal tension glaucoma. Basic experiments utilizing rodent and primate models of glaucoma revealed that antioxidants protect RGCs under various pathological conditions including glutamate neurotoxicity and optic nerve injury. These results suggested that existing drugs and food factors may be useful for prevention and hence therapy of glaucoma. In this review, we highlight some therapeutic candidates, particularly those with antioxidant properties, and discuss the therapeutic potential of RGC protection by modulating gene expressions that prevent and ameliorate glaucoma.

show abstract

“…Mice received once-daily topical administration (5 µl/day) of PBS as the control or 2% ripasudil (Kowa Co. Ltd., Tokyo, Japan) solution in PBS. We selected this dose of ripasudil because 2% is the concentration that can be stably dissolved without precipitation at normal temperature, and 2% ripasudil was effective for RGC protection in EAAC1 KO mice 10 . 2% ripasudil or PBS was administered 3 min after ONC.…”

Section: Drug Administrationmentioning

confidence: 99%

Topical ripasudil stimulates neuroprotection and axon regeneration in adult mice following optic nerve injury

Nishijima

Namekata

Kimura

et al. 2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

Optic nerve injury induces optic nerve degeneration and retinal ganglion cell (RGC) death that lead to visual disturbance. In this study, we examined if topical ripasudil has therapeutic potential in adult mice after optic nerve crush (ONC). Topical ripasudil suppressed ONC-induced phosphorylation of p38 mitogen-activated protein kinase and ameliorated RGC death. In addition, topical ripasudil significantly suppressed the phosphorylation of collapsin response mediator protein 2 and cofilin, and promoted optic nerve regeneration. These results suggest that topical ripasudil promotes RGC protection and optic nerve regeneration by modulating multiple signaling pathways associated with neural cell death, microtubule assembly and actin polymerization.

show abstract

Topical Ripasudil Suppresses Retinal Ganglion Cell Death in a Mouse Model of Normal Tension Glaucoma

Cited by 20 publications

References 65 publications

Fasudil Loaded PLGA Microspheres as Potential Intravitreal Depot Formulation for Glaucoma Therapy

Fasudil Loaded PLGA Microspheres as Potential Intravitreal Depot Formulation for Glaucoma Therapy

Suppression of Oxidative Stress as Potential Therapeutic Approach for Normal Tension Glaucoma

Topical ripasudil stimulates neuroprotection and axon regeneration in adult mice following optic nerve injury

Contact Info

Product

Resources

About