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

Nishijima, Euido; Namekata, Kazuhiko; Kimura, Atsuko; Guo, Xiaoli; Harada, Chikako; Noro, Takahiko; Nakano, Tadashi; Harada, Takayuki

doi:10.1038/s41598-020-72748-3

Cited by 8 publications

(6 citation statements)

References 33 publications

(56 reference statements)

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“…The phosphorylation of CRMP2 is known to be associated with many neurodegenerative diseases (Cole et al, 2007;Menon et al, 2011;Zhao et al, 2020). A significant change in the phosphorylation level, but not in the protein level of CRMP2, has been reported in a mice 7 days after ONC (Nishijima et al, 2020), and a previous study reported the suppression of axonal degeneration in CRMP2KI/KI mice (Kinoshita et al, 2019), resulting in axonal stabilization. Mice injected with bi-cistronic adeno-associated viral (AAV2) vectors encoding a mutant phospho-resistant version of CRMP2 (CRMP2T555A) in RGCs showed neuroprotective effects in the retina and suppression of axonal degeneration after partial optic nerve injury (Chiha et al, 2020).…”

Section: Discussionmentioning

confidence: 92%

Genetic inhibition of collapsin response mediator protein‐2 phosphorylation ameliorates retinal ganglion cell death in normal‐tension glaucoma models

et al. 2022

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Glaucoma is a neurodegenerative disorder caused by the death of retinal ganglion cells (RGCs). Elevated intraocular pressure (IOP) is a cause of glaucoma.However, glaucoma often develops with normal IOP and is known as normaltension glaucoma (NTG). Glutamate neurotoxicity is considered as one of the significant causes of NTG, resulting in excessive stimulation of retinal neurons via the N-methyl-D-aspartate (NMDA) receptors. The present study examined the phosphorylation of collapsin response mediator protein-2 (CRMP2), a protein that is abundantly expressed in neurons and involved in their development. In two mouse models, NMDA-injection and glutamate/aspartate transporter (GLAST) mutant, CRMP2 phosphorylation at the cyclin-dependent kinase-5 (Cdk5) site was elevated in RGCs. We confirmed that the decrease in the number of RGCs and thickness of the inner retinal layer (IRL) could be suppressed after NMDA administration in CRMP2KI/KI mice with genetically inhibited CRMP2 phosphorylation. Next, we investigated GLAST heterozygotes (GLAST+/À) with CRMP2KI/KI (GLAST+/À;CRMP2KI/KI) and GLAST knockout (GLASTÀ/À) mice with CRMP2KI/KI (GLASTÀ/À; CRMP2KI/KI) mice and compared them with GLAST+/À and GLASTÀ/À mice. pCRMP2 (S522) inhibition significantly reduced RGC loss and IRL thinning. These results suggest that the inhibition of CRMP2 phosphorylation could be a novel strategy for treating NTG.

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Section: Discussionmentioning

confidence: 92%

Genetic inhibition of collapsin response mediator protein‐2 phosphorylation ameliorates retinal ganglion cell death in normal‐tension glaucoma models

et al. 2022

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“…Several studies using different ROCK inhibitors focused on axonal regeneration after optic nerve injury. These ROCK inhibitors which have axonal regeneration effects include Y-27632, Y-39983, netarsudil, and ripasudil [ 16 – 19 ]. Among them, it was shown that ripasudil suppressed the phosphorylation of cofilin, a depolymerizing protein [ 19 ].…”

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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“…This provides the notion that the inability of CNS neurons to regenerate is an intrinsic property (He and Jin, 2016). Indeed, a large body of research now supports that manipulating intrinsic factors involved in CNS axon regeneration can promote robust axon regeneration in one of the popular CNS injury models, optic nerve crush (ONC) (Park et al, 2008;Smith et al, 2009;Norsworthy et al, 2017;Kondo et al, 2019;Thompson et al, 2019;Nishijima et al, 2020;Wang et al, 2020).…”

Section: Differential Nerve Injury Responses In the Peripheral And Ce...mentioning

confidence: 99%

“…Depending on the extent of axonal injury, 27-90% of RGCs can survive at two weeks post-injury; however, RGCs are not capable of spontaneously regenerating their axons after injury (Johnson and Tomarev, 2010;Sengottuvel et al, 2011). Therefore, RGCs are considered CNS neurons, and ONC has been widely used as an in vivo CNS injury model to study molecular mechanisms of neuronal survival and axon regeneration in the CNS (Park et al, 2008;Smith et al, 2009;Kondo et al, 2019;Thompson et al, 2019;Nishijima et al, 2020;Wang et al, 2020).…”

Section: Optic Nerve Crush Modelmentioning

confidence: 99%

“…Although effective in promoting CNS axon regeneration, genetic manipulation is not clinically feasible, and it cannot be ignored that it may lead to the development of cancer since PTEN and SOCS3 are known tumor suppressors while Sox11 can promote tumor progression (Yu et al, 2015;Barber et al, 2017;Huang et al, 2019a). Therefore, current research continues to focus on developing pharmacological interventions that can transiently enhance the intrinsic ability of adult RGCs to survive and regenerate their axons (Ohtake et al, 2015;Sharma et al, 2015;Li et al, 2017b;Trakhtenberg et al, 2018;Thompson et al, 2019;Nishijima et al, 2020). Members of epidermal growth factor (EGF) family have been shown to promote neuronal survival and axon regeneration in the CNS, suggesting the possibility that the EGF receptor (EGFR) pathway could be a therapeutic target for CNS regeneration (Nilsson and Kanje, 2005;White et al, 2008;Sun et al, 2010;White et al, 2011;Zhan et al, 2015;Anderson et al, 2018).…”

Section: Optic Nerve Crush Modelmentioning

confidence: 99%

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Amphiregulin and Growth Differentiation Factor 11 Promote Retinal Ganglion Cell Survival In Vivo through Activation of Smad3

Yoo¹

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Although adult neurons in the mammalian central nervous system (CNS) cannot spontaneously repair themselves after injury, a growing body of evidence indicates that genetically manipulating them can increase their intrinsic reparative ability. However, as genetic manipulation is not clinically feasible, current research continues to investigate pharmacological approaches to transiently enhance the intrinsic ability of adult CNS neurons to survive and regenerate their axons. Amphiregulin (AREG) is a unique epidermal growth factor receptor (EGFR) ligand that has been shown to be crucial in liver regeneration, and accumulating evidence suggests that AREG signaling can promote both survival and axon regeneration of neurons. Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor β (TGF-β) superfamily, and it has been shown to exert rejuvenation effects in the aged brain and promote neuronal survival in the CNS. However, it is unknown whether AREG and GDF11 are capable of inducing neuronal survival and axon regeneration in the visual system. Hence, the current study investigated: 1) the developmental and post-injury expression patterns of these two ligands and their respective receptors, EGFR and activin-like kinase 5 (ALK5), 2) the potential neuroprotective and regenerative effects of these two ligands on retinal ganglion cells (RGCs) by using optic nerve crush (ONC) model, and 3) the molecular mechanisms mediating the neuroprotective and regenerative effects of AREG and GDF11 on RGCs. Based on the western blot and immunohistochemical data, both AREG and GDF11 are consistently expressed throughout retina development, but their receptors are only upregulated during early retina development. Furthermore, AREG expression is significantly reduced in adult retina 7 days after ONC whereas GDF11 expression remains unchanged after ONC. Interestingly, while EGFR expression is only upregulated 3 days after ONC, ALK5 expression is consistently upregulated throughout the ii post-injury time course. A single intravitreal injection of AREG or GDF11 immediately after ONC promoted significant RGC survival by activating Smad2/3 pathway. Because both ligands were not able to promote RGC axon regeneration, activation of Smad2/3 pathway may promote RGC survival but suppress RGC axon regeneration. Overall, the findings indicate that both AREG and GDF11 hold therapeutic potential for both neurodegenerative diseases and retinal degenerative diseases.iii Acknowledgement I am not supposed to be where I am today. Growing up in South Korea, I was told by teachers and tutors that I am intellectually challenged, and I have no gift for science.Naturally, I never thought that I would become a scientist, and yet here I am. First and foremost, I would like to sincerely thank my graduate supervisor Dr. Patrice Smith for allowing me to join her lab and always finding time to provide guidance and encouragement during my PhD despite her super-duper busy schedule. I learned so much from you over the years, and I would not be...

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

Cited by 8 publications

References 33 publications

Genetic inhibition of collapsin response mediator protein‐2 phosphorylation ameliorates retinal ganglion cell death in normal‐tension glaucoma models

Genetic inhibition of collapsin response mediator protein‐2 phosphorylation ameliorates retinal ganglion cell death in normal‐tension glaucoma models

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

Amphiregulin and Growth Differentiation Factor 11 Promote Retinal Ganglion Cell Survival In Vivo through Activation of Smad3

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