Eye drop delivery of pigment epithelium-derived factor-34 promotes retinal ganglion cell neuroprotection and axon regeneration

Vigneswara, Vasanthy; Deer, Louise; Berry, Martin; Logan, Ann; Ahmed, Zubair

doi:10.1016/j.mcn.2015.08.001

Cited by 39 publications

(36 citation statements)

References 64 publications

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“…Topical administration (eye drops) provides a suitable noninvasive method for treating ophthalmic diseases. 19 PACAP eye drops have been shown to have topical effects in the cornea, 20,21 but it is not known whether PACAP would penetrate the ocular barriers, reaching the retina. Therefore, the aim of the present study was to investigate the retinoprotective efficacy of PACAP given as eye drops in ischemic retinopathy.…”

Section: Methodsmentioning

confidence: 99%

Ocular Delivery of PACAP1-27 Protects the Retina From Ischemic Damage in Rodents

Werling

Reglődi

Banks

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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Citation: Werling D, Reglodi D, Banks WA, et al. Ocular delivery of PACAP1-27 protects the retina from ischemic damage in rodents. Invest Ophthalmol Vis Sci. 2016;57:6683-6691. DOI: 10.1167/iovs.16-20630 PURPOSE. Pituitary adenylate cyclase activating polypeptide (PACAP) is neuroprotective in neuronal injuries. Bilateral common carotid artery occlusion (BCCAO) causes chronic hypoperfusion-induced degeneration in the rat retina, where we proved the retinoprotective effect of intravitreal PACAP. Although this route of administration is a common clinical practice in several diseases, easier routes are clinically important. Our aim was to investigate the potential retinoprotective effects of PACAP eye drops in BCCAO-induced ischemic retinopathy.METHODS. After performing BCCAO in rats, the right eyes were treated with PACAP1-27 eye drops (1 lg/drop, 2 3 1 drops/day for 5 days), containing different vehicles: saline, water for injections, thiomersal or benzalkonium solution for ophthalmic use (SOCB). Histology and immunohistochemistry were performed 2 weeks after surgery, while molecular analysis was performed 24 hours after BCCAO. Passage of PACAP1-27 through the ocular layers was tested with radioactive PACAP-SOCB in mice.RESULTS. Bilateral common carotid artery occlusion led to a severe degeneration of all retinal layers. Solution for ophthalmic use was the most effective vehicle for delivering PACAP (PACAP-SOCB), significantly ameliorating BCCAO-induced damage. The massive upregulation of GFAP was not observed in retinas treated with PACAP-SOCB eye drops. PACAP-SOCB treatment also increased activation of the protective Akt and ERK1/2 in hypoperfused retinas. The cytokine profile showing upregulation in different cytokines was attenuated by PACAP-SOCB. Radioactive PACAP reached the retina when delivered in SOCB-containing eye drops.CONCLUSIONS. PACAP1-27, delivered in the SOCB vehicle as eye drops, was retinoprotective in ischemic retinopathy, providing the basis for future therapeutic administration.

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Section: Methodsmentioning

confidence: 99%

Ocular Delivery of PACAP1-27 Protects the Retina From Ischemic Damage in Rodents

Werling

Reglődi

Banks

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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“…Palmitoyl-lysine conjugated SOCS1-KIR was reported by others as effective in preventing EAU [71,72]. Eye drop formulations of other CPPs, vascular endothelial growth inhibitor (VEGI) [73], pigment epithelium derived factor peptide (PEDF) peptide [74,75], and endostatin [76] have been reported.…”

Section: Discussionmentioning

confidence: 99%

A C-terminal peptide from type I interferon protects the retina in a mouse model of autoimmune uveitis

et al. 2020

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Experimental autoimmune uveitis (EAU) in rodents recapitulates many features of the disease in humans and has served as a useful tool for the development of therapeutics. A peptide from C-terminus of interferon α1, conjugated to palmitoyl-lysine for cell penetration, denoted as IFNα-C, was tested for its anti-inflammatory properties in ARPE-19 cells, followed by testing in a mouse model of EAU. Treatment with IFNα-C and evaluation by RT-qPCR showed the induction of anti-inflammatory cytokines and chemokine. Inflammatory markers induced by treatment with TNFα were suppressed when IFNα-C was simultaneously present. TNF-α mediated induction of NF-κB and signaling by IL-17A were attenuated by IFNα-C. Differentiated ARPE-19 cells were treated with TNFα in the presence or absence IFNα-C and analyzed by immmunhistochemistry. IFNα-C protected against the disruption integrity of tight junction proteins. Similarly, loss of transepithelial resistance caused by TNFα was prevented by IFNα-C. B10.RIII mice were immunized with a peptide from interphotoreceptor binding protein (IRBP) and treated by gavage with IFNα-C. Development of uveitis was monitored by histology, fundoscopy, SD-OCT, and ERG. Treatment with IFNα-C prevented uveitis in mice immunized with the IRBP peptide. Splenocytes isolated from mice with ongoing EAU exhibited antigen-specific T cell proliferation that was inhibited in the presence of IFNα-C. IFNα-C peptide exhibits anti-inflammatory properties and protects mice against damage to retinal structure and function suggesting that it has therapeutic potential for the treatment of autoimmune uveitis. Citation: Ahmed CM, Ildefonso CJ, Johnson HM, Lewin AS (2020) A C-terminal peptide from type I interferon protects the retina in a mouse model of autoimmune uveitis. PLoS ONE 15(2): e0227524.

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“…Blood-brain crossing cell penetrating peptide for vascular endothelial growth inhibitor (VEGI) have also been described (Gao et al, 2015). Eye drop formulations of pigment epithelium derived factor (PEDF) peptide (Liu et al, 2012;Vigneswara et al, 2015), and endostatin have also been tested. The topical delivery of R9-SOCS1-KIR we describe here seems to be applicable for other peptides as well.…”

Section: Discussionmentioning

confidence: 99%

A Cell Penetrating Peptide from SOCS-1 Prevents Ocular Damage in Experimental Autoimmune Uveitis

Ahmed

Massengill

Ildefonso

et al. 2018

Preprint

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Highlights  A peptide corresponding to the kinase inhibitory region of SOCS-1 linked to poly-arginine (R9-SOCS1-KIR) and its inactive control peptide were chemically synthesized.  R9-SOCS1-KIR attenuated pro-inflammatory effects of IFN, TNFand IL-17 in ARPE-19 cells, thus showing a simultaneous inhibition Th1 and Th17 cell functions.  Damage to barrier properties of ARPE-19 cells caused by TNF or IL-17 was prevented in the presence of R9-SOCS1-KIR.  Topical administration of R9-SOCS1-KIR prevented ocular damage in a mouse model of experimental autoimmune uveitis. AbstractWe describe an immunosuppressive peptide corresponding to the kinase inhibitory region (KIR) of the intracellular checkpoint protein suppressor of cytokine signaling 1 (SOCS-1) that binds to the phospho-tyrosine containing regions of the tyrosine kinases JAK2 and TYK2 and the adaptor protein MAL, and thereby inhibits signaling downstream from these signaling mediators.The peptide, SOCS1-KIR, is thus capable of downregulating overactive JAK/STAT or NF-kB signaling in somatic cells, including those in many compartments of the eye. Attachment of polyarginine to this peptide (R9-SOCS1-KIR) allows it to penetrate the plasma membrane in aqueous media. R9-SOCS1-KIR was tested in ARPE-19 cells and was found to attenuate mediators of inflammation by blocking the inflammatory effects of IFNTNFor IL-17A. R9-SOCS1-KIR also protected against TNF or IL-17A mediated damage to the barrier properties of ARPE-19 cells, as evidenced by immunostaining with the tight junction protein, zona occludin 1 (ZO-1), and measurement of transepithelial electrical resistance (TEER). Experimental autoimmune uveitis (EAU) was generated in B10.RIII mice using a peptide of interphotoreceptor retinal binding protein (IRBP 161-180 ) as immunogen. Topical administration of R9-SOCS1-KIR protected ocular structure and function as seen by fundoscopy, optical coherence tomography (OCT), and electroretinography (ERG). The ability R9-SOCS1-KIR to suppress ocular inflammation and preserve barrier properties of retinal pigment epithelium makes it a potential candidate for aqueous treatment of autoimmune uveitis.

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Eye drop delivery of pigment epithelium-derived factor-34 promotes retinal ganglion cell neuroprotection and axon regeneration

Cited by 39 publications

References 64 publications

Ocular Delivery of PACAP1-27 Protects the Retina From Ischemic Damage in Rodents

Ocular Delivery of PACAP1-27 Protects the Retina From Ischemic Damage in Rodents

A C-terminal peptide from type I interferon protects the retina in a mouse model of autoimmune uveitis

A Cell Penetrating Peptide from SOCS-1 Prevents Ocular Damage in Experimental Autoimmune Uveitis

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