Suppression of Rat Retinal Ganglion Cell Death by PACAP Following Transient Ischemia Induced by High Intraocular Pressure

Seki, Tamotsu; Itoh, Hiroyuki; Nakamachi, Tomoya; Endo, Kimi; Wada, Yasuhiko; Nakamura, Keisuke; Shioda, Seiji

doi:10.1007/s12031-010-9410-5

Cited by 41 publications

(28 citation statements)

References 21 publications

(20 reference statements)

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“…**p<0.01, comparing the NMDA alone and NMDA + PACAP treatment groups in the case of NMDA-induced neuronal injury reflects a simple mechanism, related to direct Ca 2+ influx into the cells via NMDA receptor activity. It has revealed that the bimodal peaks of PACAP neuroprotection has been found in the case of the other glaucoma models, high intraocular pressure, implying these models may be mediated with the complex mechanisms or factors involved in RGC death (Seki et al 2010). It is also possible that the single peak at a nanomolar concentration we observed could be mediated via the cAMP pathway, in line with previous reports.…”

Section: Discussionsupporting

confidence: 91%

Neuroprotective Effect of PACAP Against NMDA-Induced Retinal Damage in the Mouse

et al. 2010

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Retinal excitotoxicity is one of the major causes of retinal ganglion cell (RGC) death in glaucoma. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic peptide with potent neuroprotective activity; however, whether it exerts such an effect in the retina and the mechanism by which RGCs are protected is still not well understood. In this study, we examined the effect of exogenous and endogenous PACAP on RGC death induced by N-methyl-D: -aspartate acid (NMDA). The vitreous body of anesthetized adult male mice (C57/BL6J) was injected with NMDA (40 nmol in a 2 μL saline solution). The number of RGCs decreased from days 1 to 7 after NMDA injection, and the number of dUTP end-labeling (TUNEL)-positive cells, an indicator of cell death, peaked at day 3. However, when PACAP38 (10(-8), 10(-10), 10(-12), 10(-14), or 10(-16)M) was co-administered with NMDA, the 10(-10)M dose resulted in significantly increased RGC survival at day 7, and a decrease in the number of TUNEL-positive RGCs at day 3. We next investigated the neuroprotective effect of endogenous PACAP using PACAP heterozygote(+/-) mice. Under normal circumstances, there was no significant difference in the number of RGCs in the PACAP(+/-) mice compared with their wild-type counterparts. However, the number of RGCs significantly decreased in the PACAP(+/-) mice 7 days after NMDA injection, relative to their wild-type counterparts. The number of TUNEL-positive RGCs peaked at day 1 in the PACAP(+/-) mice. These effects in the PACAP(+/-) mice were reversed by intravitreous injection of 10(-10)M PACAP38. This suggests that exogenous PACAP is able to counteract NMDA-induced toxicity, and that endogenous PACAP exerts a neuroprotective effect in the retina.

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Section: Discussionsupporting

confidence: 91%

Neuroprotective Effect of PACAP Against NMDA-Induced Retinal Damage in the Mouse

et al. 2010

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“…In this model, PACAP exerted a bimodal protective effect with peaks at 10 fM and 10-100 pM. The protective effect was blocked by cAMP antagonist at both high and low protective doses, while a MAP kinase inhibitor only blocked the effects of PACAP at a low dose, suggesting that the protective effects of PACAP are mediated by different signaling at low and high doses [ 79 ].…”

Section: Ischemic Injury In the Retinamentioning

confidence: 84%

“…Seki et al [ 79 ] showed that intravitreal PACAP treatment protected ganglion cells against a different kind of ischemic lesion induced by high intraocular pressure. In this model, PACAP exerted a bimodal protective effect with peaks at 10 fM and 10-100 pM.…”

Section: Ischemic Injury In the Retinamentioning

confidence: 99%

Protective Effects of PACAP in the Retina

Atlasz

Vaczy

Werling

et al. 2016

Current Topics in Neurotoxicity

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Pituitary adenylate cyclase activating polypeptide (PACAP) is a widespread neuropeptide that is well known for its general cytoprotective effects in different neuronal injuries, such as traumatic brain and spinal cord injury, models of neurodegenerative diseases, and cerebral ischemia. PACAP and its receptors also occur in the retina. In this review, we summarize the retinoprotective effects of PACAP. In vitro, PACAP is protective against glutamate, thapsigargin, anisomycin, oxidative stress, UV light, high glucose, infl ammation, and anoxia. Both the neural retina and the pigment epithelial cells can be protected by PACAP in various experimental paradigms. In vivo, the protective effects of intravitreal PACAP treatment have been shown in the following models in rats and mice: excitotoxic injury induced by glutamate, N -methyl-D -aspartate (NMDA) or kainate, ischemic injury induced by carotid artery ligation and high intraocular pressure, degeneration caused by UV-A light, optic nerve transection, and streptozotocin-induced diabetic retinopathy as well as retinopathy of prematurity. Molecular biological methods have revealed that PACAP activates anti-apoptotic, while inhibits pro-apoptotic signaling pathways, and it also stimulates an anti-infl ammatory environment in the retina. Altogether, PACAP is suggested to be a potential therapeutic retinoprotective agent in various retinal diseases.

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“…5,12,13 Earlier we showed that PACAP1-38 ameliorates the reduction in thickness of different retinal layers as well as the loss of cells in the ganglion cell layer (GCL) in BCCAO-induced injury.…”

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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Suppression of Rat Retinal Ganglion Cell Death by PACAP Following Transient Ischemia Induced by High Intraocular Pressure

Cited by 41 publications

References 21 publications

Neuroprotective Effect of PACAP Against NMDA-Induced Retinal Damage in the Mouse

Neuroprotective Effect of PACAP Against NMDA-Induced Retinal Damage in the Mouse

Protective Effects of PACAP in the Retina

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

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