PACAP attenuates NMDA-induced retinal damage in association with modulation of the microglia/macrophage status into an acquired deactivation subtype

Yoshihiro Wada; Tomoya Nakamachi; Kimi Endo; Tamotsu Seki; Hirokazu Ohtaki; Daisuke Tsuchikawa; Motohide Hori; Masashi Tsuchida; Akira Yoshikawa; Attila Matkovits; Nobuyuki Kagami; Nori Imai; Shiho Fujisaka; Isao Usui; Kazuyuki Tobe; Ryohei Koide; Haruo Takahashi; Seiji Shioda

doi:10.1007/s12031-013-0017-5

PACAP attenuates NMDA-induced retinal damage in association with modulation of the microglia/macrophage status into an acquired deactivation subtype

Yoshihiro Wada, Tomoya Nakamachi, Kimi Endo, Tamotsu Seki, Hirokazu Ohtaki, Daisuke Tsuchikawa, Motohide Hori, Masashi Tsuchida, Akira Yoshikawa, Attila Matkovits, Nobuyuki Kagami, Nori Imai, Shiho Fujisaka, Isao Usui, Kazuyuki Tobe, Ryohei Koide, Haruo Takahashi, Seiji Shioda^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

46 Scopus citations

Abstract

Pituitary adenylate cyclase-activating polypeptide (PACAP) has been known as a neuroprotectant agent in several retinal injury models. However, a detailed mechanism of this effect is still not well understood. In this study, we examined the retinoprotective effects and associated underlying mechanisms of action of PACAP in the mouse N-methyl-d-aspartic acid (NMDA)-induced retinal injury model, focusing on the relationship between PACAP and retinal microglia/macrophage (MG/MΦ) status. Adult male C57BL/6 mice received an intravitreal injection of NMDA to induce retinal injury. Three days after NMDA injection, the number of MG/MΦ increased significantly in the retinas. The concomitant intravitreal injection of PACAP suppressed NMDA-induced cell loss in the ganglion cell layer (GCL) and significantly increased the number of MG/MΦ. These outcomes associated with PACAP were attenuated by cotreatment with PACAP6-38, while the beneficial effects of PACAP were not seen in interleukin-10 (IL-10) knockout mice. PACAP significantly elevated the messenger RNA levels of anti-inflammatory cytokines such as transforming growth factor beta 1 and IL-10 in the injured retina, with the immunoreactivities seen to overlap with markers of MG/MΦ. These results suggest that PACAP enhances the proliferation and/or infiltration of retinal MG/MΦ and modulates their status into an acquired deactivation subtype to favor conditions for neuroprotection.

Original language	English
Pages (from-to)	493-502
Number of pages	10
Journal	Journal of Molecular Neuroscience
Volume	51
Issue number	2
DOIs	https://doi.org/10.1007/s12031-013-0017-5
State	Published - 2013/10

Keywords

Glaucoma
Microglia/macrophage
NMDA
Neurotrophic factor
PACAP
Retinoprotection

ASJC Scopus subject areas

Cellular and Molecular Neuroscience

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10.1007/s12031-013-0017-5

Cite this

Wada, Y., Nakamachi, T., Endo, K., Seki, T., Ohtaki, H., Tsuchikawa, D., Hori, M., Tsuchida, M., Yoshikawa, A., Matkovits, A., Kagami, N., Imai, N., Fujisaka, S., Usui, I., Tobe, K., Koide, R., Takahashi, H., & Shioda, S. (2013). PACAP attenuates NMDA-induced retinal damage in association with modulation of the microglia/macrophage status into an acquired deactivation subtype. Journal of Molecular Neuroscience, 51(2), 493-502. https://doi.org/10.1007/s12031-013-0017-5

@article{d8d0ad3a7b284078bb7dd71430bb0018,

title = "PACAP attenuates NMDA-induced retinal damage in association with modulation of the microglia/macrophage status into an acquired deactivation subtype",

abstract = "Pituitary adenylate cyclase-activating polypeptide (PACAP) has been known as a neuroprotectant agent in several retinal injury models. However, a detailed mechanism of this effect is still not well understood. In this study, we examined the retinoprotective effects and associated underlying mechanisms of action of PACAP in the mouse N-methyl-d-aspartic acid (NMDA)-induced retinal injury model, focusing on the relationship between PACAP and retinal microglia/macrophage (MG/MΦ) status. Adult male C57BL/6 mice received an intravitreal injection of NMDA to induce retinal injury. Three days after NMDA injection, the number of MG/MΦ increased significantly in the retinas. The concomitant intravitreal injection of PACAP suppressed NMDA-induced cell loss in the ganglion cell layer (GCL) and significantly increased the number of MG/MΦ. These outcomes associated with PACAP were attenuated by cotreatment with PACAP6-38, while the beneficial effects of PACAP were not seen in interleukin-10 (IL-10) knockout mice. PACAP significantly elevated the messenger RNA levels of anti-inflammatory cytokines such as transforming growth factor beta 1 and IL-10 in the injured retina, with the immunoreactivities seen to overlap with markers of MG/MΦ. These results suggest that PACAP enhances the proliferation and/or infiltration of retinal MG/MΦ and modulates their status into an acquired deactivation subtype to favor conditions for neuroprotection.",

keywords = "Glaucoma, Microglia/macrophage, NMDA, Neurotrophic factor, PACAP, Retinoprotection",

author = "Yoshihiro Wada and Tomoya Nakamachi and Kimi Endo and Tamotsu Seki and Hirokazu Ohtaki and Daisuke Tsuchikawa and Motohide Hori and Masashi Tsuchida and Akira Yoshikawa and Attila Matkovits and Nobuyuki Kagami and Nori Imai and Shiho Fujisaka and Isao Usui and Kazuyuki Tobe and Ryohei Koide and Haruo Takahashi and Seiji Shioda",

note = "Funding Information: Acknowledgments This work was supported by Grants-in Aid for Scientific Research (KAKENHI: 23249079, 24592681, and 24592680), and by the MEXT-Support Program for the Strategic Research Foundation at Showa University (2008–2012, 2012–2016).",

year = "2013",

month = oct,

doi = "10.1007/s12031-013-0017-5",

language = "英語",

volume = "51",

pages = "493--502",

journal = "Journal of Molecular Neuroscience",

issn = "0895-8696",

publisher = "Springer",

number = "2",

}

Wada, Y, Nakamachi, T, Endo, K, Seki, T, Ohtaki, H, Tsuchikawa, D, Hori, M, Tsuchida, M, Yoshikawa, A, Matkovits, A, Kagami, N, Imai, N, Fujisaka, S, Usui, I, Tobe, K, Koide, R, Takahashi, H & Shioda, S 2013, 'PACAP attenuates NMDA-induced retinal damage in association with modulation of the microglia/macrophage status into an acquired deactivation subtype', Journal of Molecular Neuroscience, vol. 51, no. 2, pp. 493-502. https://doi.org/10.1007/s12031-013-0017-5

TY - JOUR

T1 - PACAP attenuates NMDA-induced retinal damage in association with modulation of the microglia/macrophage status into an acquired deactivation subtype

AU - Wada, Yoshihiro

AU - Nakamachi, Tomoya

AU - Endo, Kimi

AU - Seki, Tamotsu

AU - Ohtaki, Hirokazu

AU - Tsuchikawa, Daisuke

AU - Hori, Motohide

AU - Tsuchida, Masashi

AU - Yoshikawa, Akira

AU - Matkovits, Attila

AU - Kagami, Nobuyuki

AU - Imai, Nori

AU - Fujisaka, Shiho

AU - Usui, Isao

AU - Tobe, Kazuyuki

AU - Koide, Ryohei

AU - Takahashi, Haruo

AU - Shioda, Seiji

N1 - Funding Information: Acknowledgments This work was supported by Grants-in Aid for Scientific Research (KAKENHI: 23249079, 24592681, and 24592680), and by the MEXT-Support Program for the Strategic Research Foundation at Showa University (2008–2012, 2012–2016).

PY - 2013/10

Y1 - 2013/10

N2 - Pituitary adenylate cyclase-activating polypeptide (PACAP) has been known as a neuroprotectant agent in several retinal injury models. However, a detailed mechanism of this effect is still not well understood. In this study, we examined the retinoprotective effects and associated underlying mechanisms of action of PACAP in the mouse N-methyl-d-aspartic acid (NMDA)-induced retinal injury model, focusing on the relationship between PACAP and retinal microglia/macrophage (MG/MΦ) status. Adult male C57BL/6 mice received an intravitreal injection of NMDA to induce retinal injury. Three days after NMDA injection, the number of MG/MΦ increased significantly in the retinas. The concomitant intravitreal injection of PACAP suppressed NMDA-induced cell loss in the ganglion cell layer (GCL) and significantly increased the number of MG/MΦ. These outcomes associated with PACAP were attenuated by cotreatment with PACAP6-38, while the beneficial effects of PACAP were not seen in interleukin-10 (IL-10) knockout mice. PACAP significantly elevated the messenger RNA levels of anti-inflammatory cytokines such as transforming growth factor beta 1 and IL-10 in the injured retina, with the immunoreactivities seen to overlap with markers of MG/MΦ. These results suggest that PACAP enhances the proliferation and/or infiltration of retinal MG/MΦ and modulates their status into an acquired deactivation subtype to favor conditions for neuroprotection.

AB - Pituitary adenylate cyclase-activating polypeptide (PACAP) has been known as a neuroprotectant agent in several retinal injury models. However, a detailed mechanism of this effect is still not well understood. In this study, we examined the retinoprotective effects and associated underlying mechanisms of action of PACAP in the mouse N-methyl-d-aspartic acid (NMDA)-induced retinal injury model, focusing on the relationship between PACAP and retinal microglia/macrophage (MG/MΦ) status. Adult male C57BL/6 mice received an intravitreal injection of NMDA to induce retinal injury. Three days after NMDA injection, the number of MG/MΦ increased significantly in the retinas. The concomitant intravitreal injection of PACAP suppressed NMDA-induced cell loss in the ganglion cell layer (GCL) and significantly increased the number of MG/MΦ. These outcomes associated with PACAP were attenuated by cotreatment with PACAP6-38, while the beneficial effects of PACAP were not seen in interleukin-10 (IL-10) knockout mice. PACAP significantly elevated the messenger RNA levels of anti-inflammatory cytokines such as transforming growth factor beta 1 and IL-10 in the injured retina, with the immunoreactivities seen to overlap with markers of MG/MΦ. These results suggest that PACAP enhances the proliferation and/or infiltration of retinal MG/MΦ and modulates their status into an acquired deactivation subtype to favor conditions for neuroprotection.

KW - Glaucoma

KW - Microglia/macrophage

KW - NMDA

KW - Neurotrophic factor

KW - PACAP

KW - Retinoprotection

UR - http://www.scopus.com/inward/record.url?scp=84885175290&partnerID=8YFLogxK

U2 - 10.1007/s12031-013-0017-5

DO - 10.1007/s12031-013-0017-5

M3 - 学術論文

C2 - 23720065

AN - SCOPUS:84885175290

SN - 0895-8696

VL - 51

SP - 493

EP - 502

JO - Journal of Molecular Neuroscience

JF - Journal of Molecular Neuroscience

IS - 2

ER -

PACAP attenuates NMDA-induced retinal damage in association with modulation of the microglia/macrophage status into an acquired deactivation subtype

Abstract

Keywords

ASJC Scopus subject areas

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