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.
authors.affiliation: Department of Anatomy, Showa University School of Medicine, 1-5-8 Hatanodai Shinagawa-ku, Tokyo, 142-8555, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Wada
authors.forename: Tomoya
authors.initials: T
authors.lastname: Nakamachi
authors.forename: Kimi
authors.initials: K
authors.lastname: Endo
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Seki
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Ohtaki
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tsuchikawa
authors.forename: Motohide
authors.initials: M
authors.lastname: Hori
authors.forename: Masashi
authors.initials: M
authors.lastname: Tsuchida
authors.forename: Akira
authors.initials: A
authors.lastname: Yoshikawa
authors.forename: Attila
authors.initials: A
authors.lastname: Matkovits
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kagami
authors.forename: Nori
authors.initials: N
authors.lastname: Imai
authors.forename: Shiho
authors.initials: S
authors.lastname: Fujisaka
authors.forename: Isao
authors.initials: I
authors.lastname: Usui
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Tobe
authors.forename: Ryohei
authors.initials: R
authors.lastname: Koide
authors.forename: Haruo
authors.initials: H
authors.lastname: Takahashi
authors.forename: Seiji
authors.initials: S
authors.lastname: Shioda
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D005901:Glaucoma / Q000139:chemically induced / Q000188:drug therapy*; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D058449:Intravitreal Injections; D008262:Macrophage Activation; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D016202:N-Methylaspartate / Q000633:toxicity*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: C556062:IL10 protein, mouse; D018696:Neuroprotective Agents; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D016753:Interleukin-10; D016202:N-Methylaspartate