title: Neuroprotective effect of PACAP against NMDA-induced retinal damage in the mouse.
abstract: 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.
authors: Department of Anatomy, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
authors: Kimi
authors: K
authors: Endo
authors: Tomoya
authors: T
authors: Nakamachi
authors: Tamotsu
authors: T
authors: Seki
authors: Nobuyuki
authors: N
authors: Kagami
authors: Yoshihiro
authors: Y
authors: Wada
authors: Keisuke
authors: K
authors: Nakamura
authors: Koji
authors: K
authors: Kishimoto
authors: Motohide
authors: M
authors: Hori
authors: Daisuke
authors: D
authors: Tsuchikawa
authors: Norihito
authors: N
authors: Shinntani
authors: Hitoshi
authors: H
authors: Hashimoto
authors: Akemichi
authors: A
authors: Baba
authors: Ryohei
authors: R
authors: Koide
authors: Seiji
authors: S
authors: Shioda
mesh_terms: D000818:Animals; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016202:N-Methylaspartate / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D012160:Retina / Q000187:drug effects* / Q000473:pathology*
chemical_list: D018696:Neuroprotective Agents; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D016202:N-Methylaspartate