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

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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 10−16M) was co-administered with NMDA, the 10−10M 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 10−10M 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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Acknowledgment

This work was supported by the Ministry of Education, Science, Sports and Culture of Japan and in part by a High-Technology Research Center Project from the Ministry of Education, Science, Sports and Culture of Japan (T.S., T.N., S.S.).

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Authors and Affiliations

  1. Department of Anatomy, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan

    Kimi Endo, Tomoya Nakamachi, Tamotsu Seki, Nobuyuki Kagami, Yoshihiro Wada, Keisuke Nakamura, Motohide Hori, Daisuke Tsuchikawa & Seiji Shioda

  2. Department of Ophthalmology, Showa University School of Medicine, Tokyo, 142-8666, Japan

    Kimi Endo, Tamotsu Seki, Yoshihiro Wada & Ryohei Koide

  3. Center for Biotechnology, Showa University, Tokyo, 142-8555, Japan

    Tomoya Nakamachi

  4. Department of Pathology, Showa University Fujigaoka Hospital, Yokohama, 227-8501, Japan

    Koji Kishimoto

  5. Graduated School of Pharmaceutical Sciences, Osaka University, Osaka, 565-0871, Japan

    Norihito Shinntani, Hitoshi Hashimoto & Akemichi Baba

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  1. Kimi Endo
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  2. Tomoya Nakamachi
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  3. Tamotsu Seki
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  13. Ryohei Koide
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  14. Seiji Shioda
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Correspondence to Seiji Shioda.

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Endo, K., Nakamachi, T., Seki, T. et al. Neuroprotective Effect of PACAP Against NMDA-Induced Retinal Damage in the Mouse. J Mol Neurosci 43, 22–29 (2011). https://doi.org/10.1007/s12031-010-9434-x

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  • DOI: https://doi.org/10.1007/s12031-010-9434-x

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