TY - JOUR
T1 - Neuroprotective effect of PACAP against NMDA-induced retinal damage in the mouse
AU - Endo, Kimi
AU - Nakamachi, Tomoya
AU - Seki, Tamotsu
AU - Kagami, Nobuyuki
AU - Wada, Yoshihiro
AU - Nakamura, Keisuke
AU - Kishimoto, Koji
AU - Hori, Motohide
AU - Tsuchikawa, Daisuke
AU - Shinntani, Norihito
AU - Hashimoto, Hitoshi
AU - Baba, Akemichi
AU - Koide, Ryohei
AU - Shioda, Seiji
N1 - Funding Information:
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.).
PY - 2011/1
Y1 - 2011/1
N2 - 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.
AB - 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.
KW - Excitotoxicity
KW - Glaucoma
KW - NMDA
KW - Neurotrophic factor
KW - PACAP
KW - Retinoprotection
UR - http://www.scopus.com/inward/record.url?scp=79951579091&partnerID=8YFLogxK
U2 - 10.1007/s12031-010-9434-x
DO - 10.1007/s12031-010-9434-x
M3 - 学術論文
C2 - 20703829
AN - SCOPUS:79951579091
SN - 0895-8696
VL - 43
SP - 22
EP - 29
JO - Journal of Molecular Neuroscience
JF - Journal of Molecular Neuroscience
IS - 1
ER -