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Tamotsu Seki, Tomoya Nakamachi, Kimi Endo, Seiji Shioda; Investigation Of Neuroprotective Effects Of PACAP Against NMDA-induced Retinal Damage In Mice. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5378.
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Overactivation of ionotropic glutamate receptors has been implicated in the death process of retinal ganglion cells (RGCs) both in glaucoma and in animal models of retinal ischemia and optic nerve transection. It is well known that glutamate receptor-related neurotoxicity can be induced by NMDA agonist. We have previously reported that PACAP, a pleiotropic neuropeptide, prevents death of RGCs against Kainic acid in the rat retina.
We examined the protective effect of PACAP for the RGCs death induced by NMDA. To make a retinal injury model, adult male mouse (C57/BL6J) were anesthetized and injected NMDA (40 nmol) solution into the vitreous body.
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 early stages day 3. However, when PACAP38 (10–8 to –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. There was no significant difference in the number of RGCs in the intact 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 through PAC1-R in the retina.
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