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.