Neuroprotective action of endogenous PACAP in cultured rat cortical neurons.
Pituitary adenylate cyclase-activating polypeptide (PACAP) exerts neurotrophic effects both in vitro and in vivo. Here we demonstrate the upregulation of PACAP mRNA expression in cultured rat cortical neurons after excitotoxic glutamate exposure, and the exacerbating effect of the PACAP receptor antagonist, PACAP(6-38), on neuronal viability. PACAP mRNA levels were increased up to 3.5-fold 8 h after glutamate exposure. PACAP(6-38) decreased the viability of cortical neurons, irrespective of whether the cells were exposed to glutamate or not. PACAP(6-38) also inhibited glutamate-induced expression of PACAP mRNA, suggesting that PACAP acts via an autocrine or paracrine mechanism to enhance PACAP expression itself. Glutamate exposure is known to increase brain-derived neurotrophic factor (BDNF) mRNA expression. This increased expression was markedly suppressed by PACAP(6-38). Our previous study has shown that PACAP stimulates the PACAP gene transcription in PC12 cells. Taken together, these data may suggest that endogenous PACAP regulates the expression of PACAP itself and BDNF. Although it may also be possible that PACAP(6-38)-induced death of PACAP and BDNF mRNA-expressing cells, per se, results in reduced levels of these mRNAs, the present results support the idea that endogenous PACAP has a neuroprotective action.
Shintani
Norihito
N
Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
Suetake
Sayoko
S
Hashimoto
Hitoshi
H
Koga
Kazumi
K
Kasai
Atsushi
A
Kawaguchi
Chihiro
C
Morita
Yoshiko
Y
Hirose
Megumi
M
Sakai
Yoshiyuki
Y
Tomimoto
Shuhei
S
Matsuda
Toshio
T
Baba
Akemichi
A
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis / Q000235:genetics; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D018698:Glutamic Acid / Q000633:toxicity*; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000235:genetics; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide
C495403:Adcyap1 protein, rat; D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D010446:Peptide Fragments; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; C075647:pituitary adenylate-cyclase-activating-peptide (6-38); D018698:Glutamic Acid