Neuroprotective effect of endogenous pituitary adenylate cyclase-activating polypeptide on spinal cord injury.
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuroprotective peptide expressed in the central nervous system. To date, changes in the expression and effect of endogenous PACAP have not been clarified with respect to spinal cord injury (SCI). The aim of this study was to elucidate the expression pattern and function of endogenous PACAP on the contusion model of SCI using heterozygous PACAP knockout (PACAP(+/-)) and wild-type mice. Real-time polymerase chain reaction methods revealed that the level of PACAP mRNA increased gradually for 14 days after SCI and that PAC1R mRNA levels also increased for 7 days compared with intact control mice. PACAP and PAC1R immunoreactivities colabeled with a neuronal marker in the intact spinal cord. Seven days after SCI, PAC1R immunoreactivity was additionally co-expressed with an astrocyte marker. Wild-type mice gradually recovered motor function after 14 days, but PACAP(+/-) mice showed significantly impaired recovery from 3 days compared with wild-type mice. The injury volume at day 7 in PACAP(+/-) mice, and the number of single-stranded DNA-immunopositive cells as a marker of neuronal cell death at day 3 were significantly higher than values measured in wild-type mice. These data suggest that endogenous PACAP is upregulated by SCI and has a neuroprotective effect on the damaged spinal cord.
Department of Anatomy, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo 142-8555, Japan.
Daisuke
D
Tsuchikawa
Tomoya
T
Nakamachi
Masashi
M
Tsuchida
Yoshihiro
Y
Wada
Motohide
M
Hori
Jozsef
J
Farkas
Akira
A
Yoshikawa
Nobuyuki
N
Kagami
Nori
N
Imai
Norihito
N
Shintani
Hitoshi
H
Hashimoto
Takashi
T
Atsumi
Seiji
S
Shioda
D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D016923:Cell Death; D004353:Drug Evaluation, Preclinical; D005786:Gene Expression Regulation; D005838:Genotype; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000473:pathology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D020127:Recovery of Function; D013119:Spinal Cord Injuries / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D013997:Time Factors; D015854:Up-Regulation
C495402:Adcyap1 protein, mouse; C495504:Adcyap1r1 protein, mouse; D009419:Nerve Tissue Proteins; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D012333:RNA, Messenger; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I