title: Pituitary adenylate cyclase-activating polypeptide (PACAP) decreases ischemic neuronal cell death in association with IL-6.
abstract: Pituitary adenylate cyclase-activating polypeptide (PACAP) has been reported to decrease ischemic neuronal damage and increase IL-6 secretion in rats. However, the mechanisms underlying neuroprotection are still to be fully elucidated. The present study was designed to investigate the role played by PACAP and IL-6 in mediating neuroprotection after ischemia in a null mouse. Infarct volume, neurological deficits, and cytochrome c in cytoplasm were higher in PACAP(+/-) and PACAP(-/-) mice than in PACAP(+/+) animals after focal ischemia, although the severity of response was ameliorated by the injection of PACAP38. A decrease in mitochondrial bcl-2 was also accentuated in PACAP(+/-) and PACAP(-/-) mice, but the decrease could be prevented by PACAP38 injection. PACAP receptor 1 (PAC1R) immunoreactivity was colocalized with IL-6 immunoreactivity in neurons, although the intensity of IL-6 immunoreactivity in PACAP(+/-) mice was less than that in PACAP(+/+) animals. IL-6 levels increased in response to PACAP38 injection, an effect that was canceled by cotreatment with the PAC1R antagonist. However, unlike in wild-type controls, PACAP38 treatment did not reduce the infarction in IL-6 null mice. To clarify the signaling pathway associated with the activity of PACAP and IL-6, phosphorylated STAT (signal transducer and activator of transcription) 3, ERK (extracellular signal-regulated kinase), and AKT levels were examined in PACAP(+/-) and IL-6 null mice after ischemia. Lower levels of pSTAT3 and pERK were observed in the PACAP(+/-) mice, whereas a reduction in pSTAT3 was recorded in the IL-6 null mice. These results suggest that PACAP prevents neuronal cell death after ischemia via a signaling mechanism involving IL-6.
authors.affiliation: Department of Anatomy, Showa University School of Medicine, Shinagawa-Ku, Tokyo 142-8555, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Ohtaki
authors.forename: Tomoya
authors.initials: T
authors.lastname: Nakamachi
authors.forename: Kenji
authors.initials: K
authors.lastname: Dohi
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Aizawa
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takaki
authors.forename: Kei
authors.initials: K
authors.lastname: Hodoyama
authors.forename: Sachiko
authors.initials: S
authors.lastname: Yofu
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Hashimoto
authors.forename: Norihito
authors.initials: N
authors.lastname: Shintani
authors.forename: Akemichi
authors.initials: A
authors.lastname: Baba
authors.forename: Manfred
authors.initials: M
authors.lastname: Kopf
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Kouhei
authors.initials: K
authors.lastname: Matsuda
authors.forename: Akira
authors.initials: A
authors.lastname: Arimura
authors.forename: Seiji
authors.initials: S
authors.lastname: Shioda
mesh_terms: D000818:Animals; D017209:Apoptosis; D045304:Cytochromes c / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C495402:Adcyap1 protein, mouse; D015850:Interleukin-6; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D019253:Proto-Oncogene Proteins c-bcl-2; D045304:Cytochromes c