Pituitary adenylate cyclase-activating polypeptide (PACAP) decreases ischemic neuronal cell death in association with IL-6

Hirokazu Ohtaki, Tomoya Nakamachi, Kenji Dohi, Yoichi Aizawa, Atsushi Takaki, Kei Hodoyama, Sachiko Yofu, Hitoshi Hashimoto, Norihito Shintani, Akemichi Baba, Manfred Kopf, Yoichiro Iwakura, Kouhei Matsuda, Akira Arimura, Seiji Shioda

Research output: Contribution to journalArticlepeer-review

158 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)7488-7493
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number19
DOIs
Publication statusPublished - May 9 2006
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General

Fingerprint Dive into the research topics of 'Pituitary adenylate cyclase-activating polypeptide (PACAP) decreases ischemic neuronal cell death in association with IL-6'. Together they form a unique fingerprint.

Cite this