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

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168 Citations (Scopus)


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
Issue number19
Publication statusPublished - May 9 2006

All Science Journal Classification (ASJC) codes

  • General


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