2002 Fiscal Year Annual Research Report

PACAPによる脳虚血障害保護機構

Research Project

Project/Area Number	14380354
Research Institution	Showa University
Principal Investigator	塩田清二昭和大学, 医学部, 教授 (80102375)
Co-Investigator(Kenkyū-buntansha)	矢田俊彦自治医科大学, 医学部, 教授 (60166527) 中条茂男昭和大学, 薬学部, 助教授 (50119236) 舟橋久幸昭和大学, 医学部, 講師 (20317514) 澤田誠藤田保健衛生大学, 総合医科学研究所, 教授 (10187297)
Keywords	PACAP / IL-6 / 神経細胞死 / 海馬 / ラット / マウス
Research Abstract	Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP)は下垂体前葉細胞のホルモンの分泌・産生を亢進する神経ペプチドである。脳内にこのペプチドの受容体は多数発現し、とくに嗅球、海馬、小脳につよく発現することが知られている。そこで、PACAPによる海馬CA1領域の遅発性神経細胞死の抑制とその機構について機能形態学的にしらべた。虚血-再潅流後のラット海馬では、2日目以降にCA1領域の神経細胞は細胞変性をおこしはじめ、7日もすると殆どの神経細胞は遅発性神経細胞死をおこした。超微量(pMオーダー)のPACAPを持続的に脳室内注入あるいは静注すると、遅発性神経細胞死は有意に抑制された。PACAPによる海馬神経細胞の細胞内シグナル伝達機構を生化学的にしらべたところ、PACAPはMAPキナーゼカスケードのうち、JNK/SAPKおよびp38活性を強く抑制することが分かった。このことは、PACAPが遅発性神経細胞死(apoptosis)を抑制する分子機構として、MAPキナーゼカスケードの存在が明らかになった。さらに、PACAPは培養下の実験で神経膠細胞からIL-6を分泌刺激することから、PACAPによる遅発性神経細胞死抑制機能の一つに神経膠細胞を介した神経細胞死抑制系路の可能性が考えられた。そこで、PACAPによる神経膠細胞を介した神経細胞死抑制の可能性をIL-6 KOマウスを用いてしらべた。その結果、IL-6 KOマウスの海馬における遅発性神経細胞死は野生型に比べて有意に促進され、しかもPACAP投与で神経細胞死抑制効果がみられないことが明らかになった。以上の実験・観察結果から、PACAPとIL-6はsynergisticにはたらいて神経細胞死を抑制すると推察された。PACAPは神経細胞に直接作用し神経細胞死を抑制する可能性があるが、神経膠細胞にも作用しIL-6の放出を刺激して神経細胞死を抑制する可能性も考えられる。

Research Products
(16 results)

All Other

All Publications (16 results)

[Publications] Nonaka, N.: "Regional differences in PACAP transport across the blood-brain barrier in mice : a possible influence of strain, amyloid β protein, and age"Peptides. 23(12). 2197-2202 (2002)
[Publications] Takenoya, F.: "Galanin-like peptide (GALP) is co-localized with α-melanocyte stimulating hormone (α-MSH) but not with neuropeptide Y (NPY) in the rat brain"Neuroscience Letters. 331. 119-121 (2002)
[Publications] Dohi, K.: "Pituitary adenylate cyclase-activating polypeptide (PACAP) prevents hippocampal neurons from apoptosis by inhibiting Jun N-terminal kinase (JNK)/stress activated protein kinase (SAPK) and p38 signal transduction pathway"Regul Pept. 109. 83-88 (2002)
[Publications] Guan, JL.: "Ultrastructural localization of orexin-1 receptor in pre-and post-synaptic neurons in the rat arcuate nucleus"Neuroscience Letters. 329. 209-212 (2002)
[Publications] Zhou, CJ.: "Pleiotropic effects of PACAP and multiple signaling pathways under its receptors in nervous system"Curr Protein & Peptide Sci. 3. 423-439 (2002)
[Publications] Guan, JL.: "Reciprocal synaptic relationship between orexin-and melanin-concentrating hormone-containing neurons in the rat lateral hypothalamus : a novel circuit implicated in feeding regulation"Int J Obesity. 26. 1523-1532 (2002)
[Publications] Satoh, K.: "Edarabone scavenges nitric oxide"Redox Report. 7. 219-222 (2002)
[Publications] Zhou, CJ.: "ALP-binding cassette transporter ABCA2(ABC2) expression in the developing spinal cord and PNS during myelination. A comparative study with other glial markers"J Comp Neurol. 451. 334-351 (2002)
[Publications] Wang, QP.: "Endomorphin-2 immunoreactivity in the central dorsal horn of the rat spinal cord at the electron microscopic level"Neuroscience. 113. 593-605 (2002)
[Publications] Wang, QP.: "Morphological studies of the endomorphinergic neurons in the central nervous system"Jap J Pharmacol. 89. 209-215 (2002)
[Publications] Mizushima, H.: "Reduced postischemic hippocampal apoptosis in mice deficient interleukin-1"J Comp Neurol. 448. 203-216 (2002)
[Publications] Suzuki, R.: "Orexin-1 receptor immunoreactivity in chemically identified target neurons in the rat hypothalamus"Neurosci Lett. 324. 5-8 (2002)
[Publications] Lu, SL.: "Immunocytochemical observation of ghrelin-containing neurons in the rat arcuate nucleus"Neurosci Lett. 321. 157-160 (2002)
[Publications] Yamanaka, A.: "Orexins activate histaminergic neurons in the tuberomammillary nucleus via the OX2 receptor"Biochem Biophys Res Commun. 290. 1237-1247 (2002)
[Publications] Shioda, S.: "VIP & PACAP Receptors"Oxford University Press. 21 (2002)
[Publications] Shioda, S.: "PACAP Receptor Signaling"Kluwer Academic Publications. 30 (2002)

2002 Fiscal Year Annual Research Report

PACAPによる脳虚血障害保護機構

Principal Investigator

塩田 清二 昭和大学, 医学部, 教授 (80102375)

Research Products

[Publications] Nonaka, N.: "Regional differences in PACAP transport across the blood-brain barrier in mice : a possible influence of strain, amyloid β protein, and age"Peptides. 23(12). 2197-2202 (2002)

[Publications] Takenoya, F.: "Galanin-like peptide (GALP) is co-localized with α-melanocyte stimulating hormone (α-MSH) but not with neuropeptide Y (NPY) in the rat brain"Neuroscience Letters. 331. 119-121 (2002)

[Publications] Dohi, K.: "Pituitary adenylate cyclase-activating polypeptide (PACAP) prevents hippocampal neurons from apoptosis by inhibiting Jun N-terminal kinase (JNK)/stress activated protein kinase (SAPK) and p38 signal transduction pathway"Regul Pept. 109. 83-88 (2002)

[Publications] Guan, JL.: "Ultrastructural localization of orexin-1 receptor in pre-and post-synaptic neurons in the rat arcuate nucleus"Neuroscience Letters. 329. 209-212 (2002)

[Publications] Zhou, CJ.: "Pleiotropic effects of PACAP and multiple signaling pathways under its receptors in nervous system"Curr Protein & Peptide Sci. 3. 423-439 (2002)

[Publications] Guan, JL.: "Reciprocal synaptic relationship between orexin-and melanin-concentrating hormone-containing neurons in the rat lateral hypothalamus : a novel circuit implicated in feeding regulation"Int J Obesity. 26. 1523-1532 (2002)

[Publications] Satoh, K.: "Edarabone scavenges nitric oxide"Redox Report. 7. 219-222 (2002)

[Publications] Zhou, CJ.: "ALP-binding cassette transporter ABCA2(ABC2) expression in the developing spinal cord and PNS during myelination. A comparative study with other glial markers"J Comp Neurol. 451. 334-351 (2002)

[Publications] Wang, QP.: "Endomorphin-2 immunoreactivity in the central dorsal horn of the rat spinal cord at the electron microscopic level"Neuroscience. 113. 593-605 (2002)

[Publications] Wang, QP.: "Morphological studies of the endomorphinergic neurons in the central nervous system"Jap J Pharmacol. 89. 209-215 (2002)

[Publications] Mizushima, H.: "Reduced postischemic hippocampal apoptosis in mice deficient interleukin-1"J Comp Neurol. 448. 203-216 (2002)

[Publications] Suzuki, R.: "Orexin-1 receptor immunoreactivity in chemically identified target neurons in the rat hypothalamus"Neurosci Lett. 324. 5-8 (2002)

[Publications] Lu, SL.: "Immunocytochemical observation of ghrelin-containing neurons in the rat arcuate nucleus"Neurosci Lett. 321. 157-160 (2002)

[Publications] Yamanaka, A.: "Orexins activate histaminergic neurons in the tuberomammillary nucleus via the OX2 receptor"Biochem Biophys Res Commun. 290. 1237-1247 (2002)

[Publications] Shioda, S.: "VIP & PACAP Receptors"Oxford University Press. 21 (2002)

[Publications] Shioda, S.: "PACAP Receptor Signaling"Kluwer Academic Publications. 30 (2002)

塩田清二昭和大学, 医学部, 教授 (80102375)