2003 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, 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	PACAPおよびその受容体は脳内に多数発現し、その受容体は脳内のとくに嗅球、海馬、小脳につよく発現している。そこで、RACAPによる海馬CA1領域の錐体細胞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遺伝子欠損マウスを用いて脳虚血実験を行なった結果、遺伝子欠損群の個体では野生型に比べて海馬の錐体細胞が有意に増加することが明らかになった。現在、その細胞内シグナル伝達機構をしらべており、遅発性神経細胞死の過程にMAPキナーゼカスケードが強く関与していることが確認されている。以上の実験・観察結果から、PACAPは生体内で神経細胞死を抑制していることを直接証明することが出来た。しかし、PACAPは神経細胞に直接作用して神経細胞死を抑制する経路の他に、神経膠細胞にもPACAPが作用してIL-6の放出を刺激し、間接的に神経細胞死を抑制する可能性もあると考えられる。PACAPによる遅発性神経細胞死のメカニズムの解明には、さらに詳細な実験研究が必要であると考えられる。

Research Products

(21 results)

All Other

All Publications (21 results)

[Publications] Wang, QP.: "Endomorphin-2 immunoreactive neurons in the rat hypothalamus."Brain Research. 969. 126-134 (2003)
[Publications] Wang, QP.: "Morphological evidence of endomorphin as an agonist for the mu-opioid receptor in the rat spinal cord."Neuroscience Letters. 341. 107-110 (2003)
[Publications] Narita, M.: "Direct evidence for the activation of phospholipase C gamma 1 by in vivo treatment with morphine in the mouse periaqueductal gray matter."Brain Research. 970. 140-148 (2003)
[Publications] Suzuki, R.: "Expression of the receptor for pituitary adenylate cyclase-activating polypeptide (PAC1-R) in reactive astrocytes."Molecular Brain Research. 115. 10-20 (2003)
[Publications] Mitamura, K.: "Detection of nitric oxide generation by electron spin resonance spectroscopy after partial hepatectomy."Showa Univ J Med Sci. 15. 237-244 (2003)
[Publications] Nonaka, N.: "Characterization of blood-bain permeability to PYY3-36 in mouse."J Pharmacol Exp Ther. 306. 948-953 (2003)
[Publications] Matsunaga, M.: "Nucleoprotamine diet derived from salmon soft roe protects mouse hippocampal neurons from delayed cell death after transient forebrain ischemia."Neuroscience Research. 47. 269-276 (2003)
[Publications] Ohtaki, H.: "Increased expression of intercellular adhesion molecute-1 (ICAM-1) in mouse brain following transient cerebral ischemia."Acta Histochem Cytochem. 36. 385-391 (2003)
[Publications] Suzuki, R.: "A transgenic mouse model for the detailed morphological study of astrocyte."Neuroscience Research. 47. 451-454 (2003)
[Publications] Dohi, K.: "Peroxynitrite and caspase-3 expression after ischemia/reperfusion in mouse cardiac arrest model."Acta Neurochir. 86(Suppl). 87-91 (2003)
[Publications] Yin, L.: "Expression of tumor necrosis factor α (TNF α)following transient cerebral ischemia."Acta Neurochir. 86(Suppl). 93-96 (2003)
[Publications] Ohtaki, H.: "Evaluation of neuronal cell death after a new global ischemia model in infant mice."Acta Neurochir. 86(Suppl). 97-100 (2003)
[Publications] Imaizumi, Y.: "Hippocmapla heme oxigenase-1 in a murine cardiac arrest model."Acta Neurochir. 86(Suppl). 101-103 (2003)
[Publications] Dohi, K.: "Neuroprotective effect from ischemia and direct free radical scavenging activity of Choto-san (Kampo medicine)."Acta Neurochir. 86(Suppl). 123-127 (2003)
[Publications] Ohtaki, H.: "Suppression of oxidative stress after transient focal ischemia in interleukin-1 knock out mice."Acta Neurochir. 86(Suppl). 191-194 (2003)
[Publications] Wakabayashi, H.: "Cytotoxic activity of tropolones against human oral tumor cell lines."Anticancer Res. 23(in press). (2003)
[Publications] Wakabayashi, H.: "Cytotoxic activity of azulenes against human oral tumor cell lines."Anticancer Res. 23(in press). (2003)
[Publications] Okayasu, H.: "Comparison of cytotoxicity and radical scavenging activity between tea extracts and chinese medicines."In vivo. 17. 577-581 (2003)
[Publications] Narita, M.: "Neuronal protein kinase Cγ-dependent proliferation/hypertrophy of spinal cord astrocyte following repeated in vivo administration of morphine."Eur J Neurosci. 19. 479-484 (2004)
[Publications] Dohi, K.: "Choto-san (Kampo medicine for Chronic Headache) scavenges nitric oxide radical : determination by electron spin resonance."Critical Care Med. (in press). (2004)
[Publications] Min, L.: "Pituitary Adenylate Cyclase Activating Polypeptide meditated intracrine signaling in the testis."Endocrinology. (in press). (2004)

2003 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] Wang, QP.: "Endomorphin-2 immunoreactive neurons in the rat hypothalamus."Brain Research. 969. 126-134 (2003)

[Publications] Wang, QP.: "Morphological evidence of endomorphin as an agonist for the mu-opioid receptor in the rat spinal cord."Neuroscience Letters. 341. 107-110 (2003)

[Publications] Narita, M.: "Direct evidence for the activation of phospholipase C gamma 1 by in vivo treatment with morphine in the mouse periaqueductal gray matter."Brain Research. 970. 140-148 (2003)

[Publications] Suzuki, R.: "Expression of the receptor for pituitary adenylate cyclase-activating polypeptide (PAC1-R) in reactive astrocytes."Molecular Brain Research. 115. 10-20 (2003)

[Publications] Mitamura, K.: "Detection of nitric oxide generation by electron spin resonance spectroscopy after partial hepatectomy."Showa Univ J Med Sci. 15. 237-244 (2003)

[Publications] Nonaka, N.: "Characterization of blood-bain permeability to PYY3-36 in mouse."J Pharmacol Exp Ther. 306. 948-953 (2003)

[Publications] Matsunaga, M.: "Nucleoprotamine diet derived from salmon soft roe protects mouse hippocampal neurons from delayed cell death after transient forebrain ischemia."Neuroscience Research. 47. 269-276 (2003)

[Publications] Ohtaki, H.: "Increased expression of intercellular adhesion molecute-1 (ICAM-1) in mouse brain following transient cerebral ischemia."Acta Histochem Cytochem. 36. 385-391 (2003)

[Publications] Suzuki, R.: "A transgenic mouse model for the detailed morphological study of astrocyte."Neuroscience Research. 47. 451-454 (2003)

[Publications] Dohi, K.: "Peroxynitrite and caspase-3 expression after ischemia/reperfusion in mouse cardiac arrest model."Acta Neurochir. 86(Suppl). 87-91 (2003)

[Publications] Yin, L.: "Expression of tumor necrosis factor α (TNF α)following transient cerebral ischemia."Acta Neurochir. 86(Suppl). 93-96 (2003)

[Publications] Ohtaki, H.: "Evaluation of neuronal cell death after a new global ischemia model in infant mice."Acta Neurochir. 86(Suppl). 97-100 (2003)

[Publications] Imaizumi, Y.: "Hippocmapla heme oxigenase-1 in a murine cardiac arrest model."Acta Neurochir. 86(Suppl). 101-103 (2003)

[Publications] Dohi, K.: "Neuroprotective effect from ischemia and direct free radical scavenging activity of Choto-san (Kampo medicine)."Acta Neurochir. 86(Suppl). 123-127 (2003)

[Publications] Ohtaki, H.: "Suppression of oxidative stress after transient focal ischemia in interleukin-1 knock out mice."Acta Neurochir. 86(Suppl). 191-194 (2003)

[Publications] Wakabayashi, H.: "Cytotoxic activity of tropolones against human oral tumor cell lines."Anticancer Res. 23(in press). (2003)

[Publications] Wakabayashi, H.: "Cytotoxic activity of azulenes against human oral tumor cell lines."Anticancer Res. 23(in press). (2003)

[Publications] Okayasu, H.: "Comparison of cytotoxicity and radical scavenging activity between tea extracts and chinese medicines."In vivo. 17. 577-581 (2003)

[Publications] Narita, M.: "Neuronal protein kinase Cγ-dependent proliferation/hypertrophy of spinal cord astrocyte following repeated in vivo administration of morphine."Eur J Neurosci. 19. 479-484 (2004)

[Publications] Dohi, K.: "Choto-san (Kampo medicine for Chronic Headache) scavenges nitric oxide radical : determination by electron spin resonance."Critical Care Med. (in press). (2004)

[Publications] Min, L.: "Pituitary Adenylate Cyclase Activating Polypeptide meditated intracrine signaling in the testis."Endocrinology. (in press). (2004)

塩田清二昭和大学, 医学部, 教授 (80102375)