Investigation of cerebral paralysis and its development of new drugs in neonatal hypoxic-ischemia-induced slowly progressive brain damage

• Project/Area Number: 17590479
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Applied pharmacology
• Research Institution: Fukuoka University
• Principal Investigator: MISHIMA Kenichi Fukuoka University, Pharmaceutical Science, Assistant Professor, 薬学部, 助手 (00320309)
• Co-Investigator(Kenkyū-buntansha): FUJIWARA Michihiro Fukuoka University, Pharmaceutical Science, Professor, 薬学部, 教授 (10091331) ; IWASAKI Katsunori Fukuoka University, Pharmaceutical Science, Professor, 薬学部, 教授 (10183196) ; IKEDA Tomoaki National Cardiovascular Center, Perinatology, Director, 周産期科, 部長 (80202894)
• Project Period (FY): 2005 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,500,000); Fiscal Year 2006: ¥1,200,000 (Direct Cost: ¥1,200,000); Fiscal Year 2005: ¥2,300,000 (Direct Cost: ¥2,300,000)
• Keywords: neonate / astrocyte / hypoxia-ischemia / corticosterone / learning and memory / 回転行動 / GDNF

Research Abstract

The present study was designed to determine potential associations between the brain damage induced by hypoxic-ischemic (HI) insult and spatial learning impairment in 8-arm radial maze task. The brain damage was progressed from 2 weeks of recovery and up to 17 weeks of recovery. The magnetic resonance imaging (MRI) changes were similar with the histological changes, and the brain damages were exacerbated in contralateral hemisphere after 57 weeks of recovery following the HI. The spatial learning impairments of 8-arm radial maze starting at 16 weeks of recovery were more severe than those at 7 weeks of recovery, indicating that the spatial learning impairments were progressive and depended on the degree of brain damage. Therefore we called this phenomenon, slowly progressive brain damage (SPBD, Nuerosci Lett, 376,194-199,2005). We examined this mechanism of the SPBD.
1) The time course of astrocyte in thalamus and hypothalamus The GFAP-positive cell progressively increased in the thalamus from 2 weeks and in the hypothalamus from 9 weeks after the HI. The S-100 protein-positive cells were observed in both thalamus and hypothalamus 17 weeks after the HI.
2) The time course of glutamate, NOx and corticosterone in the CSF The glutamate decreased from 2 weeks to 17 weeks after the HI, and the NOx increased from 9 weeks after the HI. The corticosterone tended to decrease in the female rats.
3) Effect of the CSF at 17 weeks after the HI on the CRT task in intact rats.
The CSF was corrected at 17 weeks after the HI and was injected i.c.v. in intact rats. The CSF (20-40 uL) did not affect the CRT task.
These results suggest that the SPBD was related to the activating of astrocyte in the hypothalamus, a decrease in the glutamate and an increase in the NOx.

Research Products

• [Journal Article] High-cholesterol feeding aggravates cerebral infarction via decreasing the CB(1) receptor. (2007)
  • Author(s): Hayakawa K, Mishima K, Nozako M, Hazekawa M, Aoyama Y, Ogata A, Harada K, Fujioka M, Abe K, Egashira N, Iwasaki K, Fujiwara M
  • Journal Title: Neurosci Lett. 414 Pages: 183-187
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Delta(9)-tetrahydrocannabinol (Delta(9)-THC) prevents cerebral infarction via hypothalamic-independent hypothermia. (2007)
  • Author(s): Hayakawa K, Mishima K, Nozako M, Hazekawa M, Ogata A, Fujioka M, Harada K, Mishima S, Orito K, Egashira N, Iwasaki K, Fujiwara M
  • Journal Title: Life Sci. 80 Pages: 1466-1471
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] High-cholesterol feeding aggravates cerebral infarction via decreasing the CB(1) receptor. (2007)
  • Author(s): Hayakawa K, Mishima K, Nozako M, Hazekawa M, Aoyama Y, Ogata A, Harada K, Fujioka M, Abe K, Egashira N, Iwasaki K, Fujiwara M.
  • Journal Title: Neurosci Lett. 414 Pages: 183-187
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Delta(9)-tetrahydrocannabinol (Delta(9)-THC) prevents cerebral infarction via hypothalamic-independent hypothermia. (2007)
  • Author(s): Hayakawa K, Mishima K, Nozako M, Hazekawa M, Ogata A, Fujioka M, Harada K, Mishima S, Orito K, Egashira N, Iwasaki K, Fujiwara M.
  • Journal Title: Life Sci. 80 Pages: 1466-1471
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Comparison of Single- and Repeated-Ischemia-Induced Changes in Expression of Flip and Flop Splice Variants of AMPA Receptor Subtypes GluR1 and GluR2 in the Rats Hippocampus CA1 Subregion. (2007)
  • Author(s): Hatip-Al-Khatib I, Iwasaki K, Egashira N, Ishibashi D, Mishima K, Fujiwara M
  • Journal Title: J Pharmacol Sci. 103 Pages: 83-91
  • NAID: 10024312106
• [Journal Article] Delta(9)-tetrahydrocannabinol (Delta(9)-THC) prevents cerebral infarction via hypothalamic-independent hypothermia. (2007)
  • Author(s): Hayakawa K, Mishima K, Nozako M, Hazekawa M, Ogata A, Fujioka M, Harada K, Mishima S, Orito K, Egashira N, Iwasaki K, Fjiwara M
  • Journal Title: Life Sci. in press
• [Journal Article] Rehabilitative training tasks improve spatial learning impairment in the water maze following hypoxic-ischemic insult in neonatal rats. (2006)
  • Author(s): Ikeda T, Mishima K, Aoo N, Harada K, Liu AX, Egashira N, Iwasaki K, Fujiwara M, Ikenoue T
  • Journal Title: Pediatr Res. 59 Pages: 61-65
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Rehabilitative training tasks improve spatial learning impairment in the water maze following hypoxic-ischemic insult in neonatal rats. (2006)
  • Author(s): Ikeda T, Mishima K, Aoo N, Harada K, Liu AX, Egashira N, Iwasaki K, Fujiwara M, Ikenoue T.
  • Journal Title: Pediatr Res. 59 Pages: 61-65
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Elevated anxiety-like and depressive behavior in Desert hedgehog knockout male nice. (2006)
  • Author(s): Umehara F, Mishima K, Egashira N, Ogata A, Iwasaki K, Fujiwara M
  • Journal Title: Behav Brain Res. 174 Pages: 167-173
• [Journal Article] Protective effects of carotenoids from saffron on neuronal injury in vitro and in vivo. (2006)
  • Author(s): Ochiai T, Shimeno H, Mishima KI, Iwasaki K, Fujiwara M, Tanaka H, Shoyama Y, Toda A, Eyanagi R, Soeda S
  • Journal Title: Biochim Biophys Acta. in press
• [Journal Article] High-cholesterol feeding aggravates cerebral infarction via decreasing the CB(1) receptor. (2006)
  • Author(s): Hayakawa K, Mishima K, Nozako M, Hazekawa M, Aoyama Y, Ogata A, Harada K, Fujioka M, Abe K, Egashira N, Iwasaki K, Fujiwara M
  • Journal Title: Neurosci Lett. in press
• [Journal Article] Implantation of encapsulated glial cell line-derived neurotrophic factor-secreting cells prevents long-lasting learning impairment following neonatal hypoxic-ischemic brain insult in rats. (2005)
  • Author(s): Katsuragi S, Ikeda T, Date I, Shingo T, Yasuhara T, Mishima K, Aoo N, Harada K, Egashira N, Iwasaki K, Fujiwara M, Ikenoue T
  • Journal Title: Am J Obstet Gyneco 192 Pages: 1028-1037
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Short-Term Administration of a New Free Radical Scavenger, Edaravone, Is More Effective Than its Long-Term Administration for the Treatment of Neonatal Hypoxic-Ischemic Encephalopathy. (2005)
  • Author(s): Noor JI, Ikeda T, Mishima K, Aoo N, Ohta S, Egashira N, Iwasaki K, Fujiwara M, Ikenoue T
  • Journal Title: Stroke 36 Pages: 2468-2474
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Dexamethasone prevents long-lasting learning impairment following a combination of lipopolysaccharide and hypoxia-ischemia in neonatal rats. (2005)
  • Author(s): Ikeda T, Mishima K, Aoo N, Liu AX, Egashira N, Iwasaki K, Fujiwara M, Ikenoue T
  • Journal Title: Am J Obstet Gyneco 192 Pages: 719-726
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Hypoxia-ischemic insult in neonatal rats induced slowly progressive brain damage related to memory impairment (2005)
  • Author(s): Mishima K, Ikeda T, Aoo N, Takai N, Takahashi S, Egashira N, Ikenoue T, Iwasaki K, Fujiwara M
  • Journal Title: Neurosci Lett. 376 Pages: 194-199
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Short-Term Administration of a New Free Radical Scavenger, Edaravone, Is More Effective Than its Long-Term Administration for the Treatment of Neonatal Hypoxic-Ischemic Encephalopathy. (2005)
  • Author(s): Noor JI, Ikeda T, Mishima K, Aoo N, Ohta S, Egashira N, Iwasaki K, Fujiwara M, Ikenoue T.
  • Journal Title: Stroke 36 Pages: 2468-2474
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Implantation of encapsulated glial cell line-derived neurotrophic factor-secreting cells prevents long-lasting learning impairment of following neonatal hypoxic-ischemic brain insult in rats. (2005)
  • Author(s): Katsuragi S, Ikeda T, Date I, Shingo T, Yasuhara T, Mishima K, Aoo N, Harada K, Egashira N, Iwasaki K, Fujiwara M, Ikenoue T
  • Journal Title: Am J Obstet Gyneco 192 Pages: 1028-1037
• [Journal Article] Canabidiol Prevents Cerebral Infarction Via a Serotonergic 5-Hydroxytryptaminel A Recepter-Dependent Mechanism. (2005)
  • Author(s): Mishima K, Hayakawa K, Abe K, Ikeda T, Egashira N, Iwasaki K, Fujiwara M.
  • Journal Title: Stroke 36 Pages: 1071-1076
• [Journal Article] Post-ischemic treatment with toki-shakuyaku-san(tang-gui-shao-yao-san)prevents the impairment of spatial memory induced by repeated cerebral ischemia in rats. (2005)
  • Author(s): Pu F, Mishima K, Egashira N, Akiyoshi Y, Liu AX, Sano K, Irie K, Ishibashi D, Hatip-Al-Khatib I, Iwasaki K, Kurauchi K, Iwasaki K, Fujiwara M
  • Journal Title: Am J Chin Med. 33 Pages: 475-489