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Mechanism of Impaired Nerve Regeneration in Experimental Diabetic Rats

Research Project

Project/Area Number 08670703
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Neurology
Research InstitutionShiga University of Medical Science

Principal Investigator

TERADA Masahiko  Shiga University of Medical Science Faculty of Medicine, Instructor, 医学部, 助手 (00227521)

Project Period (FY) 1996 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 1998: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1997: ¥700,000 (Direct Cost: ¥700,000)
KeywordsDiabetic neuropathy / Nerve regeneration / Wallerian degeneration / Phosphorylation / Neurofilament / Cdk5 / JNK / ERK / アポトーシス / 後根神経節 / 坐骨神経 / p35 / 末梢神経 / P35 / ERK2 / GSK3B / 免疫組織化学 / ウエスタンブロット / 糖尿病 / ストレプトゾシン / ラット / 形態計測 / ウエスタンブッロティング
Research Abstract

To clarify the ability of diabetic nerves to regenerate in diabetic neuropathy, we evaluated nerve regeneration after nerve crush and degeneration after nerve transection in diabetic (DM) and age-matched control rats. In nerve crush model, electrophysical examination indicated that the elongation rate of regenerative nerves and their velocity was slower in DM.Morphologically, the number of regenerative nerve was significantly decreased and its diameter was smaller in DM.In nerve transection model, morphometric analysis indicated that WD was delayed in DM.Immunoblot analysis showed a delay in the degradation of neurofilaments (NFs) in DM during WD.Moreover, phosphorylated NFs detected by SMI31 were more recognized in intact diabetic nerves in comparison with control, while the opposite was true for unphosphorylated NFs detected by SMI32.
These results suggest that nerve regeneration is impaired in DM.This impairment, in part, might be due to delay of WD, because WD is prerequisite for nerve regeneration. Since it is known that the sensitivity of NF to calpain-mediated proteolysis is modulated by its carboxyl-terminal phosphorylation state and phosphorylated NFs are resistant to calpains, we concluded that abnormal NF phosphorylation state in diabetes could be one of the mechanisms by which axonal degeneration was delayed.
The excessive NF phosphorylation in STZ-diabetic rats could be due to an increase in kinase activity. Proline-directed protein kinases, such as Cdk5/p35, GSK3 beta JNK, ERK, and p38, are potential candidates for NF kinases. We confirmed the existence of Cdk5/p35, JNK, and ERK using immunoblot and immunohistochemistry. Moreover, both JNK and ERK were activated in DRG and sciatic nerve of 12 weeks STZ-diabetic rats. These results suggest that JNK and ERK make an important role in hyperphosphorylation of NF in diabetic rats.

Report

(4 results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report
  • 1996 Annual Research Report
  • Research Products

    (8 results)

All Other

All Publications (8 results)

  • [Publications] Terada M: "Tolrestat improves nerve regeneration after crush injury in streptozocin-induced diabetic rats." Metabolism. 45(10). 1189-1195 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kawai H: "Axonal contact regulates expression of α2 and β2 isoforms of Na^+, K^+-ATPase in Schwann Cells : adhesion molecules and nerve regeneration." J Neurochem. 69. 330-339 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Terada M: "Delayed Wallerian degeneration and increased neurofilament phosphorylation in rat sciatic nerve of streptozocin-induced diabetes." J Neurol Sci. 155. 23-30 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Terada M: "Expression and activity of cyclin-dependent kinase 5/p35 in adult rat peripheral nervous system." J Neurochem. 71. 2600-2606 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Terada M,Yasuda H,Kikkawa R,Shigeta Y: "Tolrestat improves nerve regeneration after crush injury in streptozocin-induced diabetic rets." Metabolism. 45 (10). 1189-1195 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kawai H,Yasuda H,Terada M,Omatsu-Kanbe M,Kikkawa R: "Axonal contact regulates expression of alpha2 and beta2 isoforms of Na^+, K^+-ATPase in Schwann cells : adhesion molecules and nerve regeneration." J Neurochem. 69. 330-339 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Terada M,Yasuda H,Kikkawa R: "Delayed Wallerian degeneration and increased neurofilament phosphorylation in rat sciatic nerve of streptozocin-induced diabetes." J Neurol Sci. 155. 23-30 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Terada M,Yasuda H,Kogawa S,Maeda K,Haneda M,Hidaka H,Kashiwagi A,Kikkawa R: "Expression and activity of cyclin-dependent kinase 5/p35 in adult rat peripheral nervous system." J Neurochem. 71. 2600-2606 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary

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Published: 1997-04-01   Modified: 2016-04-21  

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