Calpain inhibitors prevent neuronal cell death and ameliorate motor disturbances after compression-induced spinal cord injury in rats

Shinya Arataki, Kazuhito Tomizawa, Akiyoshi Moriwaki, Keiichirou Nishida, Masayuki Matsushita, Toshifumi Ozaki, Toshiyuki Kunisada, Aki Yoshida, Hajime Inoue, Hideki Matsui

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Abstract

Traumatic spinal cord injury (SCI) results in widespread neuronal cell death. Recent studies have suggested that activated calpain mediates neuronal cell death in the central nervous system. We conducted a study to determine whether calpain mediates neuronal cell death in the motor neurons of the spinal cord after SCI, and whether postinjury administration of the calpain inhibitors N-acetyl-Leu-Leu-Met-CHO (ALLM) and calpain inhibitor III (CI III) (MDL28170) reduces the motor disturbances in rats with a model of SCL Adult male Wistar rats were subjected to SCI by application of a 20-g weight impactor probe to the spinal cord at T12 for 20 min. The rats were divided into three groups according to whether they were injected intravenously with 0.05-2.5 mg/kg ALLM, 10 mg/kg CI III, or 0.1% DMSO as a control every 24 h for 1 week after SCI. Calpain was activated in the spinal cord at 8 h, 24. h, and 5 days after SCI, and administration of ALLM inhibited its activation. ALLM, as compared to the DMSO vehicle alone, also significantly reduced the number of motor neurons in spinal-cord lesions that were positively labeled at 24 h after SCI with the terminal deoxynucleotidyl transferase-uridine nucleotide end-labeling (TUNEL) technique. Additionally, both the inclined plane test and footprint analysis showed markedly better motor activity after 4 weeks in rats injected with ALLM or CI III than in rats given vehicle only. These results suggest that activation of calpain plays a critical role in the neuronal cell death that follows SCI, and that calpain inhibitors may have benefit in treating the motor disturbances that follow SCI.

Original languageEnglish
Pages (from-to)398-406
Number of pages9
JournalJournal of Neurotrauma
Volume22
Issue number3
DOIs
Publication statusPublished - Mar 1 2005

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Keywords

  • Apoptosis
  • Motor neuron
  • SCI
  • Spinal cord
  • Terminal deoxynucleotidyl transferase-uridine nucleotide end-labeling technique

ASJC Scopus subject areas

  • Clinical Neurology

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