title: Calpain inhibitors prevent neuronal cell death and ameliorate motor disturbances after compression-induced spinal cord injury in rats.
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 SCI. 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.
authors.affiliation: Department of Physiology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Arataki
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Tomizawa
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Moriwaki
authors.forename: Keiichirou
authors.initials: K
authors.lastname: Nishida
authors.forename: Masayuki
authors.initials: M
authors.lastname: Matsushita
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Ozaki
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kunisada
authors.forename: Aki
authors.initials: A
authors.lastname: Yoshida
authors.forename: Hajime
authors.initials: H
authors.lastname: Inoue
authors.forename: Hideki
authors.initials: H
authors.lastname: Matsui
mesh_terms: D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006023:Glycoproteins / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D019957:Motor Skills Disorders / Q000188:drug therapy* / Q000201:enzymology; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology; D051381:Rats; D017208:Rats, Wistar; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000201:enzymology; D013904:Thoracic Vertebrae
chemical_list: D006023:Glycoproteins; C039304:calpain inhibitors; D002154:Calpain