Calpain inhibitors prevent neuronal cell death and ameliorate motor disturbances after compression-induced spinal cord injury in rats.
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.
Arataki
Shinya
S
Department of Physiology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan.
Tomizawa
Kazuhito
K
Moriwaki
Akiyoshi
A
Nishida
Keiichirou
K
Matsushita
Masayuki
M
Ozaki
Toshifumi
T
Kunisada
Toshiyuki
T
Yoshida
Aki
A
Inoue
Hajime
H
Matsui
Hideki
H
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
D006023:Glycoproteins; C039304:calpain inhibitors; D002154:Calpain