Inhibition of calpain-mediated apoptosis by E-64 d-reduced immediate early gene (IEG) expression and reactive astrogliosis in the lesion and penumbra following spinal cord injury in rats.
Upregulation of calpain, a Ca(2+)-activated cysteine protease, has been implicated in apoptosis and tissue degeneration in spinal cord injury (SCI) that over time spreads from the site of injury to the surrounding regions. We examined calpain content and activity, regulation of immediate early genes (IEGs) such as c-jun and c-fos, reactive astrogliosis as the expression of glial fibrillary acidic protein (GFAP), and apoptosis-related features such as caspase-3 mRNA expression and internucleosomal DNA fragmentation in 1-cm long spinal cord segments (S1, distant rostral; S2, adjacent rostral; S3, lesion or injury; S4, adjacent caudal; and S5, distant caudal) following SCI in rats. Calpain content and production of 150 kD calpain-cleaved alpha-fodrin fragment, expression of IEGs, reactive astrogliosis, and apoptotic features were highly increased in the lesion (S3), moderately in adjacent areas (S2 and S4), and slightly in distant areas (S1 and S5) in SCI rats when compared to sham animals. Administration of the calpain-specific inhibitor E-64-d (1 mg/kg) to SCI rats continuously for 24 h inhibited calpain activity and other factors contributing to apoptosis in the lesion and surrounding areas, indicating that calpain played a key role in the pathophysiology of SCI. The results obtained from this animal model of SCI suggest that calpain inhibitor can provide neuroprotection in patients with SCI.
Ray
S K
SK
Department of Neurology, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 309, P.O. Box 250606, Charleston, SC 29425, USA.
Matzelle
D D
DD
Wilford
G G
GG
Hogan
E L
EL
Banik
N L
NL
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000235:genetics; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D053938:DNA Fragmentation / Q000187:drug effects / Q000502:physiology; D005260:Female; D017781:Genes, Immediate-Early / Q000187:drug effects* / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D005911:Gliosis / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D008840:Microfilament Proteins / Q000187:drug effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D013049:Spectrin
D002154:Calpain; D002352:Carrier Proteins; D053148:Caspase 3; D020169:Caspases; D015853:Cysteine Proteinase Inhibitors; D005904:Glial Fibrillary Acidic Protein; D007930:Leucine; D008840:Microfilament Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D013049:Spectrin; C505410:Casp3 protein, rat; C108192:aloxistatin