Calpain inhibitor prevented apoptosis and maintained transcription of proteolipid protein and myelin basic protein genes in rat spinal cord injury.
Spinal cord injury (SCI) is associated with progressive neurodegeneration and dysfunction. Multiple cellular and molecular mechanisms are involved in this pathogenesis. In particular, the activation of proteases following trauma can cause apoptosis in the spinal cord. Calpain, a calcium-dependent cysteine protease, plays a major role in apoptosis following trauma. We identified apoptosis and decrease in transcription of the genes for proteolipid protein (PLP) and myelin basic protein (MBP) in five 1-cm long spinal cord segments (S1, distant rostral; S2, near rostral; S3, lesion; S4, near caudal; and S5, distant caudal) 24 h after induction of SCI (40 g.cm force) in rats by weight-drop method. Sham rats underwent laminectomy and did not receive injury. Internucleosomal DNA fragmentation occurred prominently in the lesion (S3), moderately in near segments (S2 and S4), and slightly in distant segments (S1 and S5) of injured rats, indicating the occurrence of apoptosis in the lesion and penumbra. Levels of transcription of PLP and MBP were reduced highly in the lesion and moderately in near segments, suggesting that apoptotic loss of cells impaired biosynthesis of two important structural components of myelin. Immediate administration of the calpain inhibitor E-64-d (1 mg/kg) to injured rats prevented apoptosis and restored transcription of these genes, indicating the therapeutic efficacy of calpain inhibitor for treatment of SCI.
Department of Neurology, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 309, PO Box 250606, Charleston, SC 29425, USA.
Swapan K
SK
Ray
Denise D
DD
Matzelle
Eric A
EA
Sribnick
M Kelly
MK
Guyton
J Michael
JM
Wingrave
Naren L
NL
Banik
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002154:Calpain / Q000037:antagonists & inhibitors*; D053938:DNA Fragmentation / Q000187:drug effects; D004587:Electrophoresis, Agar Gel; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004676:Myelin Basic Protein / Q000096:biosynthesis / Q000235:genetics*; D018991:Myelin Proteolipid Protein / Q000096:biosynthesis / Q000235:genetics*; D009707:Nucleosomes / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013119:Spinal Cord Injuries / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*
D004676:Myelin Basic Protein; D018991:Myelin Proteolipid Protein; D009707:Nucleosomes; D012333:RNA, Messenger; D002154:Calpain; D007930:Leucine; C108192:aloxistatin