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Pretreatment with Calpain Inhibitor CEP‐4143 Inhibits Calpain I Activation and Cytoskeletal Degradation, Improves Neurological Function, and Enhances Axonal Survival After Traumatic Spinal Cord Injury
Author(s) -
Schumacher P. A.,
Siman R. G.,
Fehlings M. G.
Publication year - 2000
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2000.0741646.x
Subject(s) - calpain , cytoskeleton , spinal cord injury , spinal cord , neuroscience , anesthesia , chemistry , microbiology and biotechnology , medicine , pharmacology , biology , biochemistry , enzyme , cell
The pathophysiology of traumatic spinal cord injury (SCI)involves abnormal activation of the neutral cysteine protease calpain I (EC3.4.22.17). In the present study we examined the effect of the calpaininhibitor CEP‐4143 on cytoskeletal protection and neurological recovery afterSCI in adult rats. Microinjection of 50 m M CEP‐4143 into the T7vertebral segment 10 min before a 35‐g clip compression injury resulted ininhibition of calpain activation at 2 and 4 h postinjury, as determined bywestern blotting for calpain I‐mediated spectrin degradation, andsignificantly attenuated the degradation of dephosphorylated NF200neurofilament protein at 4 and 8 h postinjury. To examine the in vivo chronicneuroprotective effects of CEP‐4143, animals underwent microinjection withsaline or 50 m M CEP‐4143 10 min before injury, followed by weeklyblinded behavioral assessments for 6 weeks. Animals receiving CEP‐4143treatment showed significant improvement over saline‐treated controls on theBasso Beattie Bresnahan locomotor rating scale ( p < 0.02) andinclined plane test ( p < 0.05). Counts of neurons in the red nucleus retrogradely labeled by fluorogold after introduction distal to the injury site were significantly higher in CEP‐4143‐treated animals. Finally, morphometric assessment of the injury site by computer‐assisted image analysis revealed significant tissue preservation in CEP‐4143‐treated animals. We conclude that the calpain antagonist CEP‐4143 exhibits biochemical, behavioral, and anatomical neuroprotection following traumatic SCI.