Apoptosis has long been known to occur as a form of neuronal cell death during embryonic development22,25 and has been observed more recently following damage to the nervous system caused by ischemia, neurodegenerative conditions, inflammatory diseases, and traumatic injuries.3,6,22,24,41,44,46,50,54 Caspases are a family of cysteine proteases that play an important role in the effector phase of apoptosis. Caspase-3, in particular, has been shown to be important in neural development and injury. Germline deletions of this protease led to severe neurological defects in mice.34 The contribution of caspace-3 activity and apoptosis to neuronal cell death after traumatic brain injury54 and experimental transient ischemia24,41 has been reported. In both injury paradigms, the use of caspase inhibitors not only reduced the extent of apoptosis, but also resulted in functional behavioral improvement in the animals.
The presence of apoptosis in spinal cord injury (SCI) following a contusion has been reported recently in rats and monkeys.11,32,35,36 In these studies, it was shown that apoptosis contributed to the tissue damage seen after SCI. Apoptotic cell death was observed in both neurons and oligodendrocytes11,36 and was prominent in the white matter, in which wallerian degeneration was simultaneously observed. A time course analysis in rats36 revealed that apoptosis occurred as early as 4 hours postinjury and could be seen in decreasing amounts as late as 3 weeks after SCI.
We initiated this study to determine whether apoptosis is an important factor after human SCI by examining the spinal cords of patients who died between 3 hours and 2 months postinjury. Apoptosis in these 15 patients was assessed using multiple criteria, including nuclear morphology, chromatin staining techniques, and immunostaining for a processed form of caspase-3. We also determined the spatial and temporal expression of apoptotic cells and the nature of the cells involved in programmed cell death.
We are grateful to Tesha Monteith for her technical assistance and to Dr. Alexander Marcillo for his assistance in preparing the manuscript. We also thank Drs. Jacqueline Bresnahan and Hans Lassmann for their helpful advice.
Adams JC: Biotin amplification of biotin and horseradish peroxidase signals in histochemical stains. J Histochem Cytochem 40:1457–14631992Adams JC: Biotin amplification of biotin and horseradish peroxidase signals in histochemical stains. J Histochem Cytochem 40:
Bunge RPPuckett WRBecerra JLet al: Observations on the pathology of human spinal cord injury. A review and classification of 22 new cases with details from a case of chronic cord compression with extensive focal demyelination. Adv Neurol 59:75–891993Adv Neurol 59:
Wood PL: Microglia as a unique cellular target in the treatment of stroke: potential neurotoxic mediators produced by activated microglia. Neurol Res 17:242–2481995Wood PL: Microglia as a unique cellular target in the treatment of stroke: potential neurotoxic mediators produced by activated microglia. Neurol Res 17: