| Primary trauma to the spinal cord triggers a cascade of cellular and molecular events that promote continued tissue damage and expansion of the lesion for many days to months following the initial injury. Therefore, the final outcome of spinal cord injury (SCI) is related to the extent of the initial physical damage and the ensuing secondary events that lead to the death of neurons and glia and ultimate cavitation of the central gray matter. Programmed cell death (apoptosis) plays a major role in progression of spinal cord lesion after the initial injury. In fact, apoptosis has been shown to contribute to secondary degeneration at the vicinity of the spinal cord lesions and the ensuing Wallerian degeneration of the ascending and descending tracts in the white matter. Excitotoxicity, oxidative stress, and proinflammatory cytokines individually or together can trigger apoptosis. In fact, considerable evidence has emerged pointing to the critical contribution of all of these factors in secondary SCI. Diverse groups of molecules are involved in the apoptosis pathway. One set of mediators implicated in apoptosis belong to the asparate-specific cysteinyl proteases or caspases. A member of this family, caspase-3 (CPP32, apopain, YAMA) has been identified as being a key mediator of apoptosis of mammalian cells. Kothakota et al, screened the translation products of a murine protein library to find the substrates that are susceptible to cleavage by caspase-3. They found that in cells exposed to Fas, gelsolin was cleaved in vivo in a caspase dependent manner. The cleaved fragments of gelsolin led to the cleavage of the actin filaments in a Ca2+ independent manner. The expression of the gelsolin fragments also led to the apoptosis of cells. Additional evidence for the role of gelsolin in apoptosis was provided by showing that, as compared with wild-type neutrophis, those from mice lacking gelsolin exhibited a delayed onset of induced apoptosis. Therefore, the authors suggested that cleaved fragments of gelsolin may be implicated in apoptosis. Matsuyama reported that nitric oxide (NO) may be closely involved in the development of post-traumatic spinal cord cavitation and may therefore be a candidate in the development of the pathological process in vivo. NO is known to produce either neurotoxic or neuroprotective effects depending on its ambient redox milieu. NO cytotoxicity emerges, in part, by reaction with superoxide anion (O2-) to generate peroxynitrite (ONOO-), while the nitrosonium ion (NO+), an alternative redox-activated state of NO, reacts with the thiol group of the N-methyl-aspartate (NMDA) receptor to block cytotoxic neurotransmission. There are three isoforms of nitric oxide synthase (NOS). There are two calmodulin-dependent isoforms, neuronal NOS (nNOS) and endothelial NOS (eNOS), which produce NO following Ca2+ influx. Under normal conditions, NO plays a physiological role in neuronal signal transmission and vessel dilation. Following trauma, excitatory amino acids may overstimulate the NMDA receptor, leading to a high level of NO production via Ca2+ influx, which may in turn cause tissue damage. Certain immunohistochemical studies on the distribution of NADPH-diaphorase in motor neurons and at the tip of damaged axons suggest that induction of nNOS in neurons is involved in secondary damage following SCI. There is also an inducible isoform of NOS (iNOS), which is regulated at a transcriptional level and induced under pathological conditions such as infection, stab wounds, and inflammatory disorders. In the case of SCI, Hamada et al. reported that in the compression model NO produced by iNOS is neurotoxic, while NO produced by the constitutive forms of NOS, such as eNOS or nNOS is neuroprotective. The bcl-2 proteins are a family of proteins involved in the response to apoptosis. Some of these proteins (such as bcl-2 and bcl-XL) are anti-apoptotic, while others (such as Bad or Bax) are pro-apoptotic. The sensitivity of cells to apoptotic stimuli can depend on the balance of... |
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