ABSTRACT
Conclusion ...............................................................................................................65 References ................................................................................................................66
Despite extensive research, clinical advancements, and improved rehabilitation strategies, spinal cord injury (SCI) continues to be a signicant cause of disability and mortality (Sekhon and Fehlings, 2001). About 11,000 new cases of SCI are reported each year, and 250,000 patients now live in the United States. Economic costs for SCI approach $10 billion a year (https://www.Sfn.org). Pathophysiology of SCI involves two broad chronological events: the primary injury and the secondary injury. The primary injury that encompasses the focal destruction of neural tissue caused by direct mechanical trauma then instigates a progressive wave of secondary injury, which via the activation of a barrage of noxious pathophysiological mechanisms exacerbates the injury and leads to greater functional loss after SCI (reviews, see Tator and Fehlings, 1991; Hulsebosch, 2002; Profyris et al., 2004). Oligodendrocytes (OLs) are particularly susceptible to oxidative stress, glutamate excitotoxicity, and the immune responses associated with the secondary injury cascade after SCI (Springer et al., 1999; Casha et al., 2001; Beattie et al., 2002; Nottingham et al., 2002; Park et al., 2004). Oligodendrocyte death and/or apoptosis occur at the injury center as early as a few hours following injury and signicantly increase for several days thereafter (Crowe et al., 1997; Emery et al., 1998; Yong et al., 1998; Li et al., 1999). By 1 week, the number of apoptotic cells decreases at the injury center and there is an increase in apoptotic death away from the primary injury. This new apoptotic wave is predominantly localized in the white matter and can arise at large distances from the lesion center (Crowe et al., 1997; Liu et al., 1997; Li et al., 1999). The later phase of apoptosis lasts for at least a few weeks (Crowe et al., 1997; Li et al., 1999). Such delayed onset of apoptosis in OLs distant to the injury site appears to be unique to SCI and has important therapeutic implications. Because each OL myelinates multiple axons, their death leads to demyelination of many axons, which are left intact by the initial injury (Bunge et al., 1993; Totoiu and Keirstead, 2005; Cao et al., 2005b) (Figure 2.1). Consequently, the electrophysiological conductions of these axons are lost or delayed (Gledhill et al., 1973; Itoyama et al., 1983; Dusart et al., 1992). Dysfunction of these demyelinated axons in the injury epicenter and also in the areas distant to this epicenter may contribute further to long-term neurological decits after SCI. Furthermore, OLs may provide trophic support to its myelinated axons by both contact-mediated and soluble mechanisms (Grifths et al., 1998; Wilkins et al., 2001, 2003). Demyelinated axons are more vulnerable to the insults in the injured spinal cord and undergo secondary degeneration (Tsunoda and Fujinami, 2002; Compston, 2006). Importantly, preservation of a small portion of axons (5%–10%) in each individual tract can achieve signicant meaningful recovery with locomotion (Blight, 1983b; Blight and DeCrescito, 1986). Numerous demyelinated, but otherwise intact, axons are observed after SCI in both experimental animals (Totoiu and Keirstead, 2005; Cao et al., 2005b) and humans (Bunge et al., 1993). Therefore, promoting remyelination is an important therapeutic strategy to enhance functional recovery by restoring the electrophysiological conduction of the demyelinated axons as well as preventing its degeneration. Oligodendrocyte precursor cells (OPCs) are the major cells responsible for
