The growth inhibitory nature of adult CNS tissue and reduced axon growth ability of adult neurons are two major barriers to regenerating Fluorouracil axonal connections (Giger et al., 2010, Silver and Miller, 2004 and Yiu and He, 2006). Several proteases have been linked to axon regeneration including metalloprotease, Calpain, BACE1, and chondroitinase ABC, among which matrix metalloprotease is the best characterized (Alilain et al., 2011, Farah et al., 2011, Spira et al., 2001 and Yong, 2005). Many studies have demonstrated that MMPs facilitate

axonal regeneration in the mammalian PNS (Heine et al., 2004, Kobayashi et al., 2008, Shubayev and Myers, 2004 and Zuo et al., 1998), and the CNS of lower vertebrates (Chernoff et al., 2000). Researchers also found that increased MMP expression after mammalian CNS injury is correlated with areas of increased axonal outgrowth and the subsequent enhancement of functional recovery (Ahmed et al., 2005, Duchossoy et al., 2001 and Hsu et al., 2006). Mice deficient in MMP-2 display fewer serotonergic fibers caudal

to the injury site and significantly reduced motor recovery compared to wild-type mice after a contusive spinal cord injury (SCI) (Hsu et al., 2006). Mechanistically, MMPs could contribute to axon regeneration in multiple ways, including (1) degrading inhibitory extracellular molecules (Beliën et al., 1999, Imai et al., 1994, Muir et al., 2002, Siri et al., 1995 and Turk et al., 2001), (2) clearing inhibitory cellular NU7441 nmr and matrix debris (Franzen et al., 1998, Lazarov-Spiegler et al.,

1996, Rapalino et al., 1998, Rosenberg et al., 1998 and Yong et al., 2001), and (3) providing trophic support to regenerating axons by degrading the ECM and releasing sequestered growth factors like bFGF (Mott and Werb, 2004). On the other hand, these positive effects are tempered by MMPs’ detrimental effects on mediating Calpain early secondary pathogenesis after SCI like inflammation and glial scar formation (Popovich and Longbrake, 2008 and Silver and Miller, 2004). For example, mice that were treated with MMP inhibitor from 3 hr to 3 days after injury had less disruption of the blood-spinal cord barrier, fewer infiltrating inflammatory neutrophils within the spinal cord, and significant locomotor recovery compared to the vehicle controls (Noble et al., 2002). Inhibition of MMP-9 release from macrophages with the use of multipotent adult progenitor cells (MAPCs) or blocking MMP-9 activity by inhibitors effectively prevent macrophage-mediated axonal retraction from the injury site (Busch et al., 2011 and Busch et al., 2009). MMP-9 can also facilitate astrocyte migration and contribute to the formation of a glial scar in the injured spinal cord (Hsu et al., 2008). In addition, acute inhibition of MMP-9 after SCI induced proliferation of NG2+ cells, allowed for successful oligodendrocyte maturation and remyelination, and improved functional recovery (Liu and Shubayev, 2011).