6?��?0.65 vs. Vehicle, 9.3?��?1.1?mm3, p?<?0.05) (Fig.?7e). The present study shows that the neuroprotective effect of VPA might be mediated in part by attenuating BSCB disruption via inhibition of MMP-9 activity after SCI. We also demonstrated that post-injury treatment with VPA <a href="http://en.wikipedia.org/wiki/Alkylation
">Chloroambucil inhibited apoptotic cell death of neurons and oligodendrocytes and improved functional recovery after SCI. Furthermore, the present study showed that the neuroprotective effect of VPA might also be mediated in part by modulating the production of inflammatory mediators, the level of acetylated histone 3 (acetyl-H3 at lys9) and up-regulating anti-apoptotic molecules such as pAkt, HSP27, HSP70 and down-regulating p53 after injury. Based on our results, it is likely that multiple signaling pathways may be involved in the neuroprotective effect of VPA after SCI. VPA is a short-chain fatty acid that NVP-BEZ235
readily crosses the BBB and has low toxicity and acceptable tolerability in both human and animal studies (Nalivaeva et?al. 2009; Biermann et?al. 2011). In this study, VPA (300?mg/kg) was administered by subcutaneous injection twice daily for 5?days. This dosage was close to that used to control seizure in rats, and was the same that found to exert neuroprotective effects against cerebral ischemia (Ren et?al. 2004; Kim et?al. 2007), intracerebral hemorrhage (Sinn et?al. 2007) and malonate-induced toxicity (Morland et?al. 2004). In addition, we did not observe any significant change in body weight among the experimental groups (data not shown) during our experiment. Also, neither significant side effects nor an increase in mortality by VPA treatment were observed. Up-regulation of MMP-9 has been implicated in SCI-induced secondary damage and BSCB disruption by degrading the basal components of BBB and facilitating immune cell infiltration (Noble et?al. 2002). Our results also show that MMP-9 OSI-744 cost
expression was up-regulated and its enzyme activity was increased at 1?day after SCI. Furthermore, VPA treatment significantly decreased the expression and gelatinase activity of MMP-9 at 1?day after SCI (see Fig.?1). This result is consistent with a previous report showing that VPA attenuates ischemia-induced BBB disruption and brain edema by inhibiting MMP-9 induction and tight junction degradation (Wang et?al. 2011). It is also known that MMP-9 degrades gelatin, collagens (type IV, V, and XI), elastin, vitronectin, myelin-basic protein, and other substrates (Vu and Werb 2000). In addition, tight junction proteins as essential components of BBB or BSCB are known to be substrate of MMP (Yang et?al. 2007). As shown in Fig.?3a, tight junction proteins, occludin and ZO-1, was degraded after SCI and VPA significantly inhibited degradation of these molecules (Fig.?3c).