Received June 11, 2017; Accepted October 30, 2017; Published December 12, 2017
http://dx.doi.org/10.18081/2333-5106/015-06/354-368
Emiko Potácová, Shuolin Tsai, Qian Wang, Choi Xingquan, Liping Liu, Yongjun Lee
Abstract
Acute spinal cord injury (SCI) is associated with cellular and molecular pathological processes responsible for secondary injury progression and neuron damage, disability, and paralysis. This cascade involves oxidative stress, lipid peroxidation, excessive release of neurotransmitters, inflammation, and apoptosis. Neuroinflammation is the consequence of an injury, aiming to clear cellular debris. However, prolonged neuroinflammation contributes to the secondary injury cascade and exacerbates neuronal death. he efficacy of Oroxylin A as a neuroprotective and neuroregenerative agent in the context of acute spinal cord injury was investigated in vivo using a rat model. The study employed the weight-drop method to induce acute spinal cord injury at the Th10 vertebral level, followed by treatment with Oroxylin A. The results demonstrated that Oroxylin A treatment significantly reduced spinal cord tissue damage, alleviated edema, and preserved motor function. To confirm these findings, western blotting analysis was conducted to evaluate the expression levels of inflammation-related proteins and proteins associated with neuronal apoptosis and axonal regeneration. The administration of Oroxylin A following spinal cord injury effectively inhibited the activation of the NF-κB inflammatory pathway, decreased the expression of pro-inflammatory cytokines, and reduced the activation of caspase-3. Additionally, Oroxylin A treatment promoted the expression of neural growth-associated protein GAP-43 and the phosphorylation of AKT, leading to the activation of the PKB/AKT/GSK3β pathway and the promotion of neural cell regeneration and axon growth. In conclusion, using a novel “in vitro dentate gyrus-hippocampus” co-culture model and wide-field fluorescence imaging, this study has uncovered the communication between dentate gyrus NPCs and hippocampal astrogliosis, offering a platform to explore the therapeutic potential of bioactive molecules. Past mouse experiments demonstrate that OA is an attractive candidate for further development and offers hope for SCI treatment strategies.
Keywords: Oroxylin A; Spinal cord injury; Neurological evaluation; Surgical intervention
References
1. Basso DM, Beattie MS, Bresnahan JC. Graded histological and locomotor outcomes after spinal cord contusion using the NYU weight-drop device versus transection. Exp Neurol 1996;139:244–256. [PubMed]
2. Liu W, Mu R, Nie FF, et al. MAC-related mitochondrial pathway in oroxylin A-induced apoptosis in human hepatocellular carcinoma HepG2 cells. Cancer Lett 2009; 284:198–207. [PubMed]
3. Demediuk P, Saunders RD, Anderson DK, Means ED, Horrocks LA. Membrane lipid changes in laminectomized and traumatized cat spinal cord. Proc Natl Acad Sci U S A 1985;82:7071–7075. [PubMed]
4. Fitch MT, Doller C, Combs CK, Landreth GE, Silver J. Cellular and molecular mechanisms of glial scarring and progressive cavitation: in vivo and in vitro analysis of inflammation-induced secondary injury after CNS trauma. Journal of Neuroscience 1999;19:8182–8198. [PubMed]
5. Wood PL, Khan MA, Moskal JR, Todd KG, Tanay VA, Baker G. Aldehyde load in ischemia-reperfusion brain injury: neuroprotection by neutralization of reactive aldehydes with phenelzine. Brain Res 2006;1122:184–190. [PubMed]
6. Lu Z, Lu N, Li C, et al. Oroxylin A inhibits matrix metalloproteinase-2/9 expression and activation by up-regulating tissue inhibitor of metalloproteinase-2 and suppressing the ERK1/2 signaling pathway. Toxicol Lett 2012;209: 211–220. [PubMed]
7. Chen Y, Yang L, Lee TJ. Oroxylin A inhibition of lipopolysaccharide-induced iNOS and COX-2 gene expression via suppression of nuclear factor-kappaB activation. Biochem. Pharmacol 2000;59:1445–1457. [PubMed]
8. Ha J, Zhao L, Zhao Q, et al. Oroxylin A improves the sensitivity of HT-29 human colon cancer cells to 5-FU through modulation of the COX-2 signaling pathway. Biochem Cell Biol 2012; 90:521-31. [PubMed]
9. Gao Y, Lu N, Ling Y, et al. Oroxylin A inhibits angiogenesis through blocking vascular endothelial growth factor-induced KDR/Flk-1 phosphorylation. J. Cancer Res. Clin. Oncol 2010; 136(5):667-675. [PubMed]
10. Pham TA, Che H, Phan PT, Lee JW, Kim SS, Park H. Oroxylin A analogs exhibited strong inhibitory activities against iNOS-mediated nitric oxide (NO) production. Bioorganic & medicinal chemistry letters 2012; 22: 2534-2535. [PubMed]
11. Song X, Chen Y, Sun Y, et al. Oroxylin A, a classical natural product, shows a novel inhibitory effect on angiogenesis induced by lipopolysaccharide. Pharmacological reports 2012;PR 64:1189-1199. [PubMed]
12. Yoon SY, dela Peña I, Kim SM, et al. Oroxylin A improves attention deficit hyperactivity disorder-like behaviors in the spontaneously hypertensive rat and inhibits reuptake of dopamine in vitro. Archives of pharmacal research 2013;36:134-140. [PubMed]
13. Taub R. Liver regeneration: from myth to mechanism. Nat Rev Mol Cell Biol 2014; 5: 836–847. [PubMed]
14. Masuda Y. Learning toxicology from carbon tetrachloride-induced hepatotoxicity. Yakugaku Zasshi 2006; 126:885–899. [PubMed]
15. Taniguchi M, Takeuchi T, Nakatsuka R, Watanabe T, Sato K. Molecular process in acute liver injury and regeneration induced by carbon tetrachloride. Life Sci 2004; 75:1539–1549. [PubMed]
16. Basu S. Carbon Tetrachloride-Induced Hepatotoxicity: A Classic Model of Lipid Peroxidation and Oxidative Stress. In: Basu S, Wiklund L, editors. Studies on Experimental Models: Humana Press. 467–480.
17. Novobrantseva TI, Majeau GR, Amatucci A, et al. Attenuated liver fibrosis in the absence of B cells. The Journal of Clinical Investigation 2005; 115:3072–3082. [PubMed]
18. Yoneyama H, Kai Y, Koyama J, et al. Neutralization of CXCL10 accelerates liver regeneration in carbon tetrachloride-induced acute liver injury. Medical Molecular Morphology 2007;40:191–197. [PubMed]
19. Min JK, Han KY, Kim EC, et al. Capsaicin inhibits in vitro and in vivo angiogenesis. Cancer Res 2004;64:644–651. [PubMed]
20. Gao Y, Lu N, Ling Y, et al. Oroxylin A inhibits angiogenesis through blocking vascular endothelial growth factor-induced KDR/Flk-1 phosphorylation. J Cancer Res Clin Oncol 2010;136: 667–675. [PubMed]
21. Li HN, Nie FF, Liu W, et al. Apoptosis induction of oroxylin A in human cervical cancer HeLa cell line in vitro and in vivo. Toxicology 2009; 257: 80–85. [PubMed]
