Abstract
Wogonin is a natural flavonoid isolated from the root of Scutellaria baicalensis Georgi, which has been widely used in various research areas for its anti-oxidant, anti-inflammatory, and anti-cancer activities. It also presents a neuroprotective effect in the brain while encounters stress conditions, but the mechanisms controlling the neuroprotective effect of wogonin are not clear. In this study, we investigated the biomechanism underlying the neuroprotective effect of wogonin on rat dorsal root ganglion (DRG) neurons. Wogonin pre-treatment at 75 μM significantly increased the cell viability of DRG neurons and decreased the number of the propidium iodide-positive DRG neurons before the endoplasmic reticulum (ER) stress is being induced by tunicamycin (TUN) (0.75 μg/mL). In addition, Wogonin also inhibited the release of LDH and up-regulated the level of GSH. Furthermore, wogonin decreased the activation of ER stress-related molecules, including glucose-regulated protein 78 (GRP78), GRP94, C/EBP-homologous protein, active caspase12 and active caspase3, phosphorylation of pancreatic ER stress kinase, and eukaryotic initiation factor 2 alpha (eIF2α). In summary, our results indicated that wogonin could protect DRG neurons against TUN-induced ER stress.
Similar content being viewed by others
References
Badiola N, Penas C, Minano-Molina A, Barneda-Zahonero B, Fado R, Sanchez-Opazo G, Comella JX, Sabria J, Zhu C, Blomgren K, Casas C, Rodriguez-Alvarez J (2011) Induction of ER stress in response to oxygen-glucose deprivation of cortical cultures involves the activation of the PERK and IRE-1 pathways and of caspase-12. Cell Death Dis 2:e149
Chen CC, Hung TH, Wang YH, Lin CW, Wang PY, Lee CY, Chen SF (2012) Wogonin improves histological and functional outcomes, and reduces activation of TLR4/NF-kappaB signaling after experimental traumatic brain injury. PLoS ONE 7:e30294
Chen HC, Hsu PW, Tzaan WC, Lee AW (2014) Effects of the combined administration of vitamins C and E on the oxidative stress status and programmed cell death pathways after experimental spinal cord injury. Spinal Cord 52:24–28
Cho J, Lee HK (2004a) Wogonin inhibits excitotoxic and oxidative neuronal damage in primary cultured rat cortical cells. Eur J Pharmacol 485:105–110
Cho J, Lee HK (2004b) Wogonin inhibits ischemic brain injury in a rat model of permanent middle cerebral artery occlusion. Biol Pharm Bull 27:1561–1564
Ding W, Yang L, Zhang M, Gu Y (2012) Reactive oxygen species-mediated endoplasmic reticulum stress contributes to aldosterone-induced apoptosis in tubular epithelial cells. Biochem Biophys Res Commun 418:451–456
Ding T, Wen H, Wei H, Wu H, Zhao J, Chen F (2014) Increased expression of TBP/TFIID after spinal cord injury in adult rats. Cell Mol Neurobiol 34:669–677
Gasiorowski K, Lamer-Zarawska E, Leszek J, Parvathaneni K, Yendluri BB, Blach-Olszewska Z, Aliev G (2011) Flavones from root of Scutellaria baicalensis Georgi: drugs of the future in neurodegeneration? CNS Neurol Disord: Drug Targets 10:184–191
Groenendyk J, Michalak M (2005) Endoplasmic reticulum quality control and apoptosis. Acta Biochim Polonica 52:381–395
Huang YH, Chang CY, Chen CC, Yang CD, Sun WH (2013) Distinct expression of Mas1-related G-protein-coupled receptor B4 in dorsal root and trigeminal ganglia–implications for altered behaviors in acid-sensing ion channel 3-deficient mice. J Mol Neurosci 51:820–834
Kadowaki H, Nishitoh H, Ichijo H (2004) Survival and apoptosis signals in ER stress: the role of protein kinases. J Chem Neuroanat 28:93–100
Kalaivani P, Saranya S, Poornima P, Prabhakaran R, Dallemer F, Vijaya Padma V, Natarajan K (2014) Biological evaluation of new nickel(II) metallates: synthesis, DNA/protein binding and mitochondrial mediated apoptosis in human lung cancer cells (A549) via ROS hypergeneration and depletion of cellular antioxidant pool. Eur J Med Chem 82:584–599
Kim R, Emi M, Tanabe K, Murakami S (2006) Role of the unfolded protein response in cell death. Apoptosis 11:5–13
Lee H, Kim YO, Kim H, Kim SY, Noh HS, Kang SS, Cho GJ, Choi WS, Suk K (2003) Flavonoid wogonin from medicinal herb is neuroprotective by inhibiting inflammatory activation of microglia. FASEB J 17:1943–1944
Li X, Zou Y, Luo H, Weng Y, Guo Q, Huang C (2014) Spatiotemporal changes in NSF expression of DRG neurons in a rat model of spinal nerve ligation. J Mol Neurosci 53:645–653
Lin CC, Kuo CL, Lee MH, Lai KC, Lin JP, Yang JS, Yu CS, Lu CC, Chiang JH, Chueh FS, Chung JG (2011) Wogonin triggers apoptosis in human osteosarcoma U-2 OS cells through the endoplasmic reticulum stress, mitochondrial dysfunction and caspase-3-dependent signaling pathways. Int J Oncol 39:217–224
Liu YM, Wang X, Nawaz A, Kong ZH, Hong Y, Wang CH, Zhang JJ (2011) Wogonin ameliorates lipotoxicity-induced apoptosis of cultured vascular smooth muscle cells via interfering with DAG-PKC pathway. Acta Pharmacol Sin 32:1475–1482
Liu XD, Ko S, Xu Y, Fattah EA, Xiang Q, Jagannath C, Ishii T, Komatsu M, Eissa NT (2012) Transient aggregation of ubiquitinated proteins is a cytosolic unfolded protein response to inflammation and endoplasmic reticulum stress. J Biol Chem 287:19687–19698
Li-Weber M (2009) New therapeutic aspects of flavones: the anticancer properties of Scutellaria and its main active constituents Wogonin, Baicalein and Baicalin. Cancer Treat Rev 35:57–68
Marciniak SJ, Yun CY, Oyadomari S, Novoa I, Zhang Y, Jungreis R, Nagata K, Harding HP, Ron D (2004) CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev 18:3066–3077
Matsuyama D, Watanabe M, Suyama K, Kuroiwa M, Mochida J (2014) Endoplasmic reticulum stress response in the rat contusive spinal cord injury model-susceptibility in specific cell types. Spinal Cord 52:9–16
Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA, Yuan J (2000) Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 403:98–103
Naziroglu M, Cig B, Ozgul C (2014) Modulation of oxidative stress and Ca(2+) mobilization through TRPM2 channels in rat dorsal root ganglion neuron by Hypericum perforatum. Neuroscience 263:27–35
Ohri SS, Maddie MA, Zhao Y, Qiu MS, Hetman M, Whittemore SR (2011) Attenuating the endoplasmic reticulum stress response improves functional recovery after spinal cord injury. Glia 59:1489–1502
Ohri SS, Hetman M, Whittemore SR (2013) Restoring endoplasmic reticulum homeostasis improves functional recovery after spinal cord injury. Neurobiol Dis 58:29–37
Oyadomari S, Koizumi A, Takeda K, Gotoh T, Akira S, Araki E, Mori M (2002) Targeted disruption of the Chop gene delays endoplasmic reticulum stress-mediated diabetes. J Clin Invest 109:525–532
Penas C, Guzman MS, Verdu E, Fores J, Navarro X, Casas C (2007) Spinal cord injury induces endoplasmic reticulum stress with different cell-type dependent response. J Neurochem 102:1242–1255
Piao HZ, Jin SA, Chun HS, Lee JC, Kim WK (2004) Neuroprotective effect of wogonin: potential roles of inflammatory cytokines. Arch Pharm Res 27:930–936
Schroder M, Kaufman RJ (2005) The mammalian unfolded protein response. Annu Rev Biochem 74:739–789
Son D, Lee P, Lee J, Kim H, Kim SY (2004) Neuroprotective effect of wogonin in hippocampal slice culture exposed to oxygen and glucose deprivation. Eur J Pharmacol 493:99–102
Song X, Yao J, Wang F, Zhou M, Zhou Y, Wang H, Wei L, Zhao L, Li Z, Lu N, Guo Q (2013) Wogonin inhibits tumor angiogenesis via degradation of HIF-1alpha protein. Toxicol Appl Pharmacol 271:144–155
Szegezdi E, Fitzgerald U, Samali A (2003) Caspase-12 and ER-stress-mediated apoptosis: the story so far. Ann NY Acad Sci 1010:186–194
Szegezdi E, Logue SE, Gorman AM, Samali A (2006) Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep 7:880–885
Tan Y, Dourdin N, Wu C, De Veyra T, Elce JS, Greer PA (2006) Ubiquitous calpains promote caspase-12 and JNK activation during endoplasmic reticulum. J Biol Chem 281:16016–16024
Tavukcu HH, Sener TE, Tinay I, Akbal C, Ersahin M, Cevik O, Cadirci S, Reiter RJ, Sener G (2014) Melatonin and tadalafil treatment improves erectile dysfunction after spinal cord injury in rats. Clin Exp Pharmacol Physiol 41:309–316
Tsai CF, Yeh WL, Huang SM, Tan TW, Lu DY (2012) Wogonin induces reactive oxygen species production and cell apoptosis in human glioma cancer cells. Int J Mol Sci 13:9877–9892
Uguz AC, Naziroglu M (2012) Effects of selenium on calcium signaling and apoptosis in rat dorsal root ganglion neurons induced by oxidative stress. Neurochem Res 37:1631–1638
Wang XZ, Ron D (1996) Stress-induced phosphorylation and activation of the transcription factor CHOP (GADD153) by p38 MAP Kinase. Science 272:1347–1349
Wang F, Song X, Zhou M, Wei L, Dai Q, Li Z, Lu N, Guo Q (2013) Wogonin inhibits H2O2-induced vascular permeability through suppressing the phosphorylation of caveolin-1. Toxicology 305:10–19
Xu M, Lu N, Zhang H, Dai Q, Wei L, Li Z, You Q, Guo Q (2013) Wogonin induced cytotoxicity in human hepatocellular carcinoma cells by activation of unfolded protein response and inactivation of AKT. Hepatol Res 43:890–905
Yang Y, Li XJ, Chen Z, Zhu XX, Wang J, Zhang LB, Qiang L, Ma YJ, Li ZY, Guo QL, You QD (2012) Wogonin induced calreticulin/annexin A1 exposure dictates the immunogenicity of cancer cells in a PERK/AKT dependent manner. PLoS ONE 7:e50811
Zha BS, Zhou H (2012) ER stress and lipid metabolism in adipocytes. Biochem Res Int 2012:312943
Zhang HY, Wang ZG, Lu XH, Kong XX, Wu FZ, Lin L, Tan X, Ye LB, Xiao J (2014) Endoplasmic Reticulum Stress: Relevance and Therapeutics in Central Nervous System Diseases. Mol Neurobiol
Zhou Y, Cui Z, Xia X, Liu C, Zhu X, Cao J, Wu Y, Zhou L, Ben Z, Song Y, Zhang H, Zhang D (2014) Matrix Metalloproteinase-1 (MMP-1) Expression in Rat Spinal Cord Injury Model. Cell Mol Neurobiol 34:1151–1163
Acknowledgments
This study was supported by the National Natural Science Foundation of China (81272048), the special Foundation of Public Service Sectors of The Ministry of Health (201002018), the Chinese Anhui Provincial Natural Science Foundation (1308085MH152) and the chinese Wuhu of Anhui province science and technology plan project (2012hm30).
Conflict of interest
The authors declare no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Xu, S., Zhao, X., Zhao, Q. et al. Wogonin Prevents Rat Dorsal Root Ganglion Neurons Death via Inhibiting Tunicamycin-Induced ER Stress In Vitro. Cell Mol Neurobiol 35, 389–398 (2015). https://doi.org/10.1007/s10571-014-0134-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10571-014-0134-x