Subscribe to RSS
DOI: 10.1055/s-0030-1271033
© Georg Thieme Verlag KG Stuttgart · New York
Paeonol Prevents Excitotoxicity in Rat Pheochromocytoma PC12 Cells via Downregulation of ERK Activation and Inhibition of Apoptosis
Publication History
received March 9, 2011
revised March 27, 2011
accepted March 29, 2011
Publication Date:
20 April 2011 (online)

Abstract
Paeonol, an active component of Moutan Cortex, has been recognized as a potential neuroprotective drug. In the present study, an injury model based on glutamate-induced cell death of rat pheochromocytoma cells was used to investigate the neuroprotective potential of paeonol and its mechanism of action. Our findings showed that paeonol dose-dependently prevented glutamate-induced cell death as evidenced by cell viability, lactate dehydrogenase release, and trypan blue exclusion. In addition, flow cytometry of propidium iodide-stained cells revealed that paeonol pretreatment reduced the level of glutamate-induced apoptosis in pheochromocytoma cells. Paeonol was also able to decrease the glutamate-induced injury of mitochondria by normalization of mitochondrial membrane potential and cytochrome c release. The glutamate-induced activity of caspase-3 and p-ERK were dose-dependently reduced by paeonol pretreatments. Taken together, our data suggest that paeonol develops its neuroprotective effect against glutamate neurotoxicity through inhibition of the apoptotic signaling pathway and upregulation of the p-ERK pathway.
Key words
paeonol - glutamate - apoptosis - ERK1/2 - Paeonia moutan - Paeoniaceae
References
- 1 Gasic G P, Hollmann M. Molecular neurobiology of glutamate receptors. Annu Rev Physiol. 1992; 54 507-536
- 2 Li N, Liu B, Dluzen D E, Jin Y. Protective effects of ginsenoside Rg2 against glutamate-induced neurotoxicity in PC12 cells. J Ethnopharmacol. 2007; 111 458-463
- 3 Coyle J T, Puttfarcken P. Oxidative stress, glutamate, and neurodegenerative disorders. Science. 1993; 262 689-695
- 4 Lipton S A, Rosenberg P A. Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med. 1994; 330 613-622
- 5 Behl C, Widmann M, Trapp T, Holsboer F. 17-beta Estradiol protects neurons from oxidative stress-induced cell death in vitro. Biochem Biophys Res Commun. 1995; 216 473-482
- 6 Froissard P, Duval D. Cytotoxic effects of glutamic acid on PC12 cells. Neurochem Int. 1994; 24 485-493
- 7 Pettmann B, Henderson C E. Neuronal cell death. Neuron. 1998; 20 633-647
- 8 Simonian N A, Coyle J T. Oxidative stress in neurodegenerative diseases. Annu Rev Pharmacol Toxicol. 1996; 36 83-106
- 9 Chen X, Liu J, Gu X, Ding F. Salidroside attenuates glutamate-induced apoptotic cell death in primary cultured hippocampal neurons of rats. Brain Res. 2008; 1238 189-198
- 10 Beal M F. Role of excitotoxicity in human neurological disease. Curr Opin Neurobiol. 1992; 2 657-662
- 11 Atlante A, Calissano P, Bobba A, Azzariti A, Marra E, Passarella S. Cytochrome c is released from mitochondria in a reactive oxygen species (ROS)-dependent fashion and can operate as a ROS scavenger and as a respiratory substrate in cerebellar neurons undergoing excitotoxic death. J Biol Chem. 2000; 275 37159-37166
- 12 Simon H U, Haj-Yehia A, Levi-Schaffer F. Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis. 2000; 5 415-418
- 13 Kato S, Negishi K, Mawatari K, Kuo C H. A mechanism for glutamate toxicity in the C6 glioma cells involving inhibition of cystine uptake leading to glutathione depletion. Neuroscience. 1992; 48 903-914
- 14 Xu D H, Zhou C H, Wu T, Xu B L. Inhibitory effect of paeonol on hydrogen peroxide-induced apoptosis in PC12 cells. Chin J Pharmacol Toxicol. 2008; 22 401-405
- 15 Nizamutdinova I T, Jin Y C, Kim J S, Yean M H, Kang S S, Kim Y S, Lee J H, Seo H G, Kim H J, Chang K C. Paeonol and paeoniflorin, the main active principles of Paeonia albiflora, protect the heart from myocardial ischemia/reperfusion injury in rats. Planta Med. 2008; 74 14-18
- 16 Xu S P, Sun G P, Shen Y X, Wei W, Peng W R, Wang H. Antiproliferation and apoptosis induction of paeonol in HepG2 cells. World J Gastroenterol. 2007; 13 250-256
- 17 Chou T C. Anti-inflammatory and analgesic effects of paeonol in carrageenan-evoked thermal hyperalgesia. Br J Pharmacol. 2003; 139 1146-1152
- 18 Xu D H, Zhou C H, Xu B L, Luo S Y. Protective effect of paeonol on beta-amyloid 25-35-induced toxicity in PC12 cells. Neural Regen Res. 2008; 3 863-866
- 19 Wu J B, Song N N, Wei X B, Guan H S, Zhang X M. Protective effects of paeonol on cultured rat hippocampal neurons against oxygen-glucose deprivation injury. J Neurol Sci. 2008; 264 50-55
- 20 Cheng Y F, Zhu G Q, Wang M, Cheng H, Zhou A, Wang N, Fang N B, Wang X C, Xiao X Q, Chen Z W, Li Q L. Involvement of ubiquitin proteasome system in protective mechanisms of puerarin to MPP+-elicited apoptosis. Neurosci Res. 2009; 63 52-58
- 21 Emerit J, Edeas M, Bricaire F. Neurodegenerative diseases and oxidative stress. Biomed Pharmacother. 2004; 58 39-46
- 22 Halliwell B. Role of free radicals in the neurodegenerative diseases: therapeutic implications for antioxidant treatment. Drugs Aging. 2001; 18 685-716
- 23 Jou M J, Peng T I, Reiter R J, Jou S B, Wu H Y, Wen S T. Visualization of the antioxidative effects of melatonin at the mitochondrial level during oxidative stress-induced apoptosis of rat brain astrocytes. J Pineal Res. 2004; 37 55-70
- 24 Chowdhary S, Verma D L, Pande R, Kumar H. Antioxidative properties of flavonoids from Cheilanthes anceps Swartz. J Am Sci. 2010; 6 203-207
- 25 Wang N, Tang L J, Zhu G Q, Peng D Y, Wang L, Sun F N, Li Q L. Apoptosis induced by baicalin involving up-regulation of P53 and bax in MCF-7 cells. J Asian Nat Prod Res. 2008; 10 1129-1135
- 26 Watanabe S, Uesugi S, Kikuchi Y. Isoflavones for prevention of cancer, cardiovascular diseases, gynecological problems and possible immune potentiation. Biomed Pharmacother. 2002; 56 302-312
- 27 Patil C S, Singh V P, Satyanarayan P S, Jain N K, Singh A, Kulkarni S K. Protective effect of flavonoids against aging- and lipopolysaccharide-induced cognitive impairment in mice. Pharmacology. 2003; 69 59-67
- 28 Wu J B, Song N N, Wei X B, Guan H S, Zhang X M. Protective effects of paeonol on cultured rat hippocampal neurons against oxygen-glucose deprivation-induced injury. J Neurol Sci. 2008; 264 50-55
- 29 Xu D H, Zhou C H, Xu B L, Luo S Y. Protective effect of paeonol on beta-amyloid 25-35-induced toxicity in PC12 cells. Neural Regen Res. 2008; 3 863-866
- 30 Zhong S Z, Ge Q H, Qu R, Li Q, Ma S P. Paeonol attenuates neurotoxicity and ameliorates cognitive impairment induced by d-galactose in ICR mice. J Neurol Sci. 2009; 277 58-64
- 31 Creedon D J, Johnson E M, Lawrence J C. Mitogen-activated protein kinase-independent pathways mediate the effects of nerve growth factor and cAMP on neuronal survival. J Biol Chem. 1996; 271 20713-20718
- 32 Murray B, Alessandrini A, Cole A J, Yee A G, Furshpan E J. Inhibition of the p 44/42 MAP kinase pathway protects hippocampal neurons in a cell-culture model of seizure activity. Proc Natl Acad Sci USA. 1998; 95 11975-11980
- 33 Runden E, Seglen P O, Haug F M, Ottersen O P, Wieloch T, Shamloo M, Laake J H. Regional selective neuronal degeneration after protein phosphatase inhibition in hippocampal slice cultures: evidence for a MAP kinase-dependent mechanism. J Neurosci. 1998; 18 7296-7305
- 34 Karin M, Hunter T. Transcriptional control by protein phosphorylation: signal transmission from the cell surface to the nucleus. Curr Biol. 1995; 5 747-757
1 These authors contributed equally to this work.
Prof. Dr. Qinglin Li
Anhui Province Key Laboratory of R & D of Chinese Medicine
Anhui University of Traditional Chinese Medicine
103 Meishan Road
Hefei, 230038
China
Phone: +86 55 15 16 90 51
Fax: +86 55 15 16 93 71
Email: qinglin_lee@hotmail.com