Neuroprotective Effects of a Novel Single Compound 1-Methoxyoctadecan-1-ol Isolated from Uncaria sinensis in Primary Cortical Neurons and a Photothrombotic Ischemia Model
We identified a novel neuroprotective compound, 1-methoxyoctadecan-1-ol, from Uncaria sinensis (Oliv.) Havil and investigated its effects and mechanisms in primary cortical neurons and in a photothrombotic ischemic model. In primary rat cortical neurons against glutamate-induced neurotoxicity, pretreatment with 1-methoxyoctadecan-1-ol resulted in significantly reduced neuronal death in a dose-dependent manner. In addition, treatment with 1-methoxyoctadecan-1-ol resulted in decreased neuronal apoptotic death, as assessed by nuclear morphological approaches. To clarify the neuroprotective mechanism of 1-methoxyoctadecan-1-ol, we explored the downstream signaling pathways of N-methyl-D-aspartate receptor (NMDAR) with calpain activation. Treatment with glutamate leads to early activation of NMDAR, which in turn leads to calpain-mediated cleavage of striatal-enriched protein tyrosine phosphatase (STEP) and subsequent activation of p38 mitogen activated protein kinase (MAPK). However, pretreatment with 1-methoxyoctadecan-1-ol resulted in significantly attenuated activation of GluN2B-NMDAR and a decrease in calpain-mediated STEP cleavage, leading to subsequent attenuation of p38 MAPK activation. We confirmed the critical role of p38 MAPK in neuroprotective effects of 1-methoxyoctadecan-1-ol using specific inhibitor SB203580. In the photothrombotic ischemic injury in mice, treatment with 1-methoxyoctadecan-1-ol resulted in significantly reduced infarct volume, edema size, and improved neurological function. 1-methoxyoctadecan-1-ol effectively prevents cerebral ischemic damage through down-regulation of calpain-mediated STEP cleavage and activation of p38 MAPK. These results suggest that 1-methoxyoctadecan-1-ol showed neuroprotective effects through down-regulation of calpain-mediated STEP cleavage with activation of GluN2B-NMDAR, and subsequent alleviation of p38 MAPK activation. In addition, 1-methoxyoctadecan-1-ol might be a useful therapeutic agent for brain disorder such as ischemic stroke.
References
[1]
Shimada Y, Goto H, Kogure T, Shibahara N, Sakakibara I, et al. (2001) Protective effect of phenolic compounds isolated from the hooks and stems of Uncaria sinensis on glutamate-induced neuronal death. Am J Chin Med 29: 173–180.
[2]
Watanabe H, Zhao Q, Matsumoto K, Tohda M, Murakami Y, et al. (2003) Pharmacological evidence for antidementia effect of Choto-san (Gouteng-san), a traditional Kampo medicine. Pharmacol Biochem Behav 75: 635–643.
[3]
Tan SN, Yong JW, Teo CC, Ge L, Chan YW, et al. (2011) Determination of metabolites in Uncaria sinensis by HPLC and GC-MS after green solvent microwave-assisted extraction. Talanta 83: 891–898.
[4]
Zhou J, Zhou S (2010) Antihypertensive and neuroprotective activities of rhynchophylline: the role of rhynchophylline in neurotransmission and ion channel activity. J Ethnopharmacol 132: 15–27.
[5]
Park SH, Kim JH, Park SJ, Bae SS, Choi YW, et al. (2011) Protective effect of hexane extracts of Uncaria sinensis against photothrombotic ischemic injury in mice. J Ethnopharmacol 138: 774–779.
[6]
Jang JY, Kim HN, Kim YR, Hong JW, Choi YW, et al. (2012) Hexane extract from Uncaria sinensis exhibits anti-apoptotic properties against glutamate-induced neurotoxicity in primary cultured cortical neurons. Int J Mol Med 30: 1465–1472.
[7]
Volbracht C, Chua BT, Ng CP, Bahr BA, Hong W, et al. (2005) The critical role of calpain versus caspase activation in excitotoxic injury induced by nitric oxide. J Neurochem 93: 1280–1292.
[8]
Hardingham GE (2009) Coupling of the NMDA receptor to neuroprotective and neurodestructive events. Biochem Soc Trans 37: 1147–1160.
[9]
Hardingham GE, Bading H (2010) Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci 11: 682–696.
[10]
Poddar R, Deb I, Mukherjee S, Paul S (2010) NR2B-NMDA receptor mediated modulation of the tyrosine phosphatase STEP regulates glutamate induced neuronal cell death. J Neurochem 115: 1350–1362.
[11]
Gladding CM, Sepers MD, Xu J, Zhang LY, Milnerwood AJ, et al. (2012) Calpain and STriatal-Enriched protein tyrosine phosphatase (STEP) activation contribute to extrasynaptic NMDA receptor localization in a Huntington's disease mouse model. Hum Mol Genet 21: 3739–3752.
[12]
Goebel-Goody SM, Baum M, Paspalas CD, Fernandez SM, Carty NC, et al. (2012) Therapeutic implications for striatal-enriched protein tyrosine phosphatase (STEP) in neuropsychiatric disorders. Pharmacol Rev 64: 65–87.
[13]
Fan J, Gladding CM, Wang L, Zhang LY, Kaufman AM, et al. (2012) P38 MAPK is involved in enhanced NMDA receptor-dependent excitotoxicity in YAC transgenic mouse model of Huntington disease. Neurobiol Dis 45: 999–1009.
[14]
Gurd JW, Bissoon N, Nguyen TH, Lombroso PJ, Rider CC, et al. (1999) Hypoxia-ischemia in perinatal rat brain induces the formation of a low molecular weight isoform of striatal enriched tyrosine phosphatase (STEP). J Neurochem 73: 1990–1994.
[15]
Nguyen TH, Paul S, Xu Y, Gurd JW, Lombroso PJ (1999) Calcium-dependent cleavage of striatal enriched tyrosine phosphatase (STEP). J Neurochem 73: 1995–2001.
[16]
Xu J, Kurup P, Zhang Y, Goebel-Goody SM, Wu PH, et al. (2009) Extrasynaptic NMDA receptors couple preferentially to excitotoxicity via calpain-mediated cleavage of STEP. J Neurosci 29: 9330–9343.
[17]
Shimada Y, Goto H, Itoh T, Sakakibara I, Kubo M, et al. (1999) Evaluation of the protective effects of alkaloids isolated from the hooks and stems of Uncaria sinensis on glutamate-induced neuronal death in cultured cerebellar granule cells from rats. J Pharm Pharmacol 51: 715–722.
[18]
Suk K, Kim SY, Leem K, Kim YO, Park SY, et al. (2002) Neuroprotection by methanol extract of Uncaria rhynchophylla against global cerebral ischemia in rats. Life Sci 70: 2467–2480.
[19]
Nicotera P, Ankarcrona M, Bonfoco E, Orrenius S, Lipton SA (1997) Neuronal necrosis and apoptosis: two distinct events induced by exposure to glutamate or oxidative stress. Adv Neurol 72: 95–101.
[20]
Martel MA, Wyllie DJ, Hardingham GE (2009) In developing hippocampal neurons, NR2B-containing N-methyl-D-aspartate receptors (NMDARs) can mediate signaling to neuronal survival and synaptic potentiation, as well as neuronal death. Neuroscience 158: 334–343.
[21]
Braithwaite SP, Xu J, Leung J, Urfer R, Nikolich K, et al. (2008) Expression and function of striatal enriched protein tyrosine phosphatase is profoundly altered in cerebral ischemia. Eur J Neurosci 27: 2444–2452.
[22]
Hardingham GE, Fukunaga Y, Bading H (2002) Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat Neurosci 5: 405–414.
[23]
Paul S, Nairn AC, Wang P, Lombroso PJ (2003) NMDA-mediated activation of the tyrosine phosphatase STEP regulates the duration of ERK signaling. Nat Neurosci 6: 34–42.
[24]
Lin YW, Hsieh CL (2011) Oral Uncaria rhynchophylla (UR) reduces kainic acid-induced epileptic seizures and neuronal death accompanied by attenuating glial cell proliferation and S100B proteins in rats. J Ethnopharmacol 135: 313–320.
[25]
Yang JL, Sykora P, Wilson DM III, Mattson MP, Bohr VA (2011) The excitatory neurotransmitter glutamate stimulates DNA repair to increase neuronal resiliency. Mech Ageing Dev 132: 405–411.
Lipton SA, Rosenberg PA (1994) Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med 330: 613–622.
[28]
Lipton SA (1999) Redox sensitivity of NMDA receptors. Methods Mol Biol 128: 121–130.
[29]
Tu H, Xu C, Zhang W, Liu Q, Rondard P, et al. (2010) GABAB receptor activation protects neurons from apoptosis via IGF-1 receptor transactivation. J Neurosci 30: 749–759.
[30]
Qiu S, Li XY, Zhuo M (2011) Post-translational modification of NMDA receptor GluN2B subunit and its roles in chronic pain and memory. Semin Cell Dev Biol 22: 521–529.
[31]
Soriano FX, Hardingham GE (2007) Compartmentalized NMDA receptor signalling to survival and death. J Physiol 584: 381–387.
[32]
Mulholland PJ, Luong NT, Woodward JJ, Chandler LJ (2008) Brain-derived neurotrophic factor activation of extracellular signal-regulated kinase is autonomous from the dominant extrasynaptic NMDA receptor extracellular signal-regulated kinase shutoff pathway. Neuroscience 151: 419–427.
[33]
Leveille F, El Gaamouch F, Gouix E, Lecocq M, Lobner D, et al. (2008) Neuronal viability is controlled by a functional relation between synaptic and extrasynaptic NMDA receptors. FASEB J 22: 4258–4271.
[34]
Paul S, Connor JA (2010) NR2B-NMDA receptor-mediated increases in intracellular Ca2+ concentration regulate the tyrosine phosphatase, STEP, and ERK MAP kinase signaling. J Neurochem 114: 1107–1118.
[35]
Perez-Pinzon MA, Stetler RA, Fiskum G (2012) Novel mitochondrial targets for neuroprotection. J Cereb Blood Flow Metab 32: 1362–1376.
[36]
Bult A, Zhao F, Dirkx R Jr, Raghunathan A, Solimena M, et al. (1997) STEP: a family of brain-enriched PTPs. Alternative splicing produces transmembrane, cytosolic and truncated isoforms. Eur J Cell Biol 72: 337–344.
[37]
Snyder EM, Nong Y, Almeida CG, Paul S, Moran T, et al. (2005) Regulation of NMDA receptor trafficking by amyloid-beta. Nat Neurosci 8: 1051–1058.
[38]
Ghatan S, Larner S, Kinoshita Y, Hetman M, Patel L, et al. (2000) p38 MAP kinase mediates bax translocation in nitric oxide-induced apoptosis in neurons. J Cell Biol 150: 335–347.
[39]
Cuadrado A, Nebreda AR (2010) Mechanisms and functions of p38 MAPK signalling. Biochem J 429: 403–417.
[40]
Mai H, May WS, Gao F, Jin Z, Deng X (2003) A functional role for nicotine in Bcl2 phosphorylation and suppression of apoptosis. J Biol Chem 278: 1886–1891.
[41]
Asomugha CO, Linn DM, Linn CL (2010) ACh receptors link two signaling pathways to neuroprotection against glutamate-induced excitotoxicity in isolated RGCs. J Neurochem 112: 214–226.
