神經退化性疾病 (neurodegeneration diseases) 當中存在著由麩醯胺酸活化的興奮性毒殺 (excitotoxicity) ，如多麩醯胺酸疾病 (polyglutamine diseases) 、阿茲海默氏症疾病 (Alzheimer’s diseases) 和柏金森氏症疾病 (Parkinson’s disease) ，會導致過多的鈣離子流入、粒線體內細胞色素 C 的釋放、導致神經細胞凋亡的蛋白質活化，最後使細胞存活率的下降。許多研究報導指出，中草藥的使用，可能是一個治療退化性疾病新方法。因此，我們研究在人類神經母細胞 (neuroblastoma) SH-SY5Y 細胞以麩醯胺酸 (glutamate) 誘導的興奮性毒殺以及使用多西環素 (doxycycline) 誘導出小腦脊髓萎縮症第十七型 (Spinocerebellar ataxia, SCA17) nTBP/Q79-EGFP 細胞中 TBP/79Q-EGFP 融合蛋白的表現後，探討中草藥是否有保護神經細胞的作用。加入麩醯胺酸後導致神經細胞生存率下降，另一項實驗結果顯示NH018和其純化物NH018-1可能為有效的藥物可以增加神經細胞的存活率、NH018-1可以抑制神經細胞的凋亡 (apoptosis) 、降低乳酸脫氫酶 (LDH) 的釋放以及自由基的生成，並且降低鈣離子所造成的Calpain-2 及 α-spectrin breakdown products (SBDPs) 的表現，降低從粒線體釋放出的細胞色素C、增加細胞存活相關蛋白質：Bcl-2、Bax及降低凋亡相關：蛋白質 cleaved-caspase-9、cleaved-caspase-3和cleaved-PARP等的表現。在誘導TBP/79Q-EGFP 融合蛋白表現的細胞上，NH018-1為有效的藥物可以增加細胞的存活率以及降低cleaved-caspase-9、cleaved-caspase-3和cleaved-PARP等的表現。而施打NH018-1藥物在SCA17的基因轉殖鼠上，能夠有效地延長其在滾輪 (rotarod) 上面跑的時間、步行實驗 (footprint) 上的好轉，在其運動失調的症狀上發揮療效，以及降低 TATA box-binding protein (TBP) 、 Calpain-2 和 cleaved-caspase-3的表現。總合以上，實驗結果顯示出NH018和NH018-1藥物在加入麩氨酸以及誘導出小腦脊髓萎縮症第十七型細胞TBP/79Q-EGFP 融合蛋白的表現後，藉由抑制細胞的凋亡可以增加 SH-SY5Y 細胞以及小腦脊髓萎縮症第十七型細胞的存活率，因此NH018和NH018-1可能為有潛力治療小腦脊髓萎縮症第十七型疾病的藥物。

Excitotoxicity induced neurodegeneration, and polyglutamine (polyQ) diseases, such as Alzheimer’s disease, and Parkinson’s disease, via glutamatergic activation, resulting in excessive calcium influx, cytochrome C release from mytochondria, pro-apoptotic protein activation, and finally leads to decrease the cell viability. It was believed that Chinese herbal medicines (CHMs) might be one of new approaches to treat neurodegenerative diseases. Therefore, we investigated whether CHMs could protect neurons from monosodium glutamate (MSG)-induced excitotoxicity in human neuroblastoma SH-SY5Y cells and doxycycline (DOX) induced-nTBP-EGFP expression in spinocerebellar ataxia type 17 (SCA17) nTBP/Q79-EGFP cells.
Our study showed that NH018 and its active compound NH018-1 were effective against MSG induced neurotoxicity by increasing the cell viability measured by MTT assay, and decreased the LDH release and the production of reactive oxygen species, and deduced cell apoptosis after MSG treatment in SH-SY5Y cells, DOX induced SCA17 nTBP/Q79-EGFP cells. NH018-1 also showed the remarkably protective activity against the neuronal cell death as demonstrated by : (1) reducing the Annexin V-FITC and Propidium Iodide (PI) staining, (2) the decrease of cytochrome C released from mitochondria, (3) the reduction of apoptosis-related proteins such as m-calpain (calpain-2), cleaved-caspase-9, cleaved-caspase-3 and cleaved-PARP expression, (4) the decrease of survival-related proteins such as Bcl-2, and (5) the improving of SCA17 mice performance in rotarod and footprint experiments. In conclusion, present studies showed that NH018 and NH018-1 protect cell viability after MSG treatment in SH-SY5Y cells, and DOX treatment in SCA17 nTBP/Q79-EGFP cells by inhibition of cell apoptosis. Furthermore, NH018-1 of NH018 could improve the SCA17 mice performance in rotarod test and footprint analysis as well as decrease the expression of TATA box-binding protein (TBP), calpain-2, and cleaved-caspase-3. Thus, NH018 and NH018-1 could be potential CHMs for the treatment neurodegenerative diseases.

1 A. Agarwal, R. Z. Mahfouz, R. K. Sharma, O. Sarkar, D. Mangrola, and P. P. Mathur, 'Potential Biological Role of Poly (Adp-Ribose) Polymerase (Parp) in Male Gametes', Reprod Biol Endocrinol, 7 (2009), 143.
2 M. Ankarcrona, J. M. Dypbukt, E. Bonfoco, B. Zhivotovsky, S. Orrenius, S. A. Lipton, and P. Nicotera, 'Glutamate-Induced Neuronal Death: A Succession of Necrosis or Apoptosis Depending on Mitochondrial Function', Neuron, 15 (1995), 961-73.
3 B. Antonsson, 'Mitochondria and the Bcl-2 Family Proteins in Apoptosis Signaling Pathways', Mol Cell Biochem, 256-257 (2004), 141-55.
4 K. Baumann, E. M. Mandelkow, J. Biernat, H. Piwnica-Worms, and E. Mandelkow, 'Abnormal Alzheimer-Like Phosphorylation of Tau-Protein by Cyclin-Dependent Kinases Cdk2 and Cdk5', FEBS Lett, 336 (1993), 417-24.
5 F. Blandini, J. T. Greenamyre, and G. Nappi, 'The Role of Glutamate in the Pathophysiology of Parkinson's Disease', Funct Neurol, 11 (1996), 3-15.
6 E. Bossy-Wetzel, D. D. Newmeyer, and D. R. Green, 'Mitochondrial Cytochrome C Release in Apoptosis Occurs Upstream of Devd-Specific Caspase Activation and Independently of Mitochondrial Transmembrane Depolarization', EMBO J, 17 (1998), 37-49.
7 J. R. Brorson, C. J. Marcuccilli, and R. J. Miller, 'Delayed Antagonism of Calpain Reduces Excitotoxicity in Cultured Neurons', Stroke, 26 (1995), 1259-66; discussion 67.
8 S. L. Budd, and D. G. Nicholls, 'Mitochondria, Calcium Regulation, and Acute Glutamate Excitotoxicity in Cultured Cerebellar Granule Cells', J Neurochem, 67 (1996), 2282-91.
9 S. L. Budd, L. Tenneti, T. Lishnak, and S. A. Lipton, 'Mitochondrial and Extramitochondrial Apoptotic Signaling Pathways in Cerebrocortical Neurons', Proc Natl Acad Sci U S A, 97 (2000), 6161-6.
10 K. M. Carlson, J. M. Andresen, and H. T. Orr, 'Emerging Pathogenic Pathways in the Spinocerebellar Ataxias', Curr Opin Genet Dev, 19 (2009), 247-53.
11 R. J. Carter, L. A. Lione, T. Humby, L. Mangiarini, A. Mahal, G. P. Bates, S. B. Dunnett, and A. J. Morton, 'Characterization of Progressive Motor Deficits in Mice Transgenic for the Human Huntington's Disease Mutation', J Neurosci, 19 (1999), 3248-57.
12 Y. C. Chang, C. Y. Lin, C. M. Hsu, H. C. Lin, Y. H. Chen, G. J. Lee-Chen, M. T. Su, L. S. Ro, C. M. Chen, and H. M. Hsieh-Li, 'Neuroprotective Effects of Granulocyte-Colony Stimulating Factor in a Novel Transgenic Mouse Model of Sca17', J Neurochem, 118 (2011), 288-303.
13 X. Chen, T. S. Tang, H. Tu, O. Nelson, M. Pook, R. Hammer, N. Nukina, and I. Bezprozvanny, 'Deranged Calcium Signaling and Neurodegeneration in Spinocerebellar Ataxia Type 3', J Neurosci, 28 (2008), 12713-24.
14 D. H. Cheng, H. Ren, and X. C. Tang, 'Huperzine A, a Novel Promising Acetylcholinesterase Inhibitor', Neuroreport, 8 (1996), 97-101.
15 D. W. Choi, 'Glutamate Neurotoxicity and Diseases of the Nervous System', Neuron, 1 (1988), 623-34.
16 C. G. Concannon, L. P. Tuffy, P. Weisova, H. P. Bonner, D. Davila, C. Bonner, M. C. Devocelle, A. Strasser, M. W. Ward, and J. H. Prehn, 'Amp Kinase-Mediated Activation of the Bh3-Only Protein Bim Couples Energy Depletion to Stress-Induced Apoptosis', J Cell Biol, 189 (2010), 83-94.
17 S. P. Cregan, A. Fortin, J. G. MacLaurin, S. M. Callaghan, F. Cecconi, S. W. Yu, T. M. Dawson, V. L. Dawson, D. S. Park, G. Kroemer, and R. S. Slack, 'Apoptosis-Inducing Factor Is Involved in the Regulation of Caspase-Independent Neuronal Cell Death', J Cell Biol, 158 (2002), 507-17.
18 D. E. Croall, and G. N. DeMartino, 'Calcium-Activated Neutral Protease (Calpain) System: Structure, Function, and Regulation', Physiol Rev, 71 (1991), 813-47.
19 J. B. Davis, and P. Maher, 'Protein Kinase C Activation Inhibits Glutamate-Induced Cytotoxicity in a Neuronal Cell Line', Brain Res, 652 (1994), 169-73.
20 T. Decker, and M. L. Lohmann-Matthes, 'A Quick and Simple Method for the Quantitation of Lactate Dehydrogenase Release in Measurements of Cellular Cytotoxicity and Tumor Necrosis Factor (Tnf) Activity', J Immunol Methods, 115 (1988), 61-9.
21 G. P. Dietz, B. Dietz, and M. Bahr, 'Bcl-Xl Protects Cerebellar Granule Neurons against the Late Phase, but Not against the Early Phase of Glutamate-Induced Cell Death', Brain Res, 1164 (2007), 136-41.
22 A. Doble, 'The Role of Excitotoxicity in Neurodegenerative Disease: Implications for Therapy', Pharmacol Ther, 81 (1999), 163-221.
23 N. Egashira, K. Iwasaki, Y. Akiyoshi, Y. Takagaki, I. Hatip-Al-Khatib, K. Mishima, K. Kurauchi, T. Ikeda, and M. Fujiwara, 'Protective Effect of Toki-Shakuyaku-San on Amyloid Beta25-35-Induced Neuronal Damage in Cultured Rat Cortical Neurons', Phytother Res, 19 (2005), 450-3.
24 M. J. Friedman, A. G. Shah, Z. H. Fang, E. G. Ward, S. T. Warren, S. Li, and X. J. Li, 'Polyglutamine Domain Modulates the Tbp-Tfiib Interaction: Implications for Its Normal Function and Neurodegeneration', Nat Neurosci, 10 (2007), 1519-28.
25 M. Fukui, H. J. Choi, and B. T. Zhu, 'Mechanism for the Protective Effect of Resveratrol against Oxidative Stress-Induced Neuronal Death', Free Radic Biol Med, 49 (2010), 800-13.
26 A. Haacke, F. U. Hartl, and P. Breuer, 'Calpain Inhibition Is Sufficient to Suppress Aggregation of Polyglutamine-Expanded Ataxin-3', J Biol Chem, 282 (2007), 18851-6.
27 A. P. Halestrap, G. P. McStay, and S. J. Clarke, 'The Permeability Transition Pore Complex: Another View', Biochimie, 84 (2002), 153-66.
28 J. Huang, J. Tao, X. Xue, S. Yang, P. Han, Z. Lin, W. Xu, J. Lin, J. Peng, and L. Chen, 'Gua Lou Gui Zhi Decoction Exerts Neuroprotective Effects on Post-Stroke Spasticity Via the Modulation of Glutamate Levels and Ampa Receptor Expression', Int J Mol Med, 31 (2013), 841-8.
29 S. Huang, J. J. Ling, S. Yang, X. J. Li, and S. Li, 'Neuronal Expression of Tata Box-Binding Protein Containing Expanded Polyglutamine in Knock-in Mice Reduces Chaperone Protein Response by Impairing the Function of Nuclear Factor-Y Transcription Factor', Brain, 134 (2011), 1943-58.
30 M. R. Hynd, H. L. Scott, and P. R. Dodd, 'Glutamate-Mediated Excitotoxicity and Neurodegeneration in Alzheimer's Disease', Neurochem Int, 45 (2004), 583-95.
31 G. V. Johnson, R. S. Jope, and L. I. Binder, 'Proteolysis of Tau by Calpain', Biochem Biophys Res Commun, 163 (1989), 1505-11.
32 Y. Kambe, N. Nakamichi, D. D. Georgiev, N. Nakamura, H. Taniura, and Y. Yoneda, 'Insensitivity to Glutamate Neurotoxicity Mediated by Nmda Receptors in Association with Delayed Mitochondrial Membrane Potential Disruption in Cultured Rat Cortical Neurons', J Neurochem, 105 (2008), 1886-900.
33 A. Kelp, A. H. Koeppen, E. Petrasch-Parwez, C. Calaminus, C. Bauer, E. Portal, L. Yu-Taeger, B. Pichler, P. Bauer, O. Riess, and H. P. Nguyen, 'A Novel Transgenic Rat Model for Spinocerebellar Ataxia Type 17 Recapitulates Neuropathological Changes and Supplies in Vivo Imaging Biomarkers', J Neurosci, 33 (2013), 9068-81.
34 J. S. Kim, L. He, and J. J. Lemasters, 'Mitochondrial Permeability Transition: A Common Pathway to Necrosis and Apoptosis', Biochem Biophys Res Commun, 304 (2003), 463-70.
35 S. J. Kish, L. Schut, J. Simmons, J. Gilbert, L. J. Chang, and M. Rebbetoy, 'Brain Acetylcholinesterase Activity Is Markedly Reduced in Dominantly-Inherited Olivopontocerebellar Atrophy', J Neurol Neurosurg Psychiatry, 51 (1988), 544-8.
36 L. J. Ko, and C. Prives, 'P53: Puzzle and Paradigm', Genes Dev, 10 (1996), 1054-72.
37 R. Koide, S. Kobayashi, T. Shimohata, T. Ikeuchi, M. Maruyama, M. Saito, M. Yamada, H. Takahashi, and S. Tsuji, 'A Neurological Disease Caused by an Expanded Cag Trinucleotide Repeat in the Tata-Binding Protein Gene: A New Polyglutamine Disease?', Hum Mol Genet, 8 (1999), 2047-53.
38 S. Lankiewicz, C. Marc Luetjens, N. Truc Bui, A. J. Krohn, M. Poppe, G. M. Cole, T. C. Saido, and J. H. Prehn, 'Activation of Calpain I Converts Excitotoxic Neuron Death into a Caspase-Independent Cell Death', J Biol Chem, 275 (2000), 17064-71.
39 M. S. Lee, J. Chao, J. C. Yen, L. W. Lin, F. S. Tsai, M. T. Hsieh, W. H. Peng, and H. Y. Cheng, 'Schizandrin Protects Primary Rat Cortical Cell Cultures from Glutamate-Induced Apoptosis by Inhibiting Activation of the Mapk Family and the Mitochondria Dependent Pathway', Molecules, 18 (2012), 354-72.
40 T. Y. Lin, C. W. Lu, S. K. Huang, and S. J. Wang, 'Tanshinone Iia, a Constituent of Danshen, Inhibits the Release of Glutamate in Rat Cerebrocortical Nerve Terminals', J Ethnopharmacol, 147 (2013), 488-96.
41 A. C. Ludolph, and C. Munch, 'Neurotoxic Mechanisms of Degeneration in Motor Neuron Diseases', Drug Metab Rev, 31 (1999), 619-34.
42 C. M. Luetjens, N. T. Bui, B. Sengpiel, G. Munstermann, M. Poppe, A. J. Krohn, E. Bauerbach, J. Krieglstein, and J. H. Prehn, 'Delayed Mitochondrial Dysfunction in Excitotoxic Neuron Death: Cytochrome C Release and a Secondary Increase in Superoxide Production', J Neurosci, 20 (2000), 5715-23.
43 A. B. MacDermott, M. L. Mayer, G. L. Westbrook, S. J. Smith, and J. L. Barker, 'Nmda-Receptor Activation Increases Cytoplasmic Calcium Concentration in Cultured Spinal Cord Neurones', Nature, 321 (1986), 519-22.
44 P. Maher, and A. Hanneken, 'Flavonoids Protect Retinal Ganglion Cells from Oxidative Stress-Induced Death', Invest Ophthalmol Vis Sci, 46 (2005), 4796-803.
45 P. Maher, and D. Schubert, 'Signaling by Reactive Oxygen Species in the Nervous System', Cell Mol Life Sci, 57 (2000), 1287-305.
46 F. Maltecca, A. Filla, I. Castaldo, G. Coppola, N. A. Fragassi, M. Carella, A. Bruni, S. Cocozza, G. Casari, A. Servadio, and G. De Michele, 'Intergenerational Instability and Marked Anticipation in Sca-17', Neurology, 61 (2003), 1441-3.
47 H. Maruyama, Y. Izumi, H. Morino, M. Oda, H. Toji, S. Nakamura, and H. Kawakami, 'Difference in Disease-Free Survival Curve and Regional Distribution According to Subtype of Spinocerebellar Ataxia: A Study of 1,286 Japanese Patients', Am J Med Genet, 114 (2002), 578-83.
48 M. L. Mayer, and G. L. Westbrook, 'The Physiology of Excitatory Amino Acids in the Vertebrate Central Nervous System', Prog Neurobiol, 28 (1987), 197-276.
49 J. Naarala, P. Nykvist, M. Tuomala, and K. Savolainen, 'Excitatory Amino Acid-Induced Slow Biphasic Responses of Free Intracellular Calcium in Human Neuroblastoma Cells', FEBS Lett, 330 (1993), 222-6.
50 K. Nakamura, S. Y. Jeong, T. Uchihara, M. Anno, K. Nagashima, T. Nagashima, S. Ikeda, S. Tsuji, and I. Kanazawa, 'Sca17, a Novel Autosomal Dominant Cerebellar Ataxia Caused by an Expanded Polyglutamine in Tata-Binding Protein', Hum Mol Genet, 10 (2001), 1441-8.
51 G. N. Patrick, L. Zukerberg, M. Nikolic, S. de la Monte, P. Dikkes, and L. H. Tsai, 'Conversion of P35 to P25 Deregulates Cdk5 Activity and Promotes Neurodegeneration', Nature, 402 (1999), 615-22.
52 W. J. Pottorf, 2nd, T. M. Johanns, S. M. Derrington, E. E. Strehler, A. Enyedi, and S. A. Thayer, 'Glutamate-Induced Protease-Mediated Loss of Plasma Membrane Ca2+ Pump Activity in Rat Hippocampal Neurons', J Neurochem, 98 (2006), 1646-56.
53 M. M. Semenova, A. M. Maki-Hokkonen, J. Cao, V. Komarovski, K. M. Forsberg, M. Koistinaho, E. T. Coffey, and M. J. Courtney, 'Rho Mediates Calcium-Dependent Activation of P38alpha and Subsequent Excitotoxic Cell Death', Nat Neurosci, 10 (2007), 436-43.
54 P. J. Shaw, 'Calcium, Glutamate, and Amyotrophic Lateral Sclerosis: More Evidence but No Certainties', Ann Neurol, 46 (1999), 803-5.
55 S. Shimizu, Y. Eguchi, W. Kamiike, S. Waguri, Y. Uchiyama, H. Matsuda, and Y. Tsujimoto, 'Bcl-2 Blocks Loss of Mitochondrial Membrane Potential While Ice Inhibitors Act at a Different Step During Inhibition of Death Induced by Respiratory Chain Inhibitors', Oncogene, 13 (1996), 21-9.
56 R. Siman, J. C. Noszek, and C. Kegerise, 'Calpain I Activation Is Specifically Related to Excitatory Amino Acid Induction of Hippocampal Damage', J Neurosci, 9 (1989), 1579-90.
57 P. S. Spencer, 'Food Toxins, Ampa Receptors, and Motor Neuron Diseases', Drug Metab Rev, 31 (1999), 561-87.
58 G. Stevanin, and A. Brice, 'Spinocerebellar Ataxia 17 (Sca17) and Huntington's Disease-Like 4 (Hdl4)', Cerebellum, 7 (2008), 170-8.
59 G. Szalai, R. Krishnamurthy, and G. Hajnoczky, 'Apoptosis Driven by Ip(3)-Linked Mitochondrial Calcium Signals', EMBO J, 18 (1999), 6349-61.
60 T. S. Tang, X. Chen, J. Liu, and I. Bezprozvanny, 'Dopaminergic Signaling and Striatal Neurodegeneration in Huntington's Disease', J Neurosci, 27 (2007), 7899-910.
61 Y. Toyoshima, O. Onodera, M. Yamada, S. Tsuji, and H. Takahashi, 'Spinocerebellar Ataxia Type 17', in Genereviews, ed. by R. A. Pagon, M. P. Adam, T. D. Bird, C. R. Dolan, C. T. Fong and K. Stephens (Seattle WA: University of Washington, Seattle, 1993).
62 F. Trinchese, M. Fa, S. Liu, H. Zhang, A. Hidalgo, S. D. Schmidt, H. Yamaguchi, N. Yoshii, P. M. Mathews, R. A. Nixon, and O. Arancio, 'Inhibition of Calpains Improves Memory and Synaptic Transmission in a Mouse Model of Alzheimer Disease', J Clin Invest, 118 (2008), 2796-807.
63 M. Tymianski, M. P. Charlton, P. L. Carlen, and C. H. Tator, 'Source Specificity of Early Calcium Neurotoxicity in Cultured Embryonic Spinal Neurons', J Neurosci, 13 (1993), 2085-104.
64 O. Vergun, J. Keelan, B. I. Khodorov, and M. R. Duchen, 'Glutamate-Induced Mitochondrial Depolarisation and Perturbation of Calcium Homeostasis in Cultured Rat Hippocampal Neurones', J Physiol, 519 Pt 2 (1999), 451-66.
65 D. Wang, Q. R. Tan, and Z. J. Zhang, 'Neuroprotective Effects of Paeoniflorin, but Not the Isomer Albiflorin, Are Associated with the Suppression of Intracellular Calcium and Calcium/Calmodulin Protein Kinase Ii in Pc12 Cells', J Mol Neurosci (2013).
66 H. Wang, and X. C. Tang, 'Anticholinesterase Effects of Huperzine A, E2020, and Tacrine in Rats', Zhongguo Yao Li Xue Bao, 19 (1998), 27-30.
67 H. Wang, S. W. Yu, D. W. Koh, J. Lew, C. Coombs, W. Bowers, H. J. Federoff, G. G. Poirier, T. M. Dawson, and V. L. Dawson, 'Apoptosis-Inducing Factor Substitutes for Caspase Executioners in Nmda-Triggered Excitotoxic Neuronal Death', J Neurosci, 24 (2004), 10963-73.
68 K. K. Wang, 'Calpain and Caspase: Can You Tell the Difference?', Trends Neurosci, 23 (2000), 20-6.
69 R. Wang, and X. C. Tang, 'Neuroprotective Effects of Huperzine A. A Natural Cholinesterase Inhibitor for the Treatment of Alzheimer's Disease', Neurosignals, 14 (2005), 71-82.
70 Y. E. Wang, D. X. Yue, and X. C. Tang, '[Anti-Cholinesterase Activity of Huperzine A]', Zhongguo Yao Li Xue Bao, 7 (1986), 110-3.
71 M. W. Ward, A. C. Rego, B. G. Frenguelli, and D. G. Nicholls, 'Mitochondrial Membrane Potential and Glutamate Excitotoxicity in Cultured Cerebellar Granule Cells', J Neurosci, 20 (2000), 7208-19.
72 M. W. Ward, M. Rehm, H. Duessmann, S. Kacmar, C. G. Concannon, and J. H. Prehn, 'Real Time Single Cell Analysis of Bid Cleavage and Bid Translocation During Caspase-Dependent and Neuronal Caspase-Independent Apoptosis', J Biol Chem, 281 (2006), 5837-44.
73 P. Weisova, U. Anilkumar, C. Ryan, C. G. Concannon, J. H. Prehn, and M. W. Ward, ''Mild Mitochondrial Uncoupling' Induced Protection against Neuronal Excitotoxicity Requires Ampk Activity', Biochim Biophys Acta, 1817 (2012), 744-53.
74 R. J. White, and I. J. Reynolds, 'Mitochondrial Depolarization in Glutamate-Stimulated Neurons: An Early Signal Specific to Excitotoxin Exposure', J Neurosci, 16 (1996), 5688-97.
75 B. B. Wolf, J. C. Goldstein, H. R. Stennicke, H. Beere, G. P. Amarante-Mendes, G. S. Salvesen, and D. R. Green, 'Calpain Functions in a Caspase-Independent Manner to Promote Apoptosis-Like Events During Platelet Activation', Blood, 94 (1999), 1683-92.
76 H. Y. Wu, E. Y. Yuen, Y. F. Lu, M. Matsushita, H. Matsui, Z. Yan, and K. Tomizawa, 'Regulation of N-Methyl-D-Aspartate Receptors by Calpain in Cortical Neurons', J Biol Chem, 280 (2005), 21588-93.
77 J. Wu, H. K. Jeong, S. E. Bulin, S. W. Kwon, J. H. Park, and I. Bezprozvanny, 'Ginsenosides Protect Striatal Neurons in a Cellular Model of Huntington's Disease', J Neurosci Res, 87 (2009), 1904-12.
78 N. Wu, L. Song, X. X. Yang, J. L. Wei, and Z. G. Liu, '[Effects of Chinese Herbal Medicine Tianqi Pingchan Granule on G Protein-Coupled Receptor Kinase 6 Involved in the Prevention of Levodopa-Induced Dyskinesia in Rats with Parkinson Disease]', Zhong Xi Yi Jie He Xue Bao, 10 (2012), 1018-24.
79 H. Xiang, Y. Kinoshita, C. M. Knudson, S. J. Korsmeyer, P. A. Schwartzkroin, and R. S. Morrison, 'Bax Involvement in P53-Mediated Neuronal Cell Death', J Neurosci, 18 (1998), 1363-73.
80 W. Xu, T. P. Wong, N. Chery, T. Gaertner, Y. T. Wang, and M. Baudry, 'Calpain-Mediated Mglur1alpha Truncation: A Key Step in Excitotoxicity', Neuron, 53 (2007), 399-412.
81 E. Y. Yuen, Z. Gu, and Z. Yan, 'Calpain Regulation of Ampa Receptor Channels in Cortical Pyramidal Neurons', J Physiol, 580 (2007), 241-54.
82 M. M. Zeron, N. Chen, A. Moshaver, A. T. Lee, C. L. Wellington, M. R. Hayden, and L. A. Raymond, 'Mutant Huntingtin Enhances Excitotoxic Cell Death', Mol Cell Neurosci, 17 (2001), 41-53.
83 Y. C. Chang, C. M. Hsu, C. Y. Lin, C. M. Chen, and H. M. Hsieh, 'Characterization of Pathogenesis of SCA17 Transgenic Mice', BioFormosa, 45 (2010), 1-9.