海洋生物為現今開發新興藥物的重要來源，具有被開發成治療帕金森氏症等神經退化性疾病藥物的可能性。直至目前為至，仍無有效治療神經退化性疾病的用藥，因此積極發展相關新穎藥物是非常重要的課題。在本研究中，首先利用6-OHDA 誘發SH-SY5Y神經細胞死亡的帕金森氏症離體模式，大量篩選可能具有神經保護作用之海洋天然物，而後利用Alamar blue 分析法、西方點墨法以及免疫組織化學染色等分析方式，確認海洋天然物的神經保護作用，並且發現這些化合物可經由PI3K/Akt 訊息傳遞路徑磷酸化Akt，進而使Bcl-2 大量表現，藉由Bcl-2 表現抑制硫胱氨酸蛋白酶(caspase)活化，促進神經細胞存活。由本實驗結果指出，部分海洋天然確實具有保護神經細胞之功效，可被進一步發展成治療神經退化性疾病的藥物。

Marine organisms are rich sources of novel drugs with therapeutic potential. Some of these drugs may be used for the treatment of human neurodegenerative diseases such as Parkinson’s disease. Currently, there are no drugs that can effectively treat or prevent neurodegeneration, and the development of such a drug is a matter of urgent importance. In the present study, we examined the neuroprotective role of the marine-derived compounds on 6-hydroxydopamine (6-OHDA)-induced cytotoxicity in a human neuroblastoma cell line (SH-SY5Y), which is a well-established in vitro model of Parkinson’s disease. SH-SY5Y cells were pretreated with marine-derived compounds 1 h before being challenged with 6-OHDA (20 μM). The cell survival, apoptotic (caspase-3 and 7) signaling pathway, and anti-apoptotic (Akt) signaling pathway were analyzed with the Alamar Blue Assay, In Situ Assay Kit (CaspaTag™), and western blotting, respectively. Our results revealed that marine-derived compounds significantly inhibited 6-OHDA-induced cell death and caspase-3 activation. Moreover, marine-derived compounds also prevented the downregulation of phospho-Akt in 6-OHDA-stimulated SH-SY5Y cells. These results indicated that marine-derived compounds has the potential for preventing 6-OHDA-induced neurotoxicity.
Hence, we conclude that marine-derived compounds can be used as a therapeutic drug for neurodegenerative diseases.

目錄.............................................................................I
圖目錄.........................................................................II
摘要 ............................................................................IV
Abstract ......................................................................V
第壹章：前言..............................................................1
第貳章：實驗材料與方法..........................................15
第参章：結果...............................................................27
第肆章：討論...............................................................93
參考文獻 ......................................................................104

Ahmed A.F., Hsieh Y.T., Wen Z.H., Wu Y.C. and Sheu J.H. (2006) Polyoxygenated sterols from the Formosan soft coral Sinularia gibberosa. Journal of Natural Products 69, 1275-9.
Babcock A.A., Kuziel W.A., Rivest S. and Owens T. (2003) Chemokine expression by glial cells directs leukocytes to sites of axonal injury in the CNS. The Journal of neuroscience : the official journal of the Society for Neuroscience 23, 7922-30.
Beal M.F. (2000) Energetics in the pathogenesis of neurodegenerative diseases. Trends in Neurosciences 23, 298-304. Betarbet R., Sherer T.B., Di Monte D.A. and Greenamyre J.T. (2002) Mechanistic
approaches to Parkinson's disease pathogenesis. Brain pathology (Zurich, Switzerland) 12, 499-510.
Beinke S. and Ley S.C. (2004) Functions of NF kappaB1 and NF-kappaB2 in immune cell biology. The Biochemical journal 382,393-409.
Blandini F., Armentero M.T. and Martignoni E. (2008) The 6-hydroxydopamine model: news from the past. Parkinsonism & related disorders 2, S124-9.
Blum D., Torch S., Lambeng N., Nissou M., Benabid A.L., Sadoul R. and Verna J.M. (2001) Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson’s disease. Progress in Neurobiology 65, 135-72.
Bhakar A.L., Tannis L.L., Zeindler C., Russo M.P., Jobin C., Park D.S., MacPherson S. and Barker P.A. (2002) Constitutive nuclear factor-kappa B activity is
required for central neuron survival. The Journal of neuroscience : the official journal of the Society for Neuroscience 22, 8466-75.
Bian X., McAllister-Lucas L.M., Shao F., Schumacher K.R., Feng Z., Porter A.G., Castle V.P. and Opipari A.W. Jr. (2001) NF-kappa B activation mediates
doxorubicin-induced cell death in N-type neuroblastoma cells. The journal of biological chemistry 276, 48921-9.
Chang C.H., Wen Z.H., Wang S.K. and Duh C.Y. (2008) Capnellenes from the Formosan soft coral Capnella imbricata. Journal of Nature Products 71, 619-21.
Chang F., Lee J.T., Navolanic P.M., Steelman L.S., Shelton J.G., Blalock W.L., Franklin R.A. and McCubrey J.A. (2003) Involvement of PI3K/Akt pathway incell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy. Leukemia : official journal of the Leukemia Society of
America, Leukemia Research Fund, U.K 17, 590-603.
Chen C., Edelstein L.C., Gélinas C. (2000) The Rel/NF-kappaB family directly activates expression of the apoptosis inhibitor Bcl-x(L). Molecular and cellular
biology 20, 2687-95.
Davies S.P., Reddy H., Caivano M. and Cohen P. (2000) Specificity and mechanism of action of some commonly used protein kinase inhibitors. The Biochemical journal 351, 95-105.
Dawson T.M. and Dawson V.L. (2003) Rare genetic mutations shed light on the pathogenesis of Parkinson disease. Journal of Clinical Investigation 111, 145-51.
Desagher S. and Martinou J.C. (2000) Mitochondria as the central control point of apoptosis. Trends in cell biology 10, 369-77.
Di Filippo M., Picconi B., Tozzi A., Ghiglieri V., Rossi A., Calabresi P. (2008) The endocannabinoid system in Parkinson's disease. Current Pharmaceutical Design
14, 2337-47.
Fearnley J.M. and Lees A.J. (1991) Ageing and Parkinson's disease: substantia nigra regional selectivity. Brain : a journal of neurology 114, 2283-301.
Fernandez-Gomez F.J., Pastor M.D., Garcia-Martinez E.M., Melero-Fernandez de Mera R., Gou-Fabregas M., Gomez-Lazaro M., Calvo S., Soler R.M., Galindo
M.F. and Jordán J. (2006) Pyruvate protects cerebellar granular cells from 6-hydroxydopamine-induced cytotoxicity by activating the Akt signaling pathway and increasing glutathione peroxidase expression. Neurobiology of Disease 24, 296-307.
Frei K., Truong D.D. and Wolters E. (2008) Case studies in the advancement of Parkinson's disease. CNS spectrums 13, 1-6.
Fry M.J. (1994) Structure, regulation and function of phosphoinositide 3-kinases. Biochimica et biophysica acta 1226, 237-68.
Fry M.J. (2001) Phosphoinositide 3-kinase signalling in breast cancer: how big a role might it play? Breast cancer research 3, 304-12.
Galindo M.F., Jordán J., González-García C. and Ceña V. (2003) Chromaffin cell death induced by 6-hydroxydopamine is independent of mitochondrial swelling and caspase activation. Journal of neurochemistry 84, 1066-73.
Gardner A.M., Xu F.H., Fady C., Jacoby F.J., Duffey D.C., Tu Y., Lichtenstein A.(1997) Apoptotic vs. nonapoptotic cytotoxicity induced by hydrogen peroxide.
Free radical biology & medicine 22, 73-83.
Gee P., San R.H., Davison A.J. and Stich H.F. (1992) Clastogenic and mutagenic actions of active species generated in the 6-hydroxydopamine/oxygen reaction:
effects of scavengers of active oxygen, iron, and metal chelating agents. Free radical research communications 16, 1-10.
Goffi F., Boroni F., Benarese M., Sarnico I., Benetti A., Spano P.F. and Pizzi M. (2005) The inhibitor of I kappa B alpha phosphorylation BAY 11-7082 prevents
NMDA neurotoxicity in mouse hippocampal slices. Neuroscience letters 377, 147-51.
Greco D., Volpicelli F., Di Lieto A., Leo D., Perrone-Capano C., Auvinen P. and di Porzio U. (2009) Comparison of gene expression profile in embryonic
mesencephalon and neuronal primary cultures. PLoS ONE 4, e4977.
Gregorian C., Nakashima J., Le Belle J., Ohab J., Kim R, Liu A., Smith K.B., Groszer M., Garcia A.D., Sofroniew M.V., Carmichael S.T., Kornblum H.I., Liu X. and Wu H. (2009) Pten deletion in adult neural stem/progenitor cells enhances constitutive neurogenesis. The Journal of neuroscience : the official journal of the Society for Neuroscience 29, 1874-86.
Grilli M., Pizzi M., Memo M. and Spano P. (1996), Neuroprotection by aspirin and sodium salicylate through blockade of NF-κB activation. Science (New York, N.Y.) 274, 1383-5.
Halliwell B. and Aruoma O.I. (1991) DNA damage by oxygen-derived species: its mechanism and measurement in mammalian systems. FEBS Letters 281, 9-19.
Hasegawa E., Takeshige K., Oishi T., Murai Y. and Minakami S. (1990) 1-Methyl-4-phenylpyridinium (MPP+) induces NADH-dependent superoxide
formation and enhances NADH-dependent lipid peroxidation in bovine heart submitochondrial particles. Biochemical and biophysical research
communications 170, 1049-55.
Hattori N., Tanaka M., Ozawa T. and Mizuno Y. (1991) Immunohistochemical studies on complexes I, II, III, and IV of mitochondria in Parkinson’s disease.
Annals of neurology 30, 563-71.
Hirsch E.C. and Hunot S. (2009) Neuroinflammation in Parkinson's disease: a target for neuroprotection? Lancet neurology 8, 382-97.
Hockenbery D., Nuñez G., Milliman C., Schreiber R.D., Korsmeyer SJ. (1990) Bcl-2is an inner mitochondrial membrane protein that blocks programmed cell death.
Nature 348, 334-6.
Hoehn M.M. and Yahr M.D. (1967) Parkinsonism: onset, progression and mortality. Neurology 17, 427-42.
Hughes A.J., Daniel S.E., Blankson S. and Lees A.J. (1993) A clinicopathologic study of 100 cases of Parkinson's disease. Archive of Neurology 50, 140-8.
Jacobson M.D., Weil M., Raff M.C. (1997) Programmed cell death in animal development. Cell 88, 347-54.
Jean Y.H., Chen W.F., Duh C.Y., Huang S.Y., Hsu C.H., Lin C.S., Sung C.S., Chen I.M. and Wen Z.H. (2008) Inducible nitric oxide synthase and cyclooxygenase-2
participate in anti-inflammatory and analgesic effects of the natural marine compound lemnalol from Formosan soft coral Lemnalia cervicorni. European
Journal of Pharmacology 578, 323-31.
Jiang Z. and Yu P.H. (2005) Involvement of extracellular signal-regulated kinases 1/2
and (phosphoinositide 3-kinase)/Akt signal pathways in acquired resistance against neurotoxin of 6 hydroxydopamine in SH-SY5Y cells following cell-cell
interaction with astrocytes. Neuroscience 133, 405-11.
Joglar B., Rodriguez-Pallares J., Rodriguez-Perez A.I., Rey P., Guerra M.J. and Labandeira-Garcia J.L. (2009) The inflammatory response in the MPTP model of
Parkinson's disease is mediated by brain angiotensin: relevance to progression of
the disease. Journal of neurochemistry 109, 656-69.
Jordán J., Galindo M.F., Tornero D., González-García C. and Ceña V. (2004) Bcl-xL blocks mitochondrial multiple conductance channel activation and inhibits
6-OHDA-induced death in SH-SY5Y cells. Journal of Neurochemistry 89, 124-33.
Kaltschmidt B., Uherek M., Volk B., Baeuerle P.A. and Kaltschmidt C. (1997) Transcription factor NF-kappaB is activated in primary neurons by amyloid beta
peptides and in neurons surrounding early plaques from patients with Alzheimer disease. Proceedings of the National Academy of Sciences of the United States of America 94, 2642-7.
Kang M.H. and Reynolds C.P. (2009) Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clinical cancer research : an official
journal of the American Association for Cancer Research 15, 1126-32.
Kijjoa A. and Sawangwong P. (2004) Drugs and Cosmetics from the Sea. Marinedrugs 2, 73-82.
Kizilay G., Cakmak H., Yen C.F., Atabekoglu C., Arici A. and Kayisli U.A. (2008) Expression and regulation of c-Jun N-terminal kinase (JNK) in endometrial cells
in vivo and in vitro. Histochemistry and cell biology 130, 761-71.
Lauwers G.Y., Scott G.V. and Hendricks J. (1994) Immunohistochemical evidence of aberrant bcl-2 protein expression in gastric epithelial dysplasia. Cancer 73, 2900-4.
Lee C.S., Schultzer M., Mak E.K., Snow B.J., Tsui J.K., Calne S., Hammerstad, J. and Calne D.B. (1994) Clinical observations on the rate of progression of idiopathic parkinsonism. Brain 117, 501-07.
Lee H.J., Noh Y.H., Lee D.Y., Kim Y.S., Kim K.Y., Chung Y.H., Lee W.B. and Kim S.S. (2005) Baicalein attenuates 6-hydroxydopamine-induced neurotoxicity in
SH-SY5Y cells. European journal of cell biology 84, 897-905.
Lee K.Y., Sung S.H. and Kim Y.C. (2006) Neuroprotective bibenzyl glycosides of
Stemona tuberosa roots. Journal of nature products 69, 679-81.
Leslie N.R. and Downes C.P. (2002) PTEN: The down side of PI 3-kinase signalling. Cellular Signalling 14, 285-95.
Levites Y., Youdim M.B., Maor G. and Mandel S. (2002) Attenuation of 6-hydroxydopamine (6-OHDA)-induced nuclear factor-kappaB (NF-kappaB) activation and cell death by tea extracts in neuronal cultures. Biochemical
Pharmacology 63, 21-29.
Levites Y., Youdim M.B., Maor G. and Mandel S. (2002) Attenuation of 6-hydroxydopamine (6-OHDA)-induced nuclear factor-kappaB (NF-kappaB) activation and cell death by tea extracts in neuronal cultures. Biochemicalpharmacology 63, 21-9.
Li X., Bijur G.N. and Jope R.S. (2002) Glycogen synthase kinase-3beta, mood stabilizers, and neuroprotection. Bipolar disorders 4, 137-44.
Lodish H., Berk A., Matsudaira P., Kaiser C. A., Krieger M. and Scott M.P. (2003) Molecular Cell Biology fifth edition.New York: W. H. Freeman and Company.
Lovat P.E., Oliverio S., Corazzari M., Rodolfo C., Ranalli M., Goranov B., Melino G., Redfern C.P. and Piacentini M. (2003) Bak: a downstream mediator of fenretinide-induced apoptosis of SH-SY5Y neuroblastoma cells. Cancer research 63, 7310-3.
Lukas T.J., Wang A.L., Yuan M. and Neufeld A.H. (2009) Early cellular signalingresponses to axonal injury. Cell Communication and Signaling: CCS 13, 7:5.
Luthman J., Fredriksson A., Sundström E., Jonsson G. and Archer T. (1989) Selective lesion of central dopamine or noradrenaline neuron systems in the neonatal rat: motor behavior and monoamine alterations at adult stage. Behavioural brain research 33, 267-77.
Maehama T. and Dixon J.E. (1998) The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. The journal of biological chemistry 273, 13375-8.
Manáková S., Puttonen K.A., Raasmaja A. and Männistö P.T. (2004) The roles of dopamine transporter and Bcl-2 protein in the protection of CV1-P cells from 6-OHDA-induced toxicity. Toxicology letters 154, 117-23.
Mayer A.M. and Hamann M.T. (2002) Marine pharmacology in 1999: compounds with antibacterial, anticoagulant, antifungal, anthelmintic, anti inflammatory, antiplatelet, antiprotozoal and antiviral activities affecting the cardiovascular, endocrine, immune and nervous systems, and other miscellaneous mechanisms of action. Comparative Biochemistry and Physiology. Toxicology & pharmacology : CBP 132, 315-39.
Mayer A.M. and Hamann M.T. (2005) Marine pharmacology in 2001--2002: marine compounds with anthelmintic, antibacterial, anticoagulant, antidiabetic,
antifungal, anti-inflammatory, antimalarial, antiplatelet, antiprotozoal, antituberculosis, and antiviral activities; affecting the cardiovascular, immune and nervous systems and other miscellaneous mechanisms of action. Comparative biochemistry and physiology. Toxicology & pharmacology : CBP 140, 265-86.
Mazzio E.A., Reams R.R. and Soliman K.F. (2004) The role of oxidative stress, impaired glycolysis and mitochondrial respiratory redox failure in the cytotoxic
effects of 6-hydroxydopamine in vitro. Brain Research 1004, 29-44.
Mosley R.L., Benner E.J., Kadiu I., Thomas M., Boska M.D., Hasan K., Laurie C. and Gendelman H.E. (2006) Neuroinflammation, Oxidative Stress and the Pathogenesis of Parkinson's Disease. Clinical neuroscience research 6, 261-81.
Morale M.C., Serra P.A., L'episcopo F., Tirolo C., Caniglia S., Testa N., Gennuso F., Giaquinta G., Rocchitta G., Desole M.S., Miele E. and Marchetti B. (2006) Estrogen, neuroinflammation and neuroprotection in Parkinson's disease: glia
dictates resistance versus vulnerability to neurodegeneration. Neuroscience 138,869-78.
Mu X., He G., Cheng Y., Li X., Xu B. and Du G. (2009) Baicalein exerts neuroprotective effects in 6-hydroxydopamine-induced experimental parkinsonism in vivo and in vitro. Pharmacology, biochemistry, and behavior 2009 Mar 24. (accepted)
Nagao M. and Hayashi H. (2009) Mixed lineage kinase 2 and hippocalcin are localized in Lewy bodies of Parkinson's disease. Journal of the Neurological
Sciences 2009 Mar 28. (accepted)
Newhouse K., Hsuan S.L., Chang S.H., Cai B., Wang Y. and Xia Z., (2004) Rotenone-induced apoptosis is mediated by p38 and JNK MAP kinases in human
dopaminergic SH-SY5Y cells. Toxicological Sciences : an official journal of the Society of Toxicology 79, 137-46.
Newman D.J. and Cragg G.M. (2004) Marine natural products and related compounds in clinical and advanced preclinical trials. Journal of natural products 67, 1216-38.
Nicholson D.W. (1999) . Caspase structure, proteolytic substrates, and function during apoptotic cell death. Cell death and differentiation 6, 1028-42.
Pan J., Zhao Y.X., Wang Z.Q., Jin L., Sun Z.K. and Chen S.D. (2007) Expression of FasL and its interaction with Fas are mediated by c-Jun N-terminal kinase (JNK) pathway in 6-OHDA-induced rat model of Parkinson disease. Neuroscience letters 428, 82-7.
Parkinson J. (1817) Essay on the shaking palsy. The Journal of neuropsychiatry and clinical neurosciences 14, 223-36.
Peng J., Stevenson F.F., Doctrow S.R. and Andersen J.K. (2005) Superoxid dismutase/catalase mimetics are neuroprotective against selective paraquat-mediated dopaminergic neuron death in the substantial nigra: implications for Parkinson disease. The Journal of biological chemistry 280, 29194-8.
Piccioli P., Porcile C., Stanzione S., Bisaglia M., Bajetto A., Bonavia R., Florio T. and Schettini G. (2001) Inhibition of nuclear factor-kappaB activation induces
apoptosis in cerebellar granule cells. Journal of neuroscience research 66, 1064-73.
Pizzi M., Sarnico I., Lanzillotta A., Battistin L. and Spano P. (2009) Post-ischemic brain damage: NF-kappaB dimer heterogeneity as a molecular determinant ofneuron vulnerability. The FEBS journal 276, 27-35.
Proksch P., Edrada R.A. and Ebel R. (2002) Drugs from the seas - current status and microbiological implications. Applied Microbiology and Biotechnology 59, 125-34.
Qi Z., Miller G.W. and Voit E.O. (2008) Computational systems analysis of dopamine metabolism. PLos ONE 3, e2444.
Reed J.C., Meister L., Tanaka S., Cuddy M., Yum S., Geyer C. and Pleasure D. (1991) Differential expression of bcl2 protooncogene in neuroblastoma and other human tumor cell lines of neural origin. Cancer research 51, 6529-38.
Reynolds A.D., Banerjee R., Liu J., Gendelman H.E. and Mosley R.L. (2007) Neuroprotective activities of CD4+CD25+ regulatory T cells in animal model of
Parkinson’s disease. Journal of leukocyte biology 82, 1083-94.
Richter C., Park J.W. and Ames B.N. (1988) Normal oxidative damage to mitochondrial and nuclear DNA is extensive. Proceeding of the National Academy of Sciences of the United States of America 85, 6465-67.
Rickle A., Behbahani H., Ankarcrona M., Winblad B. and Cowburn RF. (2006) PTEN, Akt, and GSK3beta signalling in rat primary cortical neuronal cultures following tumor necrosis factor-alpha and trans-4-hydroxy-2-nonenal treatments. Journal
of neuroscience research 84, 596-605.
Sadoul R. (1998) Bcl-2 family members in the development and degenerative pathologies of the nervous system. Cell Death and Differentiation 10, 805-15.
Schapira A.H. (1998) Mitochondrial dysfunction in neurodegenerative disorders. Biochimica et biophysica acta 1366, 225-33.
Schober A. (2004) Classic toxin-induced animal models of parkinson’s disease: 6-OHDA and MPTP. Cell and tissue research 318, 215-24.
Schreck R., Albermann K. and Baeuerle P.A. (1992) Nuclear factor kappa B: an oxidative stress-responsive transcription factor of eukaryotic cells (a review).
Free radical research communications 17, 21-37.
Schwartz M., Shaked I., Fisher J., Mizrahi T. and Schori H. (2003) Protective autoimmunity against the enemy within: fighting glutamate toxicity. Trends in neurosciences 26, 297-302.
Sen R. and Baltimore D. (1986) Inducibility of kappa immunoglobulin enhancer-binding protein Nf-kappa B by a posttranslational mechanism. Cell 47, 921-8.
Shadel G.S. and Clayton D.A. (1997) Mitochondrial DNA maintenance in vertebrates. Annual review of biochemistry 66, 409-35.
Simonian N.A. and Coyle J.T. (1996) Oxidative stress in neurodegenerative disease. Annual review of pharmacology and toxicology 36, 83-106.
Stariha R.L. and Kim S.U. (2001) Mitogen-activated protein kinase signalling in oligodendrocytes: a comparison of primary cultures and CG-4. International
journal of developmental neuroscience : the official journal of the International society for developmental neuroscience 19, 427-37.
Stennicke H.R. and Salvesen G.S. (1999) Caspases: preparation and characterization. METHODS: A Companion to Methods in Enzymology 17, 313-9.
Sydow O. (2008) Parkinson’s disease: recent development in therapies for advanced disease with a focus on deep brain stimulation (DBS) and duodenal levodopa infusion. The FEBS journals 275, 1370-6.
Tian L.L., Zhou Z., Zhang Q., Sun Y.N., Li C.R., Cheng C.H., Zhong Z.Y. and Wang S.Q. (2007) Protective effect of (+/-) isoborneol against 6-OHDA-induced
apoptosis in SH-SY5Y cells. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology. 20, 1019-32.
Tieu K., Zuo D.M. and Yu P.H. (1999) Differential effects of staurosporine and retinoic acid on the vulnerability of the SH-SY5Y neuroblastoma cells:
involvement of bcl-2 and p53 proteins. Journal of Neuroscience Research 58, 426-35.
Ushiro H. and Cohen S. (1980). Identification of phosphotyrosine as a product of epidermal growth factor-activated protein kinase in A-431 cell membranes. The Journal of biological chemistry 255, 8363-5.
von Coelln R., Kügler S., Bähr M., Weller M., Dichgans J. and Schulz JB. (2001) Rescue from death but not from functional impairment: caspase inhibition
protects dopaminergic cells against 6 hydroxydopamine-induced apoptosis but not against the loss of their terminals. Journal of Neurochemistry 77, 263-73.
Waldmeier P.C. and Tatton W.G. (2004) Interrupting apoptosis in neurodegenerative disease: potential for effective therapy? Drug discovery today 9, 210-8.
Wellmann H., Kaltschmidt B. and Kaltschmidt C. (2001) Retrograde transport of transcription factor NF-kappa B in living neurons. The Journal of biological
chemistry 276, 11821-9.
West A.E., Griffith E.C. and Greenberg M.E. (2002) Regulation of transcription factors by neuronal activity. Nature reviews. Neuroscience 3, 921-31.
Weston C.R. and Davis R.J. (2007) The JNK signal transduction pathway. Cell Biology 19,142-9.
Yamada M., Oligino T., Mata M., Goss J.R., Glorioso J.C., Fink D.J. (1999) Herpes simplex virus vector-mediated expression of Bcl-2 prevents 6 hydroxydopamine-induced degeneration of neurons in the substantia nigra in vivo. Proceedings of the National Academy of Sciences of the United States of
America 96, 4078-83.
Youdim M.B., Amit T., Falach-Yogev M., Bar Am O., Maruyama W. and Naoi M. (2003) The essentiality of Bcl-2, PKC and proteasome–ubiquitin complex
activations in the neuroprotective-antiapoptotic action of the anti-Parkinson drug, rasagiline. Biochemical Pharmacology 66, 1635-41.
Zhang D., Zhang J.J. and Liu G.T. (2007) The novel squamosamide derivative FLZ protects against 6-hydroxydopamine-induced apoptosis through inhibition of related signal transduction in SH-SY5Y cells. European journal of pharmacology 561, 1-6.
Zhang W., Shin E.J., Wang T., Lee P.H., Pang H., Wie M.B., Kim W.K., Kim S.J., Huang W.H., Wang Y., Zhang W., Hong J.S. and Kim H.C. (2006) 3 Hydroxymorphinan, a metabolite of dextromethorphan, protects nigrostriatal pathway against MPTP-elicited damage both in vivo and in vitro. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20, 2496-511.
Zhao D.L., Zou L.B., Lin S., Shi J.G. and Zhu H.B. (2007) Anti-apoptotic effect of esculin on dopamine-induced cytotoxicity in the human neuroblastoma
SH-SY5Y cell line. Neuropharmacology 53, 724-32.
Zhou C., Huang Y. and Przedborski S. (2008) Oxidative stress in Parkinson's disease: a mechanism of pathogenic and therapeutic significance. Annals of the New York Academy of Sciences 1147, 93-104.
Zhu Y., Hoell P., Ahlemeyer B., Sure U., Bertalanffy H. and Krieglstein J. (2007) Implication of PTEN in production of reactive oxygen species and neuronal
death in in vitro models of stroke and Parkinson’s disease. Neurochemistry International 50, 507-16.