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Natural products from marine organisms with neuroprotective activity in the experimental models of Alzheimer’s disease, Parkinson’s disease and ischemic brain stroke: their molecular targets and action mechanisms

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Abstract

Continuous increases in the incidence of neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and brain stroke demand the urgent development of therapeutics. Marine organisms are well-known producers of natural products with diverse structures and pharmacological activities. Therefore, researchers have endeavored to identify marine natural products with neuroprotective effects. In this regard, this review summarizes therapeutic targets for AD, PD, and ischemic brain stroke and marine natural products with pharmacological activities on the targets according to taxonomies of marine organisms. Furthermore, several marine natural products on the clinical trials for the treatment of neurological disorders are discussed.

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References

  • Abou-Chaar, C.I., and S.N. Shamlian. 1980. A chromatographic study of the anthraquinones of Rhamnus alaternus L. I. Extraction, isolation and identification of the aglycons. Quarterly Journal of Crude Drug Research 18: 49–55.

    Google Scholar 

  • Aisen, P.S., S. Gauthier, S.H. Ferris, D. Saumier, D. Haine, D. Garceau, A. Duong, J. Suhy, J. Oh, W.C. Lau, and J. Sampalis. 2011. Tramiprosate in mild-to-moderate Alzheimer’s disease—a randomized, double-blind, placebo-controlled, multi-centre study (the alphase study). Archives of Medical Science 7: 102–111.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Aisen, P.S., D. Saumier, R. Briand, J. Laurin, F. Gervais, P. Tremblay, and D. Garceau. 2006. A phase II study targeting amyloid-beta with 3APS in mild-to-moderate Alzheimer disease. Neurology 67: 1757–1763.

    CAS  PubMed  Google Scholar 

  • Akashi, S., T. Kimura, T. Takeuchi, K. Kuramochi, S. Kobayashi, F. Sugawara, N. Watanabe, and T. Arai. 2011. Neoechinulin A impedes the progression of rotenone-induced cytotoxicity in PC12 cells. Biological and Pharmaceutical Bulletin 34: 243–248.

    CAS  PubMed  Google Scholar 

  • Alfano, G., G. Cimino, and S. De Stefano. 1979. Palinurin, a new linear sesterterpene from a marine sponge. Experientia 35: 1136–1137.

    CAS  Google Scholar 

  • Alfano, I., P. Vora, R.S. Mummery, B. Mulloy, and C.C. Rider. 2007. The major determinant of the heparin binding of glial cell-line-derived neurotrophic factor is near the N-terminus and is dispensable for receptor binding. Biochemical Journal 404: 131–140.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Alonso, E., C. Vale, M.R. Vieytes, F.M. Laferla, L. Gimenez-Llort, and L.M. Botana. 2011a. The cholinergic antagonist gymnodimine improves Aβ and tau neuropathology in an in vitro model of Alzheimer disease. Cellular Physiology and Biochemistry 27: 783–794.

    CAS  PubMed  Google Scholar 

  • Alonso, E., C. Vale, M.R. Vieytes, F.M. Laferla, L. Giménez-Llort, and L.M. Botana. 2011b. 13-Desmethyl spirolide-C is neuroprotective and reduces intracellular Aβ and hyperphosphorylated tau in vitro. Neurochemistry International 59: 1056–1065.

    CAS  PubMed  Google Scholar 

  • Alonso, E., H. Fuwa, C. Vale, Y. Suga, T. Goto, Y. Konno, M. Sasaki, F.M. LaFerla, M.R. Vieytes, L. Gimenez-Llort, and L.M. Botana. 2012. Design and synthesis of skeletal analogues of gambierol: Attenuation of amyloid-β and tau pathology with voltage-gated potassium channel and N-methyl-d-aspartate receptor implications. Journal of the American Chemical Society 134: 7467–7479.

    CAS  PubMed  Google Scholar 

  • Alonso, E., P. Otero, C. Vale, A. Alfonso, A. Antelo, L. Gimenez-Llort, L. Chabaud, C. Guillou, and L.M. Botana. 2013a. Benefit of 13-desmethyl spirolide C treatment in triple transgenic mouse model of Alzheimer disease: Beta-amyloid and neuronal markers improvement. Current Alzheimer Research 10: 279–289.

    CAS  PubMed  Google Scholar 

  • Alonso, E., C. Vale, M.R. Vieytes, and L.M. Botana. 2013b. Translocation of PKC by yessotoxin in an in vitro model of Alzheimer’s disease with improvement of tau and β-amyloid pathology. ACS Chemical Neuroscience 4: 1062–1070.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Andorfer, C., C.M. Acker, Y. Kress, P.R. Hof, K. Duff, and P. Davies. 2005. Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms. Journal of Neuroscience 25: 5446–5454.

    CAS  PubMed  Google Scholar 

  • Arnstein, H.R.V., and A.H. Cook. 1947. Production of antibiotics by fungi. III. Javanicin. An antibacterial pigment from Fusarium javanicum. Journal of the Chemical Society 1021–1028.

  • Austin, S., and J. St-Pierre. 2012. PGC1alpha and mitochondrial metabolism–emerging concepts and relevance in ageing and neurodegenerative disorders. Journal of Cell Science 125: 4963–4971.

    CAS  PubMed  Google Scholar 

  • Azam, L., C. Dowell, M. Watkins, J.A. Stitzel, B.M. Olivera, and J.M. McIntosh. 2005. α-Conotoxin BuIA, a novel peptide from Conus bullatus, distinguishes among neuronal nicotinic acetylcholine receptors. Journal of Biological Chemistry 280: 80–87.

    CAS  PubMed  Google Scholar 

  • Azam, L., and J.M. McIntosh. 2006. Characterization of nicotinic acetylcholine receptors that modulate nicotine-evoked [3H]norepinephrine release from mouse hippocampal synaptosomes. Molecular Pharmacology 70: 967–976.

    CAS  PubMed  Google Scholar 

  • Balami, J.S., R. Chen, B.A. Sutherland, and A.M. Buchan. 2013. Thrombolytic agents for acute ischaemic stroke treatment: The past, present and future. CNS & Neurological Disorders: Drug Targets 12: 145–154.

    CAS  Google Scholar 

  • Bazan, N.G. 2006. Cell survival matters: Docosahexaenoic acid signaling, neuroprotection and photoreceptors. Trends in Neurosciences 29: 263–271.

    CAS  PubMed  Google Scholar 

  • Benveniste, H., J. Drejer, A. Schousboe, and N.H. Diemer. 1984. Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis. Journal of Neurochemistry 43: 1369–1374.

  • Bergeron, M., J.M. Gidday, A.Y. Yu, G.L. Semenza, D.M. Ferriero, and F.R. Sharp. 2000. Role of hypoxia-inducible factor-1 in hypoxia-induced ischemic tolerance in neonatal rat brain. Annals of Neurology 48: 285–296.

    CAS  PubMed  Google Scholar 

  • Bharate, S.B., S. Manda, P. Joshi, B. Singh, and R.A. Vishwakarma. 2012a. Total synthesis and anti-cholinesterase activity of marine-derived bis-indole alkaloid fascaplysin. Medicinal Chemistry Communications 3: 1098–1103.

    CAS  Google Scholar 

  • Bharate, S.B., R.R. Yadav, S. Battula, and R.A. Vishwakarma. 2012b. Meridianins: Marine-derived potent kinase inhibitors. Mini-Reviews in Medicinal Chemistry 12: 618–631.

    CAS  PubMed  Google Scholar 

  • Bidon-Chanal, A., A. Fuertes, D. Alonso, D.I. Perez, A. Martinez, F.J. Luque, and M. Medina. 2013. Evidence for a new binding mode to GSK-3: Allosteric regulation by the marine compound palinurin. European Journal of Medicinal Chemistry 60: 479–489.

    CAS  PubMed  Google Scholar 

  • Binda, C., E.M. Milczek, D. Bonivento, J. Wang, A. Mattevi, and D.E. Edmondson. 2011. Lights and shadows on monoamine oxidase inhibition in neuroprotective pharmacological therapies. Current Topics in Medicinal Chemistry 11: 2788–2796.

    CAS  PubMed  Google Scholar 

  • Blihoghe, D., E. Manzo, A. Villela, A. Cutignano, G. Picariello, M. Faimali, and A. Fontana. 2011. Evaluation of the antifouling properties of 3-alyklpyridine compounds. Biofouling 27: 99–109.

    CAS  PubMed  Google Scholar 

  • Boison, D. 2006. Adenosine kinase, epilepsy and stroke: Mechanisms and therapies. Trends in Pharmacological Sciences 27: 652–658.

    CAS  PubMed  Google Scholar 

  • Bourne, Y., Z. Radic, R. Araoz, T.T. Talley, E. Benoit, D. Servent, P. Taylor, J. Molgo, and P. Marchot. 2010. Structural determinants in phycotoxins and AchBP conferring high affinity binding and nicotinic AchR antagonism. Proceedings of the National Academy of Sciences of the United States of America 107: 6076–6081.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bourque, M.J., and L.E. Trudeau. 2000. GDNF enhances the synaptic efficacy of dopaminergic neurons in culture. European Journal of Neuroscience 12: 3172–3180.

    CAS  PubMed  Google Scholar 

  • Buckingham, S.D., A.K. Jones, L.A. Brown, and D.B. Sattelle. 2009. Nicotinic acetylcholine receptor signalling: Roles in Alzheimer’s disease and amyloid neuroprotection. Pharmacological Reviews 61: 39–61.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Buttini, M., E. Masliah, R. Barbour, H. Grajeda, R. Motter, K. Johnson-Wood, K. Khan, P. Seubert, S. Freedman, D. Schenk, and D. Games. 2005. Beta-amyloid immunotherapy prevents synaptic degeneration in a mouse model of Alzheimer’s disease. Journal of Neuroscience 25: 9096–9101.

    CAS  PubMed  Google Scholar 

  • Calon, F., G.P. Lim, F. Yang, T. Morihara, B. Teter, O. Ubeda, P. Rostaing, A. Triller, N. Salem Jr, K.H. Ashe, S.A. Frautschy, and G.M. Cole. 2004. Docosahexaenoic acid protects from dendritic pathology in an Alzheimer’s disease mouse model. Neuron 43: 633–645.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Capon, R.J., and J.K. MacLeod. 1987. A revision of the absolute stereochemistry of ilimaquinone. Journal of Organic Chemistry 52: 5059–5060.

    CAS  Google Scholar 

  • Caprioli, V., G. Cimino, A. De Giulio, A. Madaio, G. Scognamiglio, and E. Trivellone. 1992. Selected biological activities of saraines. Comparative Biochemistry and Physiology. Part B: Biochemistry & Molecular Biology 103B: 293–296.

    CAS  Google Scholar 

  • Carle, J.S., and C. Christophersen. 1979. Bromo-substituted physostigmine alkaloids from a marine bryozoa Flustra foliacea. Journal of the American Chemical Society 101: 4012–4013.

    CAS  Google Scholar 

  • Casnati, G., P. Pochini, and R. Ungaro. 1972. Neoechinulin: A new isoprenyl indole metabolite from Aspergillus amstelodami Grazz. Chimica Italiana 103: 141–151.

    Google Scholar 

  • Chai, G.S., X. Jiang, Z.F. Ni, Z.W. Ma, A.J. Xie, X.S. Cheng, Q. Wang, J.Z. Wang, and G.P. Liu. 2013. Betaine attenuates Alzheimer-like pathological changes and memory deficits induced by homocysteine. Journal of Neurochemistry 124: 388–396.

    CAS  PubMed  Google Scholar 

  • Chan, G.W., S. Mong, M.E. Hemling, A.J. Freyer, P.M. Offen, C.W. De Brosse, H.M. Sarau, and J.W. Westley. 1993. New leukotriene B4 receptor antagonist: Leucettamine A and related imidazole alkaloids from the marine sponge Leucetta microraphis. Journal of Natural Products 56: 116–121.

    CAS  PubMed  Google Scholar 

  • Chang, C.Y., J.Y. Chen, D. Ke, and M.L. Hu. 2005. Plasma levels of lipophilic antioxidant vitamins in acute ischemic stroke patients: Correlation to inflammation markers and neurological deficits. Nutrition 21: 987–993.

    CAS  PubMed  Google Scholar 

  • Chen, W.L., Y. Qian, W.F. Meng, J.Y. Pang, Y.C. Lin, Y.Y. Guan, S.P. Chen, J. Liu, Z. Pei, and G.L. Wang. 2009. A novel marine compound xyloketal B protects against oxidized LDL-induced cell injury in vitro. Biochemical Pharmacology 78: 941–950.

    CAS  PubMed  Google Scholar 

  • Chen, W.-F., C. Chakraborty, C.-S. Sung, C.-W. Feng, Y.-H. Jean, Y.-Y. Lin, H.-C. Hung, T.-Y. Huang, S.-Y. Huang, T.-M. Su, P.-J. Sung, J.-H. Sheu, and Z.-H. Wen. 2012. Neuroprotection by marine-derived compound, 11-dehydrosinulariolide, in an in vitro Parkinson’s model: A promising candidate for the treatment of Parkinson’s disease. Naunyn-Schmiedeberg’s Archives of Pharmacology 385: 265–275.

    CAS  PubMed  Google Scholar 

  • Cherubini, A., C. Ruggiero, C. Morand, F. Lattanzio, G. Dell’aquila, G. Zuliani, A. Di Iorio, and C. Andres-Lacueva. 2008. Dietary antioxidants as potential pharmacological agents for ischemic stroke. Current Medicinal Chemistry 15: 1236–1248.

    CAS  PubMed  Google Scholar 

  • Choi, D.W. 1992. Excitotoxic cell death. Journal of Neurobiology 23: 1261–1276.

  • Choi, J.S., H.J. Lee, and S.S. Kang. 1994. Alaternin, cassiaside and rubrofusarin gentiobioside, radical scavenging principles from the seeds of Cassia tora on 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical. Archives of Pharmacal Research 17: 462–466.

    CAS  PubMed  Google Scholar 

  • Choi, J.S., H.J. Lee, K.-Y. Park, and G.-O. Jung. 1998. In vitro antimutagenic effects of alaternin and isorubrofusarin gentiobioside from roasted Cassia tora. Natural Product Sciences 4: 100–104.

    CAS  Google Scholar 

  • Choi, B.W., G. Ryu, S.H. Park, E.S. Kim, J. Shin, S.S. Roh, H.C. Shin, and B.H. Lee. 2007. Anticholinesterase activity of plastoquinones from Sargassum sagamianum: Lead compounds for Alzheimer’s disease therapy. Phytotherapy Research 21: 423–426.

    CAS  PubMed  Google Scholar 

  • Cimino, G., S. De Rosa, S. De Stefano, and G. Sodano. 1986a. Marine natural products: New results from Mediterranean invertebrates. Pure and Applied Chemistry 58: 375–386.

    CAS  Google Scholar 

  • Cimino, G., S. De Stefano, G. Scognamiglio, G. Sodano, and E. Trivellone. 1986b. Sarains A new class of alkaloids from the marine sponge Reniera sarai. Bulletin des Societes Chimiques Belges 95: 783–800.

    CAS  Google Scholar 

  • Cimino, G., C.A. Mattia, L. Mazzarella, R. Puliti, G. Scognamiglio, A. Spinella, and E. Trivellone. 1989a. Unprecedented alkaloid skeleton from the Mediterranean sponge Reniera sarai: X-ray structure of an acetate derivative of sarain-A. Tetrahedron 45: 3863–3872.

    CAS  Google Scholar 

  • Cimino, G., A. Spinella, and E. Trivellone. 1989b. Isosarain-1: A new alkaloid from the Mediterranean sponge Reniera sarai. Tetrahedron Letters 30: 133–136.

    CAS  Google Scholar 

  • Cole, S.L., and R. Vassar. 2007. The Alzheimer’s disease beta-secretase enzyme, BACE1. Molecular Neurodegeneration 2: 22.

    PubMed Central  PubMed  Google Scholar 

  • Corona, J.C., and M.R. Duchen. (2014). PPARgamma and PGC-1alpha as therapeutic targets in Parkinson’s. Neurochemical Research.

  • Coval, S.J., P.J. Scheuer, G.K. Matsumoto, and J. Clardy. 1984. Two new xenicin diterpenoids from the octocoral Anthelia edmondsoni. Tetrahedron 40: 3823–3828.

    CAS  Google Scholar 

  • Crmwell, B.T., and S.D. Rennie. 1953. The biosynthesis and metabolism of betaines in plants. 1. The estimation and distribution of glycinebetaine (betaine) in Beta vulgaris L. and other plants. Biochemical Journal 55: 189–192.

    CAS  PubMed  Google Scholar 

  • Cunha, R.A. 2005. Neuroprotection by adenosine in the brain: From A(1) receptor activation to A (2A) receptor blockade. Purinergic Signalling 1: 111–134.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Dai, J., A. Sorribas, W.Y. Yoshida, M. Kelly, and P.G. Williams. 2010a. Xestosaprols from the Indonesian marine sponge Xestospongia sp. Journal of Natural Products 73: 1188–1191.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Dai, J., A. Sorribas, W.Y. Yoshida, M. Kelly, and P.G. Williams. 2010b. Topsentinols, 24-isopropyl steroids from the marine sponge Topsentia sp. Journal of Natural Products 73: 1597–1600.

    CAS  PubMed  Google Scholar 

  • Dawson, T.M., and V.L. Dawson. 2003. Molecular pathways of neurodegeneration in Parkinson’s disease. Science 302: 819–822.

    CAS  PubMed  Google Scholar 

  • De Strooper, B., T. Iwatsubo, and M.S. Wolfe. 2012. Presenilins and gamma-secretase: Structure, function, and role in Alzheimer Disease. Cold Spring Harbor Perspectives in Medicine 2: a006304.

    PubMed Central  PubMed  Google Scholar 

  • Defant, A., I. Mancini, L. Raspor, G. Guella, T. Turk, and K. Sepcic. 2011. New structural insights into saraines A, B, and C, macrocyclic alkaloids from the Mediterranean sponge Reniera (Haliclona) saraiEuropean Journal of Organic Chemistry 2011: 3761–3767.

  • Deng, C.-M., S.-X. Liu, C.-H. Huang, J.-Y. Pang, and Y.-C. Lin. 2013. Secondary metabolites of a mangrove endophytic fungus Aspergillus terreus (No. GX7-3B) from the South China Sea. Marine Drugs 11: 2616–2624.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Devore, E.E., E. Feskens, M.A. Ikram, T. Den Heijer, M. Vernooij, F. Van Der Lijn, A. Hofman, W.J. Niessen, and M.M. Breteler. 2013. Total antioxidant capacity of the diet and major neurologic outcomes in older adults. Neurology 80: 904–910.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Dewapriya, P., Y.-X. Li, S.W.A. Himaya, R. Pangestuti, and S.-K. Kim. 2013. Neoechinulin A suppresses amyloid-β oligomer-induced microglia activation and thereby protects PC-12 cells from inflammation-mediated toxicity. NeuroToxicology 35: 30–40.

    CAS  PubMed  Google Scholar 

  • Dodart, J.C., K.R. Bales, K.S. Gannon, S.J. Greene, R.B. Demattos, C. Mathis, C.A. Delong, S. Wu, X. Wu, D.M. Holtzman, and S.M. Paul. 2002. Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer’s disease model. Nature Neuroscience 5: 452–457.

    CAS  PubMed  Google Scholar 

  • Dolgin, E. 2012. First therapy targeting Parkinson’s proteins enters clinical trials. Nature Medicine 18: 992–993.

    PubMed  Google Scholar 

  • Du, L., Y.-D. Zhou, and D.G. Nagle. 2013. Inducers of hypoxic response: Marine sesquiterpene quinones activate HIF-1. Journal of Natural Products 76: 1175–1181.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Echalier, A., K. Bettayeb, Y. Ferandin, and O. Lozach. 2008. Cle´ment, M., Valette, A., Liger, F., Marquet, B., Morris, J.C., Endicott, J.A., Joseph, B., and Meijer, L., Meriolins (3-(pyrimidin-4-yl)-7-azaindoles): Synthesis, kinase inhibitory activity, cellular effects, and structure of a CDK2/cyclin A/meriolin complex. Journal of Medicinal Chemistry 51: 737–751.

    CAS  PubMed  Google Scholar 

  • Ernst, R.L., and J.W. Hay. 1994. The US economic and social costs of Alzheimer’s disease revisited. American Journal of Public Health 84: 1261–1264.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Escoubas, P., J.R. De Weille, A. Lecoq, S. Diochot, R. Waldmann, G. Champigny, D. Moinier, A. Menez, and M. Lazdunski. 2000. Isolation of a tarantula toxin specific for a class of proton-gated Na+ channels. Journal of Biological Chemistry 275: 25116–25121.

    CAS  PubMed  Google Scholar 

  • Etcheberrigaray, R., M. Tan, I. Dewachter, C. Kuiperi, I. Van der Auwera, S. Wera, L. Qiao, B. Bank, T.J. Nelson, A.P. Kozikowski, F. Van Leuven, and D.L. Alkon. 2004. Therapeutic effects of PKC activators in Alzheimer’s disease transgenic mice. Proceedings of the National Academy of Sciences of the United States of America 101: 11141–11146.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Etienne, J. 1956. Research on the biochemistry of choline and its derivatives. XXXV. Betaine in Patella vulgate. Bulletin de la Societe de Chimie Biologique (Paris) 38: 1315–1328.

    CAS  Google Scholar 

  • Falk, M., I.W. Burton, T. Hu, J.A. Walter, and J.L.C. Wright. 2001. Assignment of the relative stereochemistry of the spirolides, macrocyclic toxins isolated from shellfish and from the cultured dinoflagellate Alexandrium ostenfeldii. Tetrahedron 57: 8659–8665.

    CAS  Google Scholar 

  • Faria, T.Q., A. Mingote, F. Siopa, R. Ventura, C. Maycock, and H. Santos. 2008. Design of new enzyme stabilizers inspired by glycosides of hyperthermophilic microorganisms. Carbohydrate Research 373: 3025–3033.

    Google Scholar 

  • Faria, C., C.D. Jorge, N. Borges, S. Tenreiro, T.F. Outeiro, and H. Santos. 2013. Inhibition of formation of α-synuclein inclusions by mannosylglycerate in a yeast model of Parkinson’s disease. Biochimica et Biophysica Acta 1830: 4065–4072.

    CAS  PubMed  Google Scholar 

  • Fariello, R.G., G.T. Golden, and M. Pisa. 1982. Homotaurine (3 aminopropanesulfonic acid, 3APS) protects from the convulsant and cytotoxic effect of systemically administered kainic acid. Neurology 32: 241–245.

    CAS  PubMed  Google Scholar 

  • Farooqui, T., and A.A. Farooqui. 2009. Aging: An important factor for the pathogenesis of neurodegenerative diseases. Mechanisms of Ageing and Development 130: 203–215.

    CAS  PubMed  Google Scholar 

  • Fernandez, H.H., and J.J. Chen. 2007. Monoamine oxidase-B inhibition in the treatment of Parkinson’s disease. Pharmacotherapy 27: 174S–185S.

    CAS  PubMed  Google Scholar 

  • Finck, B.N., and D.P. Kelly. 2006. PGC-1 coactivators: Inducible regulators of energy metabolism in health and disease. The Journal of Clinical Investigation 116: 615–622.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Findley, L., M. Aujla, P.G. Bain, M. Baker, C. Beech, C. Bowman, J. Holmes, W.K. Kingdom, D.G. Macmahon, V. Peto, and J.R. Playfer. 2003. Direct economic impact of Parkinson’s disease: A research survey in the United Kingdom. Movement Disorders: Official Journal of the Movement Disorder Society 18: 1139–1145.

    Google Scholar 

  • Forenza, S., L. Minale, R. Riccio, and E. Fattorusso. 1971. New bromo-pyrrole derivatives from the sponge Agelas oroides. Journal of the Chemical Society D: Chemical Communications 18: 1129–1130.

    Google Scholar 

  • Fotuhi, M., P. Mohassel, and K. Yaffe. 2009. Fish consumption, long-chain omega-3 fatty acids and risk of cognitive decline or Alzheimer disease: A complex association. Nat. Clin. Pract. Neurol. 5: 140–152.

    CAS  PubMed  Google Scholar 

  • Franco, L.H., E.B.D.K. Joffe, L. Puricelli, M. Tatian, A.M. Seldes, and J.A. Palermo. 1998. Indole alkaloids from the tunicate Aplidium meridianum. Journal of Natural Products 61: 1130–1132.

    CAS  PubMed  Google Scholar 

  • Fukuyama, Y., I. Miura, Z. Kinzyo, H. Mori, M. Kido, Y. Nakayama, M. Takahashi, and M. Ochi. 1985. Eckols, novel phlorotannins with a dibenzo-p-dioxin skeleton possessing inhibitory effects on α2-macroglobulin from the brown alga Ecklonia kurome Okamura. Chemistry Letters 6: 739–742.

    Google Scholar 

  • Garcia, E.E., L.E. Benjamin, and R.I. Fryer. 1973. Reinvestigation into the structure of oroidin, a bromopyrrole derivative from marine sponge. Journal of the Chemical Society, Chemical Communications 3: 78–79.

    Google Scholar 

  • García-Palomero, E., P. Usán, J. Pérez-Baz, R.I. Fernández, A. Martínez, A. Fernández, and M. Medina. 2007. Therapeutic potential of potent marine neuroprotectants. In New trends in Alzheimer and Parkinson related disorders: ADPD, ed. I. Hanin, M. Windisch, W. Poewe, and A. Fisher, 289–294. Salzburg: Medimond S.r.l-Monduzzi International Proceedings Division.

    Google Scholar 

  • Gariballa, S.E., T.P. Hutchin, and A.J. Sinclair. 2002. Antioxidant capacity after acute ischaemic stroke. QJM 95: 685–690.

    CAS  PubMed  Google Scholar 

  • Georgievska, B., J. Sandin, J. Doherty, A. Mortberg, J. Neelissen, A. Andersson, S. Gruber, Y. Nilsson, P. Schott, P.I. Arvidsson, S. Hellberg, G. Osswald, S. Berg, J. Falting, and R.V. Bhat. 2013. AZD1080, a novel GSK3 inhibitor, rescues synaptic plasticity deficits in rodent brain and exhibits peripheral target engagement in humans. Journal of Neurochemistry 125: 446–456.

    CAS  PubMed  Google Scholar 

  • Gervais, F., J. Paquette, C. Morissette, P. Krzywkowski, M. Yu, M. Azzi, D. Lacombe, X. Kong, A. Aman, J. Laurin, W.A. Szarek, and P. Tremblay. 2007. Targeting soluble Abeta peptide with Tramiprosate for the treatment of brain amyloidosis. Neurobiology of Aging 28: 537–547.

    CAS  PubMed  Google Scholar 

  • Gerwick, W.H., and B.S. Moore. 2012. Lessons from the past and charting the future of marine natural products drug discovery and chemical biology. Chemistry & Biology 19: 85–98.

    CAS  Google Scholar 

  • Ghiaroni, V., M. Sasaki, H. Fuwa, G.P. Rossini, G. Scalera, T. Yasumoto, P. Pietra, and A. Bigiani. 2005. Inhibition of voltage-gated potassium currents by gambierol in mouse taste cells. Toxicological Sciences 85: 657–665.

    CAS  PubMed  Google Scholar 

  • Gillman, K.W., J.E. Starrett, M.F. Parker, K. Xie, J.J. Bronson, L.R. Marcin, K.E. McElhone, C.P. Bergstrom, R.A. Mate, R. Williams, J.E. Meredith, C.R. Burton, D.M. Barten, J.H. Toyn, S.B. Roberts, K.A. Lentz, J.G. Houston, R. Zaczek, C.F. Albright, C.P. Decicco, J.E. Macor, and R.E. Olson. 2010. Discovery and evaluation of BMS-708163, a potent, selective and orally bioavailable γ-secretase inhibitor. ACS Medicinal Chemistry Letters 1: 120–124.

  • Goldstein, L.B. 2007. Acute ischemic stroke treatment in 2007. Circulation 116: 1504–1514.

    PubMed  Google Scholar 

  • Gompel, M., M. Leost, E.B. De Kier Joffe, L. Puricelli, L.H. Franco, J. Puricelli, and L. Meijer. 2004. Meridianins, a new family of protein kinase inhibitors isolated from the ascidian Aplidium meridianum. Bioorganic & Medicinal Chemistry Letters 14: 1703–1707.

    CAS  Google Scholar 

  • Gordillo, D.A., I.D. Diaz, A.M. Gil, G.P. del Pliego, A.F. Huerta, M.J.P. Puerto, E.M. Aparicio, D.P. Navarro and M.M. Padilla. 2004. GSK-3 inhibitors isolated from marine organisms. WO 2005054221.

  • Green, K.N., H. Martinez-Coria, H. Khashwji, E.B. Hall, K.A. Yurko-Mauro, L. Ellis, and F.M. LaFerla. 2007. Dietary docosahexaenoic acid and docosapentaenoic acid ameliorate amyloid-beta and tau pathology via a mechanism involving presenilin 1 levels. Journal of Neuroscience 27: 4385–4395.

    CAS  PubMed  Google Scholar 

  • Guo, Y., A. Madaio, E. Trivellone, G. Scognamiglio, and G. Cimino. 1996. Further studies of alkaloids from Reniera sarai: Structures of saraine-3 and isosaraine-3, absolute stereochemistry of saraine-1 and saraine-2. Tetrahedron 52: 14961–14974.

    CAS  Google Scholar 

  • Guo, Y., E. Trivellone, G. Scognamiglio, and G. Cimino. 1998. Absolute stereochemistry of isosaraine-1 and isosaraine-2. Tetrahedron Letters 39: 463–466.

    CAS  Google Scholar 

  • Gupta-Bansal, R., R.C. Frederickson, and K.R. Brunden. 1995. Proteoglycan-mediated inhibition of A beta proteolysis. A potential cause of senile plaque accumulation. Journal of Biological Chemistry 270: 18666–18671.

    CAS  PubMed  Google Scholar 

  • Hamann, M., A. Alonso, E. Martin-Aparicio, and A. Fuertes. 2007. Pérez-Puerto, M.J., Castro, A., Morales, S., Navarro, M.L., del Monte-Millán, M., Medina, M., Pennaka, H., Balaiah, A., Peng, J., Cook, J., Wahyuono, S., and Martínez, A., Glycogen synthasekinase-3 (GSK-3) inhibitory activity and structure-activity relationship (SAR) studies of themanzamine alkaloids. Potential for Alzheimer’s disease. Journal of Natural Products 70: 1397–1405.

    CAS  PubMed  Google Scholar 

  • Hamill, R.L., C.E. Higgens, H.E. Boaz, and M. Gorman. 1969. The structure of beauvericin, a new depsipeptide antibiotic toxic to Artemia salina. Tetrahedron Letters 49: 4255–4258.

    CAS  Google Scholar 

  • Hanger, D.P., B.H. Anderton, and W. Noble. 2009. Tau phosphorylation: The therapeutic challenge for neurodegenerative disease. Trends in Molecular Medicine 15: 112–119.

    CAS  PubMed  Google Scholar 

  • Harada, M., S. Yano, H. Watanabe, M. Yamazaki, and K. Miyaki. 1974. Phlogistic activity of secalonic acid A. Chemical & Pharmaceutical Bulletin 22: 1600–1606.

    CAS  Google Scholar 

  • Hennings, H., P.M. Blumberg, G.R. Pettit, C.L. Herald, R. Shores, and S.H. Yuspa. 1987. Bryostatin 1, an activator of protein kinase C, inhibits tumor promotion by phorbol esters in SENCAR mouse skin. Carcinogenesis 8: 1343–1346.

    CAS  PubMed  Google Scholar 

  • Hernandez, F., E.Gomez De Barreda, A. Fuster-Matanzo, J.J. Lucas, and J. Avila. 2010. GSK3: A possible link between beta amyloid peptide and tau protein. Experimental Neurology 223: 322–325.

    CAS  PubMed  Google Scholar 

  • Holst, P.B., U. Anthoni, C. Christophersen, and P.H. Nielsen. 1994. Marine alkaloids, 15. Two alkaloids, flustramine E and debromoflustramine B, from the marine bryozoan Flustra foliacea. Journal of Natural Products 57: 997–1000.

    CAS  PubMed  Google Scholar 

  • Hondares, E., M. Rosell, J. Diaz-Delfin, Y. Olmos, M. Monsalve, R. Iglesias, F. Villarroya, and M. Giralt. 2011. Peroxisome proliferator-activated receptor alpha (PPARalpha) induces PPARgamma coactivator 1alpha (PGC-1alpha) gene expression and contributes to thermogenic activation of brown fat: Involvement of PRDM16. Journal of Biological Chemistry 286: 43112–43122.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Huse, J.T., D. Byant, Y. Yang, D.S. Pijak, I. D’souza, J.J. Lah, V.M. Lee, R.W. Doms, and D.G. Cook. 2003. Endoproteolysis of beta-secretase (beta-site amyloid precursor protein-cleaving enzyme) within its catalytic domain. A potential mechanism for regulation. Journal of Biological Chemistry 278: 17141–17149.

    CAS  PubMed  Google Scholar 

  • Ibanez, C.F. 1995. Neurotrophic factors: From structure-function studies to designing effective therapeutics. Trends in Biotechnology 13: 217–227.

    CAS  PubMed  Google Scholar 

  • Jacobsen, J.S., C.C. Wu, J.M. Redwine, T.A. Comery, R. Arias, M. Bowlby, R. Martone, J.H. Morrison, M.N. Pangalos, P.H. Reinhart, and F.E. Bloom. 2006. Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer’s disease. Proceedings of the National Academy of Sciences of the United States of America 103: 5161–5166.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Jiang, N., E.A. Kowaluk, C.H. Lee, H. Mazdiyasni, and M. Chopp. 1997. Adenosine kinase inhibition protects brain against transient focal ischemia in rats. European Journal of Pharmacology 320: 131–137.

    CAS  PubMed  Google Scholar 

  • Jin, A.H., H. Brandstaetter, S.T. Nevin, C.C. Tan, R.J. Clark, D.J. Adams, P.F. Alewood, D.J. Craik, and N.L. Daly. 2007. Structure of α-conotoxin BuIA: Influences of disulfide connectivity on structural dynamics. BMC Structural Biology 7: 28.

    PubMed Central  PubMed  Google Scholar 

  • Kajimura, Y., T. Aoki, K. Kuramochi, S. Kobayashi, F. Sugawara, N. Watanabe, and T. Arai. 2008. Neoechinulin A protects PC12 cells against MPP+-induced cytotoxicity. Journal of Antibiotics 61: 330–333.

    CAS  PubMed  Google Scholar 

  • Kang, H., and W. Fenical. 1997. Ningalins A-D: Novel aromatic alkaloids from a Western Australian ascidian of the genus Didemnum. The Journal of Organic Chemistry 62: 3254–3262.

  • Kawahara, T., M. Takagi, and K. Shin-ya. 2012. JBIR-124: A novel antioxidative agent from a marine sponge-derived fungus Penicillium citrinum SpI080624G1f01. Journal of Antibiotics 65: 45–47.

    CAS  PubMed  Google Scholar 

  • Kem, W.R., and B.C. Abbott. 1971. Isolation and structure of a hoplonemertine toxin. Toxicon 9: 15–22.

    CAS  PubMed  Google Scholar 

  • Kem, W.R., V.M. Mahnir, R.L. Papke, and C.J. Lingle. 1997. Anabaseine is a potent agonist on muscle and neuronal alpha-bungarotoxin-sensitive nicotinic receptors. Journal of Pharmacology and Experimental Therapeutics 283: 979–992.

    CAS  PubMed  Google Scholar 

  • Khanfar, M.A., B.A. Asal, M. Mudit, A. Kaddoumi, and K.A. El Sayed. 2009. The marine natural-derived inhibitors of glycogen synthase kinase-3b phenylmethylene hydantoins: In vitro and in vivo activities and pharmacophore modeling. Bioorganic & Medicinal Chemistry 17: 6032–6039.

    CAS  Google Scholar 

  • Kharbanda, K.K., M.E. Mailliard, C.R. Baldwin, H.C. Beckenhauer, M.F. Sorrell, and D.J. Tuma. 2007. Betaine attenuates alcoholic steatosis by restoring phosphatidylcholine generation via the phosphatidylethanolamine methyltransferase pathway. Journal of Hepatology 46: 314–321.

    CAS  PubMed  Google Scholar 

  • Kharrat, R., D. Servent, E. Girard, G. Ouanounou, M. Amar, R. Marrouchi, E. Benoit, and J. Molgo. 2008. The marine phycotoxin gymnodimine targets muscular and neuronal nicotinic acetylcholine receptor subtypes with high affinity. Journal of Neurochemistry 107: 952–963.

    CAS  PubMed  Google Scholar 

  • Kihara, T., S. Shimohama, M. Urushitani, H. Sawada, J. Kimura, T. Kume, T. Maeda, and A. Akaike. 1998. Stimulation of alpha4beta2 nicotinic acetylcholine receptors inhibits beta-amyloid toxicity. Brain Research 792: 331–334.

    CAS  PubMed  Google Scholar 

  • Kimoto, K., T. Aoki, Y. Shibata, S. Kamisuki, F. Sugawara, K. Kuramochi, A. Nakazaki, S. Kobayashi, K. Kuroiwa, N. Watanabe, and T. Arai. 2007. Structure-activity relationships of neoechinulin A analogues with cytoprotection against peroxynitrite-induced PC12 cell death. Journal of Antibiotics 60: 614–621.

    CAS  PubMed  Google Scholar 

  • Kimura, Y., A. Shimada, H. Nakajima, and T. Hamasaki. 1988. Structures of naphthoquinones produced by the fungus, Fusarium sp., and their biological activity toward pollen germination. Agricultural and Biological Chemistry 52: 1253–1259.

    CAS  Google Scholar 

  • Klein, W.L., G.A. Krafft, and C.E. Finch. 2001. Targeting small Abeta oligomers: The solution to an Alzheimer’s disease conundrum? Trends in Neurosciences 24: 219–224.

    CAS  PubMed  Google Scholar 

  • Kolarova, M., F. Garcia-Sierra, A. Bartos, J. Ricny, and D. Ripova. 2012. Structure and pathology of tau protein in Alzheimer disease. International Journal of Alzheimer’s Disease 2012: 731526.

    PubMed Central  PubMed  Google Scholar 

  • Kowaluk, E.A., and M.F. Jarvis. 2000. Therapeutic potential of adenosine kinase inhibitors. Expert Opinion on Investigational Drugs 9: 551–564.

    CAS  PubMed  Google Scholar 

  • Kreft, A.F., R. Martone, and A. Porte. 2009. Recent advances in the identification of gamma-secretase inhibitors to clinically test the Abeta oligomer hypothesis of Alzheimer’s disease. Journal of Medicinal Chemistry 52: 6169–6188.

    CAS  PubMed  Google Scholar 

  • Kristipati, R., L. Nadasdi, K. Tarczy-Hornoch, K. Lau, G.P. Miljanich, J. Ramachandran, and J. Bell. 1994. Characterization of the binding of omega-conopeptides to different classes of non-L-type neuronal calcium channels. Molecular and Cellular Neuroscience 5: 219–228.

    CAS  PubMed  Google Scholar 

  • Kruger, R., W. Kuhn, T. Muller, D. Woitalla, M. Graeber, S. Kosel, H. Przuntek, J.T. Epplen, L. Schols, and O. Riess. 1998. Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nature Genetics 18: 106–108.

    CAS  PubMed  Google Scholar 

  • Kubota, T., Y. Ishiguro, S. Yamamoto, J. Fromont, and J. Kobayashi. 2010. Platisidines A-C, N-methylpyridinium alkaloids from an Okinawan marine sponge of Plakortis species. Heterocycles 80: 1407–1412.

    CAS  Google Scholar 

  • Kurobane, I., S. Iwahashi, and A. Fukuda. 1987. Cytostatic activity of naturally isolated isomers of secalonic acids and their chemically rearranged dimers. Drugs Under Experimental and Clinical Research 13: 339–344.

    CAS  PubMed  Google Scholar 

  • Kusumi, T., Y. Shibata, M. Ishitsuka, T. Kinoshita, and H. Kakisawa. 1979. Structures of new plastoquinones from the brown alga Sargassum serratifolium. Chemistry Letters 3: 277–278.

    Google Scholar 

  • Lacor, P.N., M.C. Buniel, P.W. Furlow, A.S. Clemente, P.T. Velasco, M. Wood, K.L. Viola, and W.L. Klein. 2007. Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer’s disease. Journal of Neuroscience 27: 796–807.

    CAS  PubMed  Google Scholar 

  • Lam, A.P., J.A. Sparano, V. Vinciguerra, A.J. Ocean, P. Christos, H. Hochster, F. Camacho, S. Goel, S. Mani, and A. Kaubisch. 2010. Phase II study of paclitaxel plus the protein kinase C inhibitor bryostatin-1 in advanced pancreatic carcinoma. American Journal of Clinical Oncology 33: 121–124.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Langjae, R., S. Bussarawit, S. Yuenyongsawad, K. Ingkaninan, and A. Plubrukarn. 2007. Acetylcholinesterase-inhibiting steroidal alkaloid from the sponge Corticium sp. Steroids 72: 682–685.

    CAS  PubMed  Google Scholar 

  • Lansbury Jr, P.T. 2004. Back to the future: The ‘old-fashioned’ way to new medications for neurodegeneration. Nature Medicine 10(Suppl): S51–S57.

    PubMed  Google Scholar 

  • Lanz, T.A., K.M. Wood, K.E. Richter, C.E. Nolan, S.L. Becker, N. Pozdnyakov, B.A. Martin, P. Du, C.E. Oborski, D.E. Wood, T.M. Brown, J.E. Finley, S.A. Sokolowski, C.D. Hicks, K.J. Coffman, K.F. Geoghegan, M.A. Brodney, D. Liston, and B. Tate. 2010. Pharmacodynamics and pharmacokinetics of the gamma-secretase inhibitor PF-3084014. Journal of Pharmacology and Experimental Therapeutics 334: 269–277.

    CAS  PubMed  Google Scholar 

  • Lashuel, H.A., C.R. Overk, A. Oueslati, and E. Masliah. 2013. The many faces of alpha-synuclein: From structure and toxicity to therapeutic target. Nature Reviews Neuroscience 14: 38–48.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lebar, M.D., and B.J. Baker. 2010. Synthesis and structure reassessment of psammopemmin A. Australian Journal of Chemistry 63: 862–866.

    CAS  Google Scholar 

  • Lee, H.K., P. Kumar, Q. Fu, K.M. Rosen, and H.W. Querfurth. 2009. The insulin/Akt signaling pathway is targeted by intracellular beta-amyloid. Molecular Biology of the Cell 20: 1533–1544.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Leirós, M., J.A. Sánchez, E. Alonso, M.E. Rateb, W.E. Houssen, R. Ebel, M. Jaspars, A. Alfonso, and L.M. Botana. 2014. Spongionella secondary metabolites protect mitochondrial function in cortical neurons against oxidative stress. Marine Drugs 12: 700–718.

    PubMed Central  PubMed  Google Scholar 

  • Leng, T., Y. Shi, Z.G. Xiong, and D. Sun. 2014. Proton-sensitive cation channels and ion exchangers in ischemic brain injury: New therapeutic targets for stroke? Progress in Neurobiology 115: 189–209.

    CAS  PubMed  Google Scholar 

  • Lewis, R.J., K.J. Nielsen, D.J. Craik, M.L. Loughnan, D.A. Adams, I.A. Sharpe, T. Luchian, D.J. Adams, T. Bond, L. Thomas, A. Jones, J.L. Matheson, R. Drinkwater, P.R. Andrews, and P.F. Alewood. 2000. Novel omega-conotoxins from Conus catus discriminate among neuronal calcium channel subtypes. Journal of Biological Chemistry 275: 35335–35344.

    CAS  PubMed  Google Scholar 

  • Li, Y., X. Li, J.S. Kang, H.D. Choi, and B.W. Son. 2004. New radical scavenging and ultraviolet-A protecting prenylated dioxopiperazine alkaloid related to isoechinulin A from a marine isolate of the fungus Aspergillus. Journal of Antibiotics 57: 337–340.

    CAS  PubMed  Google Scholar 

  • Li, Y., W. Zhou, Y. Tong, G. He, and W. Song. 2006. Control of APP processing and Abeta generation level by BACE1 enzymatic activity and transcription. FASEB J. 20: 285–292.

    PubMed  Google Scholar 

  • Li, Y., Z.J. Qian, and S.K. Kim. 2008. Cathepsin B inhibitory activities of three new phthalate derivatives isolated from seahorse, Hippocampus Kuda Bleeler. Bioorganic & Medicinal Chemistry Letters 18: 6130–6134.

    CAS  Google Scholar 

  • Li, Z.X., J.-W. Chen, F. Yuan, Y.-Y. Huang, L.-Y. Zhao, J. Li, H.-X. Su, J. Liu, J.-Y. Pang, Y.-C. Lin, X.-L. Lu, Z. Pei, G.-L. Wang, and Y.-Y. Guan. 2013. Xyloketal B exhibits its antioxidant activity through induction of HO-1 in vascular endothelial cells and zebrafish. Marine Drugs 11: 504–522.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lim, G.P., F. Calon, T. Morihara, F. Yang, B. Teter, O. Ubeda, N. Salem Jr, S.A. Frautschy, and G.M. Cole. 2005. A diet enriched with the omega-3 fatty acid docosahexaenoic acid reduces amyloid burden in an aged Alzheimer mouse model. Journal of Neuroscience 25: 3032–3040.

    CAS  PubMed  Google Scholar 

  • Lin, L.F., D.H. Doherty, J.D. Lile, S. Bektesh, and F. Collins. 1993. GDNF: A glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science 260: 1130–1132.

    CAS  PubMed  Google Scholar 

  • Lin, Y., X. Wu, S. Feng, G. Jiang, J. Luo, S. Zhou, L.L.P. Vrijmoed, E.B.G. Jones, K. Krohn, K. Steingroever, and F. Zsila. 2001. Five unique compounds: Xyloketals from mangrove fungus Xylaria sp. from the South China Sea coast. Journal of Organic Chemistry 66: 6252–6256.

    CAS  PubMed  Google Scholar 

  • Lipton, P. 1999. Ischemic cell death in brain neurons. Physiological Reviews 79: 1431–1568.

  • Liu, X.-P., X. Qian, Y. Xie, Y. Qi, M.-F. Peng, B.-C. Zhan, and Z.-Q. Lou. 2014. Betaine suppressed Aβ generation by altering amyloid precursor protein processing. Neurological Sciences 35: 1009–1013.

    CAS  PubMed  Google Scholar 

  • Liu, Y., W. Zhang, L. Li, L.A. Salvador, T. Chen, W. Chen, K.M. Felsenstein, T.B. Ladd, A.R. Price, T.E. Golde, J. He, Y. Xu, Y. Li, and H. Luesch. 2012. Cyanobacterial peptides as a prototype for the design of potent β-secretase inhibitors and the development of selective chemical probes for other aspartic proteases. Journal of Medicinal Chemistry 55: 10749–10765.

    CAS  PubMed  Google Scholar 

  • Lobello, K., J.M. Ryan, E. Liu, G. Rippon, and R. Black. 2012. Targeting Beta amyloid: A clinical review of immunotherapeutic approaches in Alzheimer’s disease. International Journal of Alzheimer’s Disease 2012: 628070.

    PubMed Central  PubMed  Google Scholar 

  • Longo, F.M., and S.M. Massa. 2013. Small-molecule modulation of neurotrophin receptors: A strategy for the treatment of neurological disease. Nature Review Drug Discovery 12: 507–525.

    Google Scholar 

  • López, A.M., J.J.G. Rodriguez, A.S. Mirón, F.G. Camacho, and E.M. Grima. 2011. Immunoregulatory potential of marine algal toxins yessotoxin and okadaic acid in mouse T lymphocyte cell line EL-4. Toxicology Letters 207: 167–172.

    PubMed  Google Scholar 

  • Lu, X.L., X.-L. Yao, Z.-Y. Liu, H. Zhang, W. Li, Z.-X. Li, G.-L. Wang, J.-Y. Pang, Y.-C. Lin, Z. Xu, L. Chen, Z. Pei, and J. Zenq. 2010. Protective effects of xyloketal B against MPP + -induced neurotoxicity in Caenorhabditis elegans and PC12 cells. Brain Research 1332: 110–119.

    CAS  PubMed  Google Scholar 

  • Luibrand, R.T., T.R. Erdman, J.J. Vollmer, P.J. Scheuer, J. Finer, and J. Clardy. 1979. Ilimaquinone, a sesquiterpenoid quinone from a marine sponge. Tetrahedron 35: 609–612.

    CAS  Google Scholar 

  • Lukiw, W.J., J.G. Cui, V.L. Marcheselli, M. Bodker, A. Botkjaer, K. Gotlinger, C.N. Serhan, and N.G. Bazan. 2005. A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease. The Journal of Clinical Investigation 115: 2774–2783.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lynch, S.S., C.M. Cheng, and J.L. Yee. 2006. Intrathecal ziconotide for refractory chronic pain. Annals of Pharmacotherapy 40: 1293–1300.

    CAS  PubMed  Google Scholar 

  • Maries, E., B. Dass, T.J. Collier, J.H. Kordower, and K. Steece-Collier. 2003. The role of alpha-synuclein in Parkinson’s disease: Insights from animal models. Nature Reviews Neuroscience 4: 727–738.

    CAS  PubMed  Google Scholar 

  • Marrouchi, R., G. Rome, R. Kharrat, J. Molgó, and E. Benoit. 2013. Analysis of the action of gymnodimine-A and 13-desmethyl spirolide C on the mouse neuromuscular system in vivo. Toxicon 75: 27–34.

    CAS  PubMed  Google Scholar 

  • Martin, E.J., K.S. Panikar, M.A. King, M. Deyrup, B. Hunter, G. Wang, and E. Meyer. 1994. Cytoprotective actions of 2,4-dimethoxybenzylidene anabaseine in differentiated PC12 cells and septal cholinergic cells. Drug Development Research 31: 134–141.

    Google Scholar 

  • Martinez, A. 2007. Marine-derived drugs in neurology. Current Opinion in Investigational Drugs 8: 525–530.

    CAS  PubMed  Google Scholar 

  • Martins, A., H. Vieira, H. Gaspar, and S. Santos. 2014. Marketed marine natural products in the pharmaceutical and cosmeceutical industries: Tips for success. Marine Drugs 12: 1066–1101.

  • Masliah, E., E. Rockenstein, I. Veinbergs, M. Mallory, M. Hashimoto, A. Takeda, Y. Sagara, A. Sisk, and L. Mucke. 2000. Dopaminergic loss and inclusion body formation in alpha-synuclein mice: Implications for neurodegenerative disorders. Science 287: 1265–1269.

    CAS  PubMed  Google Scholar 

  • May, P.C., R.A. Dean, S.L. Lowe, F. Martenyi, S.M. Sheehan, L.N. Boggs, S.A. Monk, B.M. Mathes, D.J. Mergott, B.M. Watson, S.L. Stout, and D.E. Timm. 2011. Smith Labell, E., Gonzales, C.R., Nakano, M., Jhee, S.S., Yen, M., Ereshefsky, L., Lindstrom, T.D., Calligaro, D.O., Cocke, P.J., Greg Hall, D., Friedrich, S., Citron, M., and Audia, J.E., Robust central reduction of amyloid-beta in humans with an orally available, non-peptidic beta-secretase inhibitor. Journal of Neuroscience 31: 16507–16516.

    CAS  PubMed  Google Scholar 

  • Mayer, S.C., A.F. Kreft, B. Harrison, M. Abou-Gharbia, M. Antane, S. Aschmies, K. Atchison, M. Chlenov, D.C. Cole, T. Comery, G. Diamantidis, J. Ellingboe, K. Fan, R. Galante, C. Gonzales, D.M. Ho, M.E. Hoke, Y. Hu, D. Huryn, U. Jain, M. Jin, K. Kremer, D. Kubrak, M. Lin, P. Lu, R. Magolda, R. Martone, W. Moore, A. Oganesian, M.N. Pangalos, A. Porte, P. Reinhart, L. Resnick, D.R. Riddell, J. Sonnenberg-Reines, J.R. Stock, S.C. Sun, E. Wagner, T. Wang, K. Woller, Z. Xu, M.M. Zaleska, J. Zeldis, M. Zhang, H. Zhou, and J.S. Jacobsen. 2008. Discovery of begacestat, a Notch-1-sparing gamma-secretase inhibitor for the treatment of Alzheimer’s disease. Journal of Medicinal Chemistry 51: 7348–7351.

    CAS  PubMed  Google Scholar 

  • Mcgill, J.K., and M.F. Beal. 2006. PGC-1alpha, a new therapeutic target in Huntington’s disease? Cell 127: 465–468.

    CAS  PubMed  Google Scholar 

  • McIntosh, J.M., B.M. Olivera, L.J. Cruz, and W.R. Gray. 1984. Gamma-carboxyglutamate in a neuroactive toxin. Journal of Biological Chemistry 259: 14343–14346.

    CAS  PubMed  Google Scholar 

  • Mclean, C.A., R.A. Cherny, F.W. Fraser, S.J. Fuller, M.J. Smith, K. Beyreuther, A.I. Bush, and C.L. Masters. 1999. Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer’s disease. Annals of Neurology 46: 860–866.

    CAS  PubMed  Google Scholar 

  • Mehta, M., A. Adem, and M. Sabbagh. 2012. New acetylcholinesterase inhibitors for Alzheimer’s disease. International Journal of Alzheimer’s Disease 2012: 728983.

    PubMed Central  PubMed  Google Scholar 

  • Meijer, L., A.M.W.H. Thunnissen, A.W. White, M. Garnier, M. Nikolic, L.H. Tsai, J. Walter, K.E. Cleverley, P.C. Salinas, Y.Z. Wu, J. Biernat, E.M. Mandelkow, S.H. Kim, and G.R. Pettit. 2000. Inhibition of cyclin-dependent kinases, GSK-3β and CK1 by hymenialdisine, a marine sponge constituent. Chemistry & Biology 7: 51–63.

  • Meijer, L., A.L. Skaltsounis, P. Magiatis, P. Polychronopoulos, M. Knockaert, M. Leost, X.P. Ryan, C.A. Vonica, A. Brivanlou, R. Dajani, C. Crovace, C. Tarricone, A. Musacchio, S.M. Roe, L. Pearl, and P. Greengard. 2003. GSK-3-selective inhibitors derived from tyrian purple indirubins. Chemistry & Biology 10: 1255–1266.

    CAS  Google Scholar 

  • Mena, M.A., M.J. Casarejos, R. Solano, J.A. Rodríguez-Navarro, A. Gómez, I. Rodal, M. Medina, and J.G. De Yebenes. 2009. NP7 protects from cell death induced by oxidative stress in neuronal and glial midbrain cultures from parkin null mice. FEBS Letters 583: 168–174.

    CAS  PubMed  Google Scholar 

  • Meyer, E.M., M.A. King, and C. Meyers. 1998a. Neuroprotective effects of 2,4-dimethoxybenzylidene anabaseine (DMXB) and tetrahydroaminoacridine (THA) in neocortices of nucleus basalis lesioned rats. Brain Research 786: 152–154.

    Google Scholar 

  • Meyer, E., A. Kuryatov, V. Gerzanich, J. Lindstrom, and R.L. Papke. 1998b. Analysis of 4OH-GTS-21 selectivity and activity at human and rat α7 nicotinic receptors. Journal of Pharmacology and Experimental Therapeutics 287: 918–925.

    CAS  PubMed  Google Scholar 

  • Miles, C.O., A.L. Wilkins, A.D. Hawkes, A.I. Selwood, D.J. Jensen, R. Munday, J.M. Cooney, and V. Beuzenberg. 2005. Polyhydroxylated amide analogs of yessotoxin from Protoceratium reticulatum. Toxicon 45: 61–71.

    CAS  PubMed  Google Scholar 

  • Millán-Aguiñaga, N., I.E. Soria-Mercado, and P. Williams. 2010. Xestosaprol D and E from the Indonesian marine sponge Xestospongia sp. Tetrahedron Letters 51: 751–753.

    Google Scholar 

  • Miller, L.P., L.A. Jelovich, L. Yao, J. Dare, B. Ugarkar, and A.C. Foster. 1996. Pre- and peristroke treatment with the adenosine kinase inhibitor, 5′-deoxyiodotubercidin, significantly reduces infarct volume after temporary occlusion of the middle cerebral artery in rats. Neuroscience Letters 220: 73–76.

    CAS  PubMed  Google Scholar 

  • Miyasawa, K., K. Ito, and F. Matsumoto. 1970. Occurrence of (+)-2-hydroxy-3-aminopropanesulfonic acid and 3-aminopropanesulfonic acid in a red alga, Grateloupia livida. Nippon Suisan Gakkaishi 36: 109–114.

    Google Scholar 

  • Mocchetti, I., and M. Brown. 2008. Targeting neurotrophin receptors in the central nervous system. CNS & Neurological Disorders: Drug Targets 7: 71–82.

    CAS  Google Scholar 

  • Mohamed, G.A., S.R.M. Ibrahim, J.M. Badr, and D.T.A. Youssef. 2014. Didemnaketals D and E, bioactive terpenoids from a Red Sea ascidian Didemnum species. Tetrahedron 70: 35–40.

    CAS  Google Scholar 

  • Molinski, T.F., E. Fahy, D.J. Faulkner, G.D. Van Duyne, and J. Clardy. 1988. Petrosamine, a novel pigment from the marine sponge Petrosia sp. Journal of Organic Chemistry 53: 1340–1341.

    CAS  Google Scholar 

  • Morgan, D., D.M. Diamond, P.E. Gottschall, K.E. Ugen, C. Dickey, J. Hardy, K. Duff, P. Jantzen, G. Dicarlo, D. Wilcock, K. Connor, J. Hatcher, C. Hope, M. Gordon, and G.W. Arendash. 2000. A beta peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease. Nature 408: 982–985.

    CAS  PubMed  Google Scholar 

  • Mortari, M.R., A.O.S. Cunha, L.B. Ferreira, and W.F. dos Santos. 2007. Neurotoxins from invertebrates as anticonvulsants: From basic research to therapeutic application. Pharmacology & Therapeutics 114: 171–183.

    CAS  Google Scholar 

  • Mount, H.T., D.O. Dean, J. Alberch, C.F. Dreyfus, and I.B. Black. 1995. Glial cell line-derived neurotrophic factor promotes the survival and morphologic differentiation of Purkinje cells. Proceedings of the National Academy of Sciences of the United States of America 92: 9092–9096.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Mudit, M., M. Khanfar, A. Muralidharan, S. Thomas, G.V. Shah, R.W.M. van Soest, and K.A. El Sayed. 2009. Discovery, design, and synthesis of anti-metastatic lead phenylmethylene hydantoins inspired by marine natural products. Bioorganic & Medicinal Chemistry 17: 1731–1738.

    CAS  Google Scholar 

  • Mutter, R., and M. Wills. 2000. Chemistry and clinical biology of the bryostatins. Bioorganic & Medicinal Chemistry 8: 1841–1860.

    CAS  Google Scholar 

  • Nedergaard, M., R.P. Kraig, J. Tanabe, and W.A. Pulsinelli. 1991. Dynamics of interstitial and intracellular pH in evolving brain infarct. American Journal of Physiology 260: R581–R588.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Newman, D.J., and G.M. Cragg. 2004. Advanced preclinical and clinical trials of natural products and related compounds from marine sources. Current Medicinal Chemistry 11: 1693–1713.

    CAS  PubMed  Google Scholar 

  • Newman, D.J., and G.M. Cragg. 2014. Marine-sourced anti-cancer and cancer pain control agents in clinical and late preclinical development. Marine Drugs 12: 255–278.

    PubMed Central  PubMed  Google Scholar 

  • Nicholls, D., and D. Attwell. 1990. The release and uptake of excitatory amino acids. Trends in Pharmacological Sciences 11: 462–468.

  • Nozawa, Y., N. Sakai, K. Matsumoto, and K. Mizoue. 2002. A novel neuritogenic compound, NGA0187. Journal of Antibiotics 55: 629–634.

    CAS  PubMed  Google Scholar 

  • Nukoolkarn, V.S., S. Saen-oon, T. Rungrotmongkol, S. Hannongbua, K. Ingkaninan, and K. Suwanborirux. 2008. Petrosamine, a potent anticholinesterase pyridoacridine alkaloid from a Thai marine sponge Petrosia n. sp. Bioorganic & Medicinal Chemistry 16: 6560–6567.

    CAS  Google Scholar 

  • Nyyssola, A., J. Kerovuo, P. Kaukinen, N. von Weymarn, and T. Reinikainen. 2000. Extreme halophiles synthesize betaine from glycine by methylation. Journal of Biological Chemistry 275: 22196–22201.

    CAS  PubMed  Google Scholar 

  • Okada, Y., A. Ishimaru, R. Suzuki, and T. Okuyama. 2004. A new phloroglucinol derivative from the brown alga Eisenia bicylis: Potential for the effective treatment of diabetic complications. Journal of Natural Products 67: 103–105.

    CAS  PubMed  Google Scholar 

  • Olivera, B.M., L.J. Cruz, V. de Santos, G.W. LeCheminant, D. Griffin, R. Zeikus, J.M. McIntosh, R. Galyean, J. Varga, W.R. Gray, and J. Rivier. 1987. Neuronal calcium channel antagonists. Discrimination between calcium channel subtypes using ω-conotoxin from Conus magus venom. Biochemistry 26: 2086–2090.

    CAS  PubMed  Google Scholar 

  • Orhan, I.E., B. Ozcelik, B. Konuklugil, A. Putz, U.G. Kaban, and P. Proksch. 2012. Bioactivity screening of the selected Turkish marine sponges and three compounds from Agelas oroides. Records of Natural Products 6: 356–367.

    Google Scholar 

  • Pacelli, C., D. De Rasmo, A. Signorile, I. Grattagliano, G. Di Tullio, A. D’orazio, B. Nico, G.P. Comi, D. Ronchi, E. Ferranini, D. Pirolo, P. Seibel, S. Schubert, A. Gaballo, G. Villani, and T. Cocco. 2011. Mitochondrial defect and PGC-1alpha dysfunction in parkin-associated familial Parkinson’s disease. Biochimica et Biophysica Acta 1812: 1041–1053.

    CAS  PubMed  Google Scholar 

  • Pangestuti, R., B. Ryu, S.W.A. Himaya, and S.K. Kim. 2013. Optimization of hydrolysis conditions, isolation, and identification of neuroprotective peptides derived from seahorse Hippocampus trimaculatus. Amino Acids 45: 369–381.

    CAS  PubMed  Google Scholar 

  • Papke, R.L., E.M. Meyer, S. Lavieri, S.R. Bollampally, T.A. Papke, N.A. Horenstein, Y. Itoh, and J.K. Porter Papke. 2004. Effects at a distance in α7 nAChR selective agonists: Benzylidene substitutions that regulate potency and efficacy. Neuropharmacology 46: 1023–1038.

    CAS  PubMed  Google Scholar 

  • Paz, B., P. Riobo, M.L. Fernandez, S. Fraga, and J.M. Franco. 2004. Production and release of yessotoxins by the dinoflagellates Protoceratium reticulatum and Lingulodinium polyedrum in culture. Toxicon 44: 251–258.

    CAS  PubMed  Google Scholar 

  • Perry, N.B., L. Ettouati, M. Litaudon, J.W. Blunt, M.H.G. Munro, S. Parkin, and H. Hope. 1994. Alkaloids from the Antarctic sponge Kirkpatrickia varialosa. Part 1: Variolin B, a new antitumour and antiviral compound. Tetrahedron 50: 3987–3992.

    CAS  Google Scholar 

  • Pettit, G.R., C.L. Herald, D.L. Doubek, D.L. Herald, E. Arnold, and J. Clardy. 1982. Isolation and structure of bryostatin 1. Journal of the American Chemical Society 104: 6846–6848.

    CAS  Google Scholar 

  • Pignataro, G., R.P. Simon, and D. Boison. 2007. Transgenic overexpression of adenosine kinase aggravates cell death in ischemia. Journal of Cerebral Blood Flow and Metabolism 27: 1–5.

    CAS  PubMed  Google Scholar 

  • Pignataro, G., S. Maysami, F.E. Studer, A. Wilz, R.P. Simon, and D. Boison. 2008. Downregulation of hippocampal adenosine kinase after focal ischemia as potential endogenous neuroprotective mechanism. Journal of Cerebral Blood Flow and Metabolism 28: 17–23.

    CAS  PubMed  Google Scholar 

  • Plisson, F., M. Conte, Z. Khalil, X.-C. Huang, A.M. Piggott, and R.J. Capon. 2012. Kinase inhibitor scaffolds against neurodegenerative diseases from a Southern Australian ascidian, Didemnum sp. ChemMedChem 7: 983–990.

  • Polymeropoulos, M.H., C. Lavedan, E. Leroy, S.E. Ide, A. Dehejia, A. Dutra, B. Pike, H. Root, J. Rubenstein, R. Boyer, E.S. Stenroos, S. Chandrasekharappa, A. Athanassiadou, T. Papapetropoulos, W.G. Johnson, A.M. Lazzarini, R.C. Duvoisin, G. Di Iorio, L.I. Golbe, and R.L. Nussbaum. 1997. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276: 2045–2047.

    CAS  PubMed  Google Scholar 

  • Puyal, J., V. Ginet, and P.G. Clarke. 2013. Multiple interacting cell death mechanisms in the mediation of excitotoxicity and ischemic brain damage: A challenge for neuroprotection. Progress in Neurobiology 105: 24–48.

  • Quinn, J.F., R. Raman, R.G. Thomas, K. Yurko-Mauro, E.B. Nelson, C. Van Dyck, J.E. Galvin, J. Emond, C.R. Jack Jr, M. Weiner, L. Shinto, and P.S. Aisen. 2010. Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: A randomized trial. Journal of the American Medical Association 304: 1903–1911.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Radwan, M.A., and M. El-Sherbiny. 2007. Synthesis and antitumor activity of indolylpyrimidines: Marine natural product meridianin D analogues. Bioorganic & Medicinal Chemistry 15: 1206–1211.

    CAS  Google Scholar 

  • Ragan, M.A., and K.W. Glombitza. 1986. Phlorotannins, brown algal polyphenols. Progress in Phycological Research 4: 130–241.

    Google Scholar 

  • Rateb, M.E., W.E. Houssen, M. Schumacher, W.T. Harrison, M. Diederich, R. Ebel, and M. Jaspars. 2009. Bioactive diterpene derivatives from the marine sponge Spongionella sp. Journal of Natural Products 72: 1471–1476.

    CAS  PubMed  Google Scholar 

  • Rivera-Becerril, E., P. Joseph-Nathan, V.M. Perez-Alvarez, and M.S. Morales-Rıos. 2008. Synthesis and biological evaluation of (−)- and (+)-debromoflustramine B and its analogues as selective butyrylcholinesterase inhibitors. Journal of Medicinal Chemistry 51: 5271–5284.

    CAS  PubMed  Google Scholar 

  • Rodin, F.H. 1947. Eserine; its history in the practice of ophthalmology (physostigmine; Physostigma venenosum (Balfour); Calabar bean). American Journal of Ophthalmology 30: 19–28.

    CAS  PubMed  Google Scholar 

  • Roll, D.M., C.M. Ireland, H.S.M. Lu, and J. Clardy. 1988. Fascaplysin, an unusual antimicrobial pigment from the marine sponge Fascaplysinopsis sp. Journal of Organic Chemistry 53: 3276–3278.

    CAS  Google Scholar 

  • Ross, C.A., and M.A. Poirier. 2004. Protein aggregation and neurodegenerative disease. Nature Medicine 10(Suppl): S10–S17.

    PubMed  Google Scholar 

  • Ryu, B., and S.K. Kim. 2013. Potential beneficial effects of marine peptide on human neuron health. Current Protein and Peptide Science 14: 173–176.

    CAS  PubMed  Google Scholar 

  • Sakai, R., T. Higa, C.W. Jefford, and G. Bernardinelli. 1986. Manzamine A, a novel antitumor alkaloid from a sponge. Journal of the American Chemical Society 108: 6404–6405.

    CAS  Google Scholar 

  • Salem, N., B. Litman, H.Y. Kim, and K. Gawrisch. 2001. Mechanisms of action of docosahexaenoic acid in the nervous system. Lipids 36: 945–959.

    CAS  PubMed  Google Scholar 

  • Sangnoi, Y., O. Sakulkeo, S. Yuenyongsawad, A. Kanjana-opas, K. Ingkaninan, A. Plubrukarn, and K. Suwanborirux. 2008. Acetylcholinesterase-inhibiting activity of pyrrole derivatives from a novel marine gliding bacterium, Rapidithrix thailandica. Marine Drugs 6: 578–586.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Santacruz, K., J. Lewis, T. Spires, J. Paulson, L. Kotilinek, M. Ingelsson, A. Guimaraes, M. Deture, M. Ramsden, E. Mcgowan, C. Forster, M. Yue, J. Orne, C. Janus, A. Mariash, M. Kuskowski, B. Hyman, M. Hutton, and K.H. Ashe. 2005. Tau suppression in a neurodegenerative mouse model improves memory function. Science 309: 476–481.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Santos, H., P. Lamosa, T.Q. Faria, N. Borges, and C. Neves. 2007. The physiological role, biosynthesis and mode of action of compatible solutes from (hyper)thermophiles. In Physiology and biochemistry of extremophiles, ed. C. Gerday, and N. Glansdorff, 86–103. Washington: ASM Press.

    Google Scholar 

  • Satake, M., L. MacKenzie, and T. Yasumoto. 1997. Identification of Protoceratium reticulatum as the biogenetic origin of yessotoxin. Natural Toxins 5: 164–167.

    CAS  PubMed  Google Scholar 

  • Satake, M., M. Murata, and T. Yasumoto. 1993. Gambierol: A new toxic polyether compound isolated from the marine dinoflagellate Gambierdiscus toxicus. Journal of the American Chemical Society 115: 361–362.

    CAS  Google Scholar 

  • Schapira, A.H. 2011. Monoamine oxidase B inhibitors for the treatment of Parkinson’s disease: A review of symptomatic and potential disease-modifying effects. CNS drugs 25: 1061–1071.

    CAS  PubMed  Google Scholar 

  • Segraves, N.L., S.J. Robinson, D. Garcia, S.A. Said, X. Fu, F.J. Schmitz, H. Pietraszkiewicz, F.A. Valeriote, and P. Crews. 2004. Comparison of fascaplysin and related alkaloids: A study of structures, cytotoxicities, and sources. Journal of Natural Products 67: 783–792.

    CAS  PubMed  Google Scholar 

  • Seki, T., M. Satake, L. Mackenzie, H.F. Kaspar, and T. Yasumoto. 1995. Gymnodimine, a new marine toxin of unprecedented structure isolated from New Zealand oysters and the dinoflagellate Gymnodinium sp. Tetrahedron Letters 36: 7093–7096.

    Google Scholar 

  • Semenza, G.L. 2007. Life with oxygen. Science 318: 62–64.

    CAS  PubMed  Google Scholar 

  • Semenza, G.L., and G.L. Wang. 1992. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Molecular and Cellular Biology 12: 5447–5454.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sen, N.P. 1962. Synthesis and properties of homotaurine. Canadian Journal of Chemistry 40: 2189–2191.

    CAS  Google Scholar 

  • Serrano-Pozo, A., M.P. Frosch, E. Masliah, and B.T. Hyman. 2011. Neuropathological alterations in Alzheimer disease. Cold Spring Harbor Perspectives in Medicine 1: a006189.

    PubMed Central  PubMed  Google Scholar 

  • Shah, G.V., A. Muralidharan, S. Thomas, M. Gokulgandhi, M. Mudit, M. Khanfar, and K.A. El Sayed. 2009. Identification of a small molecule class to enhance cell–cell adhesion and attenuate prostate tumor growth and metastasis. Molecular Cancer Therapeutics 8: 509–520.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sharma, G.M., S.S. Buyer, and M.W. Pomerantz. 1980. Characterization of a yellow compound isolated from the marine sponge Phakellia flabellate. Journal of the Chemical Society, Chemical Communications 10: 435–436.

    Google Scholar 

  • Shiembob, D.L., R.L. Roberts, C.W. Luetje, and J.M. McIntosh. 2006. Determinants of α-conotoxin BuIA selectivity on the nicotinic acetylcholine receptor beta subunit. Biochemistry 45: 11200–11207.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Shimohama, S., D.L. Greenwald, D.H. Shafron, A. Akaike, T. Maeda, S. Kaneko, J. Kimura, C.E. Simpkins, A.L. Day, and E.M. Meyer. 1998. Nicotinic α7 receptors protect against glutamate neurotoxicity and neuronal ischemic damage. Brain Research 779: 359–363.

    CAS  PubMed  Google Scholar 

  • Shin, B.Y., D.H. Kim, S.K. Hyun, H.A. Jung, J.M. Kim, S.J. Park, S.Y. Kim, J.H. Cheong, J.S. Choi, and J.H. Ryu. 2010. Alaternin attenuates delayed neuronal cell death induced by transient cerebral hypoperfusion in mice. Food and Chemical Toxicology 48: 1528–1536.

    CAS  PubMed  Google Scholar 

  • Shindo, K., K. Kikuta, A. Suzuki, A. Katsuta, H. Kasai, M. Yasumoto-Hirose, Y. Matsuo, N. Misawa, and S. Takaichi. 2007. Rare carotenoids (3R)-saproxanthin and (3R,2′S)-myxol, isolated from novel marine bacteria (Flavobacteriaceae) and their antioxidative activities. Applied Microbiology and Biotechnology 74: 1350–1357.

    CAS  PubMed  Google Scholar 

  • Siesjö, B.K. 1992. Pathophysiology and treatment of focal cerebral ischemia. Part I: Pathophysiology. Journal of Neurosurgery 77: 169–184.

  • Simone, M., E. Erba, G. Damia, F. Vikhanskaya, A.M. Di Francesco, R. Riccardi, C. Bailly, C. Cuevas, J.M. Fernandez Sousa-Faro, and M. D’Incalci. 2005. Variolin B and its derivate deoxy-variolin B: New marine natural compounds with cyclin-dependent kinase inhibitor activity. European Journal of Cancer 41: 2366–2377.

    CAS  PubMed  Google Scholar 

  • Singh, N., G. Sharma, and V. Mishra. 2012. Hypoxia inducible factor-1: Its potential role in cerebral ischemia. Cellular and Molecular Neurobiology 32: 491–507.

    CAS  PubMed  Google Scholar 

  • Singleton, A.B., M. Farrer, J. Johnson, A. Singleton, S. Hague, J. Kachergus, M. Hulihan, T. Peuralinna, A. Dutra, R. Nussbaum, S. Lincoln, A. Crawley, M. Hanson, D. Maraganore, C. Adler, M.R. Cookson, M. Muenter, M. Baptista, D. Miller, J. Blancato, J. Hardy, and K. Gwinn-Hardy. 2003. alpha-Synuclein locus triplication causes Parkinson’s disease. Science 302: 841.

    CAS  PubMed  Google Scholar 

  • Skolnick, P., K. Boje, R. Miller, M. Pennington, and M. Maccecchini. 1992. Noncompetitive inhibition of N-methyl-d-aspartate by conantokin-G: Evidence for an allosteric interaction at polyamine sites. Journal of Neurochemistry 59: 1516–1521.

    CAS  PubMed  Google Scholar 

  • Soni, R., L. Muller, P. Furet, J. Schoepfer, C. Stephan, S. Zumstein-Mecker, H. Fretz, and B. Chaudhuri. 2000. Inhibition of cyclin-dependent kinase 4 (Cdk4) by fascaplysin, a marine natural product. Biochemical and Biophysical Research Communications 275: 877–884.

    CAS  PubMed  Google Scholar 

  • Spillantini, M.G., M.L. Schmidt, V.M. Lee, J.Q. Trojanowski, R. Jakes, and M. Goedert. 1997. Alpha-synuclein in Lewy bodies. Nature 388: 839–840.

    CAS  PubMed  Google Scholar 

  • Sramek, J.J., E.J. Frackiewicz, and N.R. Cutler. 2000. Review of the acetylcholinesterase inhibitor galantamine. Expert Opinion on Investigational Drugs 9: 2393–2402.

    CAS  PubMed  Google Scholar 

  • Stewart, M., J.W. Blunt, M.H.G. Munro, W.T. Robinson, and D.J. Hannah. 1997. The absolute stereochemistry of the New Zealand shellfish toxin gymnodimine. Tetrahedron Letters 38: 4889–4890.

    CAS  Google Scholar 

  • Steyn, P.S., and P.L. Wessels. 1979. Pigments from Fusarium moniliforme sheldon : Structure and 13C nuclear magnetic resonance assignments of an azaanthraquinone and three naphthoquinones. Tetrahedron 35: 1551–1555.

    CAS  Google Scholar 

  • St-Pierre, J., S. Drori, M. Uldry, J.M. Silvaggi, J. Rhee, S. Jager, C. Handschin, K. Zheng, J. Lin, W. Yang, D.K. Simon, R. Bachoo, and B.M. Spiegelman. 2006. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell 127: 397–408.

    CAS  PubMed  Google Scholar 

  • Suemitsu, R., J. Iwai, and K. Kawaguchi. 1975. Isolation and identification of physcion, 4,5-dihydroxy-7-methoxy-2-methylanthraquinone, from the mycelium of Alternaria porri. Agricultural and Biological Chemistry 39: 2249–2250.

    CAS  Google Scholar 

  • Sugaya, K., E. Giacobini, and V.A. Chiappinelli. 1990. Nicotinic acetylcholine receptor subtypes in human frontal cortex: Changes in Alzheimer’s disease. Journal of Neuroscience Research 27: 349–359.

    CAS  PubMed  Google Scholar 

  • Sulzer, D. 2010. Clues to how alpha-synuclein damages neurons in Parkinson’s disease. Movement Disorders 25(Suppl 1): S27–S31.

    PubMed  Google Scholar 

  • Supriyono, A., B. Schwarz, V. Wray, L. Witte, W.E. Müller, R. van Soest, W. Sumaryono, and P. Proksch. 1995. Bioactive alkaloids from the tropical marine sponge Axinella carteri. Zeitschrift für Naturforschung C 50: 669–674.

  • Sutherland, B.A., J. Minnerup, J.S. Balami, F. Arba, A.M. Buchan, and C. Kleinschnitz. 2012. Neuroprotection for ischaemic stroke: Translation from the bench to the bedside. International Journal of Stroke 7: 407–418.

    PubMed  Google Scholar 

  • Tahtouh, T., J.M. Elkins, P. Filippakopoulos, M. Soundararajan, G. Burgy, E. Durieu, C. Cochet, R.S. Schmid, D.C. Lo, F. Delhommel, A.E. Oberholzer, L.H. Pearl, F. Carreaux, J.-P. Bazureau, S. Knapp, and L. Meijer. 2012. Selectivity, cocrystal structures, and neuroprotective properties of leucettines, a family of protein kinase inhibitors derived from the marine sponge alkaloid leucettamine B. Journal of Medicinal Chemistry 55: 9312–9330.

    CAS  PubMed  Google Scholar 

  • Tai, K.K., and D.D. Truong. 2013. Amiloride but not memantine reduces neurodegeneration, seizures and myoclonic jerks in rats with cardiac arrest-induced global cerebral hypoxia and reperfusion. PLoS One 8: e60309.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Takemoto, T., and T. Sai. 1964. Constituents of Ceratodictyon spongiosum ZANAROINI. I. Amino acids. Journal of the Pharmaceutical Society of Japan 84: 1224–1227.

    CAS  PubMed  Google Scholar 

  • Takizawa, S., K. Matsushima, H. Fujita, K. Nanri, S. Ogawa, and Y. Shinohara. 1995. A selective N-type calcium channel antagonist reduces extracellular glutamate release and infarct volume in focal cerebral ischemia. Journal of Cerebral Blood Flow and Metabolism 15: 611–618.

    CAS  PubMed  Google Scholar 

  • Tan, Z., R.C. Turner, R.L. Leon, X. Li, J. Hongpaisan, W. Zheng, A.F. Logsdon, Z.J. Naser, D.L. Alkon, C.L. Rosen, and J.D. Huber. 2013. Bryostatin improves survival and reduces ischemic brain injury in aged rats after acute ischemic stroke. Stroke 44: 3490–3497.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Tatlisumak, T., K. Takano, R.A. Carano, L.P. Miller, A.C. Foster, and M. Fisher. 1998. Delayed treatment with an adenosine kinase inhibitor, GP683, attenuates infarct size in rats with temporary middle cerebral artery occlusion. Stroke 29: 1952–1958.

    CAS  PubMed  Google Scholar 

  • Thompson, J.W., S.V. Narayanan, and M.A. Perez-Pinzon. 2012. Redox signaling pathways involved in neuronal ischemic preconditioning. Current Neuropharmacology 10: 354–369.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Tringali, C., and M. Piatelli. 1982. Two chrome derivatives from the brown alga Zonaria tournefortii. Tetrahedron Letters 23: 1509–1512.

    CAS  Google Scholar 

  • Trojanowski, J.Q., and V.M. Lee. 1998. Aggregation of neurofilament and alpha-synuclein proteins in Lewy bodies: Implications for the pathogenesis of Parkinson disease and Lewy body dementia. Archives of Neurology 55: 151–152.

    CAS  PubMed  Google Scholar 

  • Truelsen, T., B. Piechowski-Jozwiak, R. Bonita, C. Mathers, J. Bogousslavsky, and G. Boysen. 2006. Stroke incidence and prevalence in Europe: A review of available data. European Journal of Neurology 13: 581–598.

    CAS  PubMed  Google Scholar 

  • Ueda, J., J. Hashimoto, S. Inaba, M. Takagi, and K. Shin-ya. 2010. JBIR-59, a new sorbicillinoid, from a marine-derived fungus Penicillium citrinum SpI080624G1f01. Journal of Antibiotics 63: 203–205.

    CAS  PubMed  Google Scholar 

  • Valentino, K., R. Newcomb, T. Gadbois, T. Singh, S. Bowersox, S. Bitner, A. Justice, D. Yamashiro, B.B. Hoffman, R. Ciaranello, G. Miljanich, and J. Ramachandran. 1993. A selective N-type calcium channel antagonist protects against neuronal loss after global cerebral ischemia. Proceedings of the National Academy of Sciences of the United States of America 90: 7894–7897.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Van Der Worp, H.B., and J. Van Gijn. 2007. Clinical practice. Acute ischemic stroke. The New England Journal of Medicine 357: 572–579.

    PubMed  Google Scholar 

  • Vassar, R., and P.C. Kandalepas. 2011. The beta-secretase enzyme BACE1 as a therapeutic target for Alzheimer’s disease. Alzheimer’s Research & Therapy 3: 20.

    CAS  Google Scholar 

  • Visanji, N.P., A. Orsi, T.H. Johnston, P.A. Howson, K. Dixon, N. Callizot, J.M. Brotchie, and D.D. Rees. 2008. PYM50028, a novel, orally active, nonpeptide neurotrophic factor inducer, prevents and reverses neuronal damage induced by MPP+ in mesencephalic neurons and by MPTP in a mouse model of Parkinson’s disease. FASEB Journal 22: 2488–2497.

    CAS  PubMed  Google Scholar 

  • Wang, H., R. Li, and Y. Shen. 2013. Beta-secretase: Its biology as a therapeutic target in diseases. Trends in Pharmacological Sciences 34: 215–225.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Watanabe, K., Y. Tsuda, M. Iwashima, and K. Iguchi. 2000. A new bioactive triene aldehyde from the marine sponge Leucetta microraphis. Journal of Natural Products 63: 258–260.

    CAS  PubMed  Google Scholar 

  • Watters, C., C. Edmonds, L. Rosner, K. Sloss, and P. Leung. 2012. A cost analysis of EPA and DHA in fish, supplements and foods. Journal of Nutrition & Food Sciences 2: 1000159.

    Google Scholar 

  • Wen, L., D. Du, F. Liu, Z. She, Y. Lin, and Z. Zheng. 2007. Secondary metabolites of a marine mangrove fungus Paecilomyces sp. Tree 1–7. Zhongshan Daxue Xuebao, Ziran Kexueban 46: 125–127.

    CAS  Google Scholar 

  • Wen, L., Y.-C. Lin, Z.-G. She, D.-S. Du, W.-L. Chan, and Z.-H. Zheng. 2008. Paeciloxanthone, a new cytotoxic xanthone from the marine mangrove fungus Paecilomyces sp. (Tree 1–7). Journal of Asian Natural Products Research 10: 133–137.

    CAS  PubMed  Google Scholar 

  • Wheeler, J.W., O. Olubajo, C.B. Storm, and R.M. Duffield. 1981. Anabaseine: Venom alkaloid of Aphaenogaster ants. Science 211: 1051–1052.

    CAS  PubMed  Google Scholar 

  • Williams, A.J., J.R. Dave, J.B. Phillips, Y. Lin, R.T. McCabe, and F.C. Tortella. 2000. Neuroprotective efficacy and therapeutic window of the high-affinity N-methyl-d-aspartate antagonist conantokin-G: In vitro (primary cerebellar neurons) and in vivo (rat model of transient focal brain ischemia) studies. Journal of Pharmacology and Experimental Therapeutics 294: 378–386.

    CAS  PubMed  Google Scholar 

  • Williams, J.A., M. Day, and J.E. Heavner. 2008. Ziconotide: An update and review. Expert Opinion on Pharmacotherapy 9: 1575–1583.

    CAS  PubMed  Google Scholar 

  • Wolfe, M.S., W. Xia, B.L. Ostaszewski, T.S. Diehl, W.T. Kimberly, and D.J. Selkoe. 1999. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature 398: 513–517.

    CAS  PubMed  Google Scholar 

  • Worth, P.F. 2013. How to treat Parkinson’s disease in 2013. Clin. Med. 13: 93–96.

    PubMed  Google Scholar 

  • Yoon, N.Y., H.Y. Chung, H.R. Kim, and J.S. Choi. 2008. Acetyl- and butyrylcholinesterase inhibitory activities of sterols and phlorotannins from Ecklonia stolonifera. Fisheries Science 74: 200–207.

    CAS  Google Scholar 

  • Zarranz, J.J., J. Alegre, J.C. Gomez-Esteban, E. Lezcano, R. Ros, I. Ampuero, L. Vidal, J. Hoenicka, O. Rodriguez, B. Atares, and V. Llorens. 2004. Gomez Tortosa, E., Del Ser, T., Munoz, D.G., and De Yebenes, J.G., The new mutation, E46 K, of alpha-synuclein causes Parkinson and Lewy body dementia. Annals of Neurology 55: 164–173.

    CAS  PubMed  Google Scholar 

  • Zhai, A., X. Zhu, X. Wang, R. Chen, and H. Wang. 2013. Secalonic acid A protects dopaminergic neurons from 1-methyl-4-phenylpyridinium (MPP +)-induced cell death via the mitochondrial apoptotic pathway. European Journal of Pharmacology 713: 58–67.

    CAS  PubMed  Google Scholar 

  • Zhai, A.F., Y. Zhang, X.N. Zhu, J.T. Liang, X.L. Wang, Y.C. Lin, and R.Z. Chen. 2011. Secalonic acid A reduced colchicine cytotoxicity through suppression of JNK, p38 MAPKs and calcium influx. Neurochemistry International 58: 85–91.

    CAS  PubMed  Google Scholar 

  • Zhang, C. 2012. Natural compounds that modulate BACE1-processing of amyloid-beta precursor protein in Alzheimer’s disease. Discovery Medicine 14: 189–197.

    CAS  PubMed  Google Scholar 

  • Zhang, H., Z. Khalil, M.M. Conte, F. Plisson, and R.J. Capon. 2012a. A search for kinase inhibitors and antibacterial agents: Bromopyrrolo-2-aminoimidazoles from a deep-water Great Australian Bight sponge Axinella sp. Tetrahedron Letters 53: 3784–3787.

    CAS  Google Scholar 

  • Zhang, H., X. Xiao, M.M. Conte, Z. Khalil, and R.J. Capon. 2012b. Spiralisones A-D: acylphloroglucinol hemiketals from an Australian marine brown alga, Zonaria spiralis. Organic & Biomolecular Chemistry 10: 9671–9676.

    CAS  Google Scholar 

  • Zhang, H., M.M. Conte, X.-C. Huang, Z. Khalil, and R.J. Capon. 2012c. A search for BACE inhibitors reveals new biosynthetically related pyrrolidones, furanones and pyrroles from a southern Australian marine sponge Ianthella sp. Organic & Biomolecular Chemistry 10: 2656–2663.

    CAS  Google Scholar 

  • Zhang, H., M.M. Conte, Z. Khalil, X.-C. Huang, and R.J. Capon. 2012d. New dictyodendrins as BACE inhibitors from a southern Australian marine sponge Ianthella sp. RSC Advances 2: 4209–4214.

    CAS  Google Scholar 

  • Zhang, L., R. Sheng, and Z. Qin. 2009. The lysosome and neurodegenerative diseases. Acta Biochimica et Biophysica Sinica 41: 437–445.

    CAS  PubMed  Google Scholar 

  • Zhao, Y., F. Calon, C. Julien, J.W. Winkler, N.A. Petasis, W.J. Lukiw, and N.G. Bazan. 2011. Docosahexaenoic acid-derived neuroprotectin D1 induces neuronal survival via secretase- and PPARγ-mediated mechanisms in Alzheimer’s disease models. PLoS One 6: e15816.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zhao, J., L. Li, C. Ling, J. Li, J.Y. Pang, Y.C. Lin, J. Liu, R. Huang, G.L. Wang, Z. Pei, and J. Zeng. 2009. Marine compound Xyloketal B protects PC12 cells against OGD-induced cell damage. Brain Research 1302: 240–247.

    CAS  PubMed  Google Scholar 

  • Zheng, B., Z. Liao, J.J. Locascio, K.A. Lesniak, S.S. Roderick, M.L. Watt, A.C. Eklund, Y. Zhang-James, P.D. Kim, M.A. Hauser, E. Grunblatt, L.B. Moran, S.A. Mandel, P. Riederer, R.M. Miller, H.J. Federoff, U. Wullner, S. Papapetropoulos, M.B. Youdim, I. Cantuti-Castelvetri, A.B. Young, J.M. Vance, R.L. Davis, J.C. Hedreen, C.H. Adler, T.G. Beach, M.B. Graeber, F.A. Middleton, J.C. Rochet, and C.R. Scherzer. 2010. PGC-1alpha, a potential therapeutic target for early intervention in Parkinson’s disease. Science Translational Medicine 2: 52ra73.

    PubMed Central  PubMed  Google Scholar 

  • Zhou, X., J. Sun, W. Ma, W. Fang, Z. Chen, B. Yang, and Y. Liu. 2014. Bioactivities of six sterols isolated from marine invertebrates. Pharmaceutical Biology 52: 187–190.

    CAS  PubMed  Google Scholar 

  • Zhu, W., W. Xie, T. Pan, J. Jankovic, J. Li, M.B. Youdim, and W. Le. 2008. Comparison of neuroprotective and neurorestorative capabilities of rasagiline and selegiline against lactacystin-induced nigrostriatal dopaminergic degeneration. Journal of Neurochemistry 105: 1970–1978.

    CAS  PubMed  Google Scholar 

  • Zierler, S., G. Yao, Z. Zhang, W.C. Kuo, P. Pörzgen, R. Penner, F.D. Horgen, and A. Fleig. 2011. Waixenicin A inhibits cell proliferation through magnesium-dependent block of transient receptor potential melastatin 7 (TRPM7) channels. Journal of Biological Chemistry 286: 39328–39335.

    CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the 2014 Yeungnam University Research Grant.

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Choi, DY., Choi, H. Natural products from marine organisms with neuroprotective activity in the experimental models of Alzheimer’s disease, Parkinson’s disease and ischemic brain stroke: their molecular targets and action mechanisms. Arch. Pharm. Res. 38, 139–170 (2015). https://doi.org/10.1007/s12272-014-0503-5

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