Astaxanthin as a potential neuroprotective agent for neurological diseases

Marine Drugs

Volumn 13, Issue 9, 2015, Pages 5750-5766

  Wu, Haijian ^a   Niu, Huanjiang ^a   Shao, Anwen ^b   Wu, Cheng ^a   Dixon, Brandon J ^c   Zhang, Jianmin ^b   Yang, Shuxu ^a   Wang, Yirong ^a  

^a ZHEJIANG UNIVERSITY   (China)

^b THE SECOND AFFILIATED HOSPITAL OF ZHEJIANG UNIVERSITY SCHOOL OF MEDICINE   (China)

^c LOMA LINDA UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Apoptosis; Astaxanthin; Inflammation; Neurological diseases; Neuroprotection; Oxidative stress

Indexed keywords

ASTAXANTHIN; NEUROPROTECTIVE AGENT; XANTHOPHYLL;

ANTIINFLAMMATORY ACTIVITY; ANTIOXIDANT ACTIVITY; APOPTOSIS; CELL PROTECTION; CONCENTRATION RESPONSE; DRUG BIOAVAILABILITY; DRUG MECHANISM; DRUG SAFETY; HUMAN; NEUROLOGIC DISEASE; NEUROPROTECTION; NONHUMAN; REVIEW; CENTRAL NERVOUS SYSTEM DISEASES;

CENTRAL NERVOUS SYSTEM DISEASES; HUMANS; NEUROPROTECTIVE AGENTS; XANTHOPHYLLS;

EID: 84942882625     PISSN: None     EISSN: 16603397     Source Type: Journal    
DOI: 10.3390/md13095750     Document Type: Review

References (100)

1. Corrigan, J.D.; Selassie, A.W.; Orman, J.A. The epidemiology of traumatic brain injury. J. Head Trauma Rehabil. 2010, 25, 72-80.
2. Mayeux, R. Epidemiology of neurodegeneration. Annu. Rev. Neurosci. 2003, 26, 81-104.
3. Bramlett, H.M.; Dietrich, W.D. Pathophysiology of cerebral ischemia and brain trauma: Similarities and differences. J. Cereb. Blood Flow Metab. 2004, 24, 133-150.
4. Bossy-Wetzel, E.; Schwarzenbacher, R.; Lipton, S.A. Molecular pathways to neurodegeneration. Nat. Med. 2004, 10, S2-S9.
5. Manczak, M.; Anekonda, T.S.; Henson, E.; Park, B.S.; Quinn, J.; Reddy, P.H. Mitochondria are a direct site of A beta accumulation in Alzheimer's disease neurons: Implications for free radical generation and oxidative damage in disease progression. Hum. Mol. Genet. 2006, 15, 1437-1449.
6. Cutler, R.G.; Kelly, J.; Storie, K.; Pedersen, W.A.; Tammara, A.; Hatanpaa, K.; Troncoso, J.C.; Mattson, M.P. Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer's disease. Proc. Natl. Acad. Sci. USA 2004, 101, 2070-2075.
7. Hanzel, C.E.; Pichet-Binette, A.; Pimentel, L.S.; Iulita, M.F.; Allard, S.; Ducatenzeiler, A.; do Carmo, S.; Cuello, A.C. Neuronal driven pre-plaque inflammation in a transgenic rat model of Alzheimer's disease. Neurobiol. Aging 2014, 35, 2249-2262.
8. Moore, D.J.; West, A.B.; Dawson, V.L.; Dawson, T.M. Molecular pathophysiology of Parkinson's disease. Annu. Rev. Neurosci. 2005, 28, 57-87.
9. Dawson, T.M.; Dawson, V.L. Molecular pathways of neurodegeneration in Parkinson's disease. Science 2003, 302, 819-822.
10. Ross, C.A.; Tabrizi, S.J. Huntington's disease: From molecular pathogenesis to clinical treatment. Lancet Neurol. 2011, 10, 83-98.
11. Bano, D.; Zanetti, F.; Mende, Y.; Nicotera, P. Neurodegenerative processes in Huntington's disease. Cell Death Dis. 2011, 2, e228.
12. Regnier, P.; Bastias, J.; Rodriguez-Ruiz, V.; Caballero-Casero, N.; Caballo, C.; Sicilia, D.; Fuentes, A.; Maire, M.; Crepin, M.; Letourneur, D.; et al. Astaxanthin from Haematococcus Pluvialis Prevents Oxidative Stress on Human Endothelial Cells without Toxicity. Mar. Drugs 2015, 13, 2857-2874.
13. Ambati, R.R.; Phang, S.M.; Ravi, S.; Aswathanarayana, R.G. Astaxanthin: Sources, extraction, stability, biological activities and its commercial applications-A review. Mar. Drugs 2014, 12, 128-152.
14. Fassett, R.G.; Coombes, J.S. Astaxanthin: A potential therapeutic agent in cardiovascular disease. Mar. Drugs 2011, 9, 447-465.
15. Monroy-Ruiz, J.; Sevilla, M.A.; Carron, R.; Montero, M.J. Astaxanthin-enriched-diet reduces blood pressure and improves cardiovascular parameters in spontaneously hypertensive rats. Pharmacol. Res. 2011, 63, 44-50.
16. Augusti, P.R.; Quatrin, A.; Somacal, S.; Conterato, G.M.; Sobieski, R.; Ruviaro, A.R.; Maurer, L.H.; Duarte, M.M.; Roehrs, M.; Emanuelli, T. Astaxanthin prevents changes in the activities of thioredoxin reductase and paraoxonase in hypercholesterolemic rabbits. J. Clin. Biochem. Nutr. 2012, 51, 42-49.
17. Shen, H.; Kuo, C.C.; Chou, J.; Delvolve, A.; Jackson, S.N.; Post, J.; Woods, A.S.; Hoffer, B.J.; Wang, Y.; Harvey, B.K. Astaxanthin reduces ischemic brain injury in adult rats. FASEB J. 2009, 23, 1958-1968.
18. Ying, C.J.; Zhang, F.; Zhou, X.Y.; Hu, X.T.; Chen, J.; Wen, X.R.; Sun, Y.; Zheng, K.Y.; Tang, R.X.; Song, Y.J. Anti-inflammatory Effect of Astaxanthin on the Sickness Behavior Induced by Diabetes Mellitus. Cell. Mol. Neurobiol. 2015, doi:10.1007/s10571-015-0197-3.
19. Zhang, X.S.; Zhang, X.; Zhou, M.L.; Zhou, X.M.; Li, N.; Li, W.; Cong, Z.X.; Sun, Q.; Zhuang, Z.; Wang, C.X.; et al. Amelioration of oxidative stress and protection against early brain injury by astaxanthin after experimental subarachnoid hemorrhage. J. Neurosurg. 2014, 121, 42-54.
20. Zhang, X.S.; Zhang, X.; Wu, Q.; Li, W.; Wang, C.X.; Xie, G.B.; Zhou, X.M.; Shi, J.X.; Zhou, M.L. Astaxanthin offers neuroprotection and reduces neuroinflammation in experimental subarachnoid hemorrhage. J. Surg. Res. 2014, 192, 206-213.
21. Zhang, X.S.; Zhang, X.; Wu, Q.; Li, W.; Zhang, Q.R.; Wang, C.X.; Zhou, X.M.; Li, H.; Shi, J.X.; Zhou, M.L. Astaxanthin alleviates early brain injury following subarachnoid hemorrhage in rats: Possible involvement of Akt/bad signaling. Mar. Drugs 2014, 12, 4291-4310.
22. Higuera-Ciapara, I.; Felix-Valenzuela, L.; Goycoolea, F.M. Astaxanthin: A review of its chemistry and applications. Crit. Rev. Food Sci. Nutr. 2006, 46, 185-196.
23. Hussein, G.; Nakamura, M.; Zhao, Q.; Iguchi, T.; Goto, H.; Sankawa, U.; Watanabe, H. Antihypertensive and neuroprotective effects of astaxanthin in experimental animals. Biol. Pharm. Bull. 2005, 28, 47-52.
24. Stahl, W.; Sies, H. Bioactivity and protective effects of natural carotenoids. Biochim. Biophys. Acta 2005, 1740, 101-107.
25. Guerin, M.; Huntley, M.E.; Olaizola, M. Haematococcus astaxanthin: Applications for human health and nutrition. Trends Biotechnol. 2003, 21, 210-216.
26. Jyonouchi, H.; Sun, S.; Gross, M. Effect of carotenoids on in vitro immunoglobulin production by human peripheral blood mononuclear cells: Astaxanthin, a carotenoid without vitamin A activity, enhances in vitro immunoglobulin production in response to a T-dependent stimulant and antigen. Nutr. Cancer 1995, 23, 171-183.
27. Yuan, J.P.; Chen, F. Hydrolysis kinetics of astaxanthin esters and stability of astaxanthin of Haematococcus pluvialis during saponification. J. Agric. Food Chem. 1999, 47, 31-35.
28. Yuan, J.P.; Peng, J.; Yin, K.; Wang, J.H. Potential health-promoting effects of astaxanthin: A high-value carotenoid mostly from microalgae. Mol. Nutr. Food Res. 2011, 55, 150-165.
29. Okada, Y.; Ishikura, M.; Maoka, T. Bioavailability of astaxanthin in Haematococcus algal extract: The effects of timing of diet and smoking habits. Biosci. Biotechnol. Biochem. 2009, 73, 1928-1932.
30. Coral-Hinostroza, G.N.; Ytrestoyl, T.; Ruyter, B.; Bjerkeng, B. Plasma appearance of unesterified astaxanthin geometrical E/Z and optical R/S isomers in men given single doses of a mixture of optical 3 and 3?R/S isomers of astaxanthin fatty acyl diesters. Comp. Biochem. Physiol. C Toxicol. Pharmacol. 2004, 139, 99-110.
31. Kistler, A.; Liechti, H.; Pichard, L.; Wolz, E.; Oesterhelt, G.; Hayes, A.; Maurel, P. Metabolism and CYP-inducer properties of astaxanthin in man and primary human hepatocytes. Arch. Toxicol. 2002, 75, 665-675.
32. Parker, R.S. Absorption, metabolism, and transport of carotenoids. FASEB J. 1996, 10, 542-551.
33. Rao, A.R.; Reddy, R.L.R.; Baskaran, V.; Sarada, R.; Ravishankar, G.A. Characterization of microalgal carotenoids by mass spectrometry and their bioavailability and antioxidant properties elucidated in rat model. J. Agric. Food Chem. 2010, 58, 8553-8559.
34. Stewart, J.S.; Lignell, A.; Pettersson, A.; Elfving, E.; Soni, M.G. Safety assessment of astaxanthin-rich microalgae biomass: Acute and subchronic toxicity studies in rats. Food. Chem. Toxicol. 2008, 46, 3030-3036.
35. Spiller, G.A.; Dewell, A. Safety of an astaxanthin-rich Haematococcus pluvialis algal extract: A randomized clinical trial. J. Med. Food 2003, 6, 51-56.
36. Satoh, A.; Tsuji, S.; Okada, Y.; Murakami, N.; Urami, M.; Nakagawa, K.; Ishikura, M.; Katagiri, M.; Koga, Y.; Shirasawa, T. Preliminary Clinical Evaluation of Toxicity and Efficacy of A New Astaxanthin-Rich Haematococcus Pluvialis Extract. J. Clin. Biochem. Nutr. 2009, 44, 280-284.
37. Katagiri, M.; Satoh, A.; Tsuji, S.; Shirasawa, T. Effects of astaxanthin-rich Haematococcus pluvialis extract on cognitive function: A randomised, double-blind, placebo-controlled study. J. Clin. Biochem. Nutr. 2012, 51, 102-107.
38. Kidd, P. Astaxanthin, cell membrane nutrient with diverse clinical benefits and anti-aging potential. Altern. Med. Rev. 2011, 16, 355-364.
39. Yamagishi, R.; Aihara, M. Neuroprotective effect of astaxanthin against rat retinal ganglion cell death under various stresses that induce apoptosis and necrosis. Mol. Vis. 2014, 20, 1796-1805.
40. Gasche, Y.; Copin, J.C.; Sugawara, T.; Fujimura, M.; Chan, P.H. Matrix metalloproteinase inhibition prevents oxidative stress-associated blood-brain barrier disruption after transient focal cerebral ischemia. J. Cereb. Blood Flow Metab. 2001, 21, 1393-400.
41. Giasson, B.I.; Duda, J.E.; Murray, I.V.; Chen, Q.; Souza, J.M.; Hurtig, H.I.; Ischiropoulos, H.; Trojanowski, J.Q.; Lee, V.M. Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science 2000, 290, 985-989.
42. Wu, D.C.; Teismann, P.; Tieu, K.; Vila, M.; Jackson-Lewis, V.; Ischiropoulos, H.; Przedborski, S. NADPH oxidase mediates oxidative stress in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease. Proc. Natl. Acad. Sci. USA 2003, 100, 6145-6150.
43. Valko, M.; Leibfritz, D.; Moncol, J.; Cronin, M.T.; Mazur, M.; Telser, J. Free radicals and antioxidants in normal physiological functions and human disease. Int. J. Biochem. Cell Biol. 2007, 39, 44-84.
44. Jilani, K.E.B.; Panee, J.; He, Q.; Berry, M.J.; Li, P.A. Overexpression of selenoprotein H reduces Ht22 neuronal cell death after UVB irradiation by preventing superoxide formation. Int. J. Biol. Sci. 2007, 3, 198-204.
45. Kamsler, A.; Segal, M. Hydrogen peroxide as a diffusible signal molecule in synaptic plasticity. Mol. Neurobiol. 2004, 29, 167-178.
46. Fridovich, I. Superoxide radical and superoxide dismutases. Annu. Rev. Biochem. 1995, 64, 97-112.
47. Sutton, V.R.; Mettert, E.L.; Beinert, H.; Kiley, P.J. Kinetic analysis of the oxidative conversion of the [4Fe-4S]2+ cluster of FNR to a [2Fe-2S]2+ Cluster. J. Bacteriol. 2004, 186, 8018-8025.
48. Tripathi, D.N.; Jena, G.B. Intervention of astaxanthin against cyclophosphamide-induced oxidative stress and DNA damage: A study in mice. Chem. Biol. Interact. 2009, 180, 398-406.
49. Stahl, W.; Sies, H. Antioxidant activity of carotenoids. Mol. Asp. Med. 2003, 24, 345-351.
50. Naito, Y.; Uchiyama, K.; Aoi, W.; Hasegawa, G.; Nakamura, N.; Yoshida, N.; Maoka, T.; Takahashi, J.; Yoshikawa, T. Prevention of diabetic nephropathy by treatment with astaxanthin in diabetic db/db mice. Biofactors 2004, 20, 49-59.
51. Camera, E.; Mastrofrancesco, A.; Fabbri, C.; Daubrawa, F.; Picardo, M.; Sies, H.; Stahl, W. Astaxanthin, canthaxanthin and beta-carotene differently affect UVA-induced oxidative damage and expression of oxidative stress-responsive enzymes. Exp. Dermatol. 2009, 18, 222-231.
52. Nishigaki, I.; Rajendran, P.; Venugopal, R.; Ekambaram, G.; Sakthisekaran, D.; Nishigaki, Y. Cytoprotective role of astaxanthin against glycated protein/iron chelate-induced toxicity in human umbilical vein endothelial cells. Phytother. Res. 2010, 24, 54-59.
53. Augusti, P.R.; Conterato, G.M.; Somacal, S.; Sobieski, R.; Spohr, P.R.; Torres, J.V.; Charao, M.F.; Moro, A.M.; Rocha, M.P.; Garcia, S.C.; et al. Effect of astaxanthin on kidney function impairment and oxidative stress induced by mercuric chloride in rats. Food Chem. Toxicol. 2008, 46, 212-219.
54. Nakajima, Y.; Inokuchi, Y.; Shimazawa, M.; Otsubo, K.; Ishibashi, T.; Hara, H. Astaxanthin, a dietary carotenoid, protects retinal cells against oxidative stress in vitro and in mice in vivo. J. Pharm. Pharmacol. 2008, 60, 1365-1374.
55. Tripathi, D.N.; Jena, G.B. Astaxanthin intervention ameliorates cyclophosphamide-induced oxidative stress, DNA damage and early hepatocarcinogenesis in rat: Role of Nrf2, p53, p38 and phase-II enzymes. Mutat. Res. 2010, 696, 69-80.
56. Li, Z.; Dong, X.; Liu, H.; Chen, X.; Shi, H.; Fan, Y.; Hou, D.; Zhang, X. Astaxanthin protects ARPE-19 cells from oxidative stress via upregulation of Nrf2-regulated phase II enzymes through activation of PI3K/Akt. Mol. Vis. 2013, 19, 1656-1666.
57. Lee, D.H.; Lee, Y.J.; Kwon, K.H. Neuroprotective Effects of Astaxanthin in Oxygen-Glucose Deprivation in SH-SY5Y Cells and Global Cerebral Ischemia in Rat. J. Clin. Biochem. Nutr. 2010, 47, 121-129.
58. Wu, Q.; Zhang, X.S.; Wang, H.D.; Zhang, X.; Yu, Q.; Li, W.; Zhou, M.L.; Wang, X.L. Astaxanthin activates nuclear factor erythroid-related factor 2 and the antioxidant responsive element (Nrf2-ARE) pathway in the brain after subarachnoid hemorrhage in rats and attenuates early brain injury. Mar. Drugs 2014, 12, 6125-6141.
59. Wang, H.Q.; Sun, X.B.; Xu, Y.X.; Zhao, H.; Zhu, Q.Y.; Zhu, C.Q. Astaxanthin upregulates heme oxygenase-1 expression through ERK1/2 pathway and its protective effect against beta-amyloid-induced cytotoxicity in SH-SY5Y cells. Brain Res. 2010, 1360, 159-167.
60. Motterlini, R.; Green, C.J.; Foresti, R. Regulation of heme oxygenase-1 by redox signals involving nitric oxide. Antioxid. Redox Signal. 2002, 4, 615-624.
61. Bae, J.W.; Kim, M.J.; Jang, C.G.; Lee, S.Y. Protective effects of heme oxygenase-1 against MPP(+)-induced cytotoxicity in PC-12 cells. Neurol. Sci. 2010, 31, 307-313.
62. Ye, Q.; Huang, B.; Zhang, X.; Zhu, Y.; Chen, X. Astaxanthin protects against MPP(+)-induced oxidative stress in PC12 cells via the HO-1/NOX2 axis. BMC Neurosci. 2012, 13, 156.
63. Ye, Q.; Zhang, X.; Huang, B.; Zhu, Y.; Chen, X. Astaxanthin suppresses MPP(+)-induced oxidative damage in PC12 cells through a Sp1/NR1 signaling pathway. Mar. Drugs 2013, 11, 1019-1034.
64. Turrin, N.P.; Rivest, S. Molecular and cellular immune mediators of neuroprotection. Mol. Neurobiol. 2006, 34, 221-242.
65. Brown, G.C.; Neher, J.J. Inflammatory neurodegeneration and mechanisms of microglial killing of neurons. Mol. Neurobiol. 2010, 41, 242-247.
66. Lucas, S.M.; Rothwell, N.J.; Gibson, R.M. The role of inflammation in CNS injury and disease. Br. J. Pharmacol. 2006, 147, S232-S240.
67. Ohgami, K.; Shiratori, K.; Kotake, S.; Nishida, T.; Mizuki, N.; Yazawa, K.; Ohno, S. Effects of astaxanthin on lipopolysaccharide-induced inflammation in vitro and in vivo. Investig. Ophthalmol. Vis. Sci. 2003, 44, 2694-2701.
68. Suzuki, Y.; Ohgami, K.; Shiratori, K.; Jin, X.H.; Ilieva, I.; Koyama, Y.; Yazawa, K.; Yoshida, K.; Kase, S.; Ohno, S. Suppressive effects of astaxanthin against rat endotoxin-induced uveitis by inhibiting the NF-êB signaling pathway. Exp. Eye Res. 2006, 82, 275-281.
69. Ghosh, S.; May, M.J.; Kopp, E.B. NF-êB and Rel proteins: Evolutionarily conserved mediators of immune responses. Annu. Rev. Immunol. 1998, 16, 225-260.
70. Yamamoto, Y.; Yin, M.J.; Gaynor, R.B. IkappaB kinase alpha (IKKalpha) regulation of IKKbeta kinase activity. Mol. Cell. Biol. 2000, 20, 3655-3666.
71. Poyet, J.L.; Srinivasula, S.M.; Lin, J.H.; Fernandes-Alnemri, T.; Yamaoka, S.; Tsichlis, P.N.; Alnemri, E.S. Activation of the Ikappa B kinases by RIP via IKKgamma /NEMO-mediated oligomerization. J. Biol. Chem. 2000, 275, 37966-37977.
72. Shao, A.W.; Wu, H.J.; Chen, S.; Ammar, A.B.; Zhang, J.M.; Hong, Y. Resveratrol attenuates early brain injury after subarachnoid hemorrhage through inhibition of NF-kappaB-dependent inflammatory/MMP-9 pathway. CNS Neurosci. Ther. 2014, 20, 182-185.
73. Bhuvaneswari, S.; Yogalakshmi, B.; Sreeja, S.; Anuradha, C.V. Astaxanthin reduces hepatic endoplasmic reticulum stress and nuclear factor-kappaB-mediated inflammation in high fructose and high fat diet-fed mice. Cell Stress Chaperones 2014, 19, 183-191.
74. Speranza, L.; Pesce, M.; Patruno, A.; Franceschelli, S.; de Lutiis, M.A.; Grilli, A.; Felaco, M. Astaxanthin treatment reduced oxidative induced pro-inflammatory cytokines secretion in U937: SHP-1 as a novel biological target. Mar. Drugs 2012, 10, 890-899.
75. Izumi-Nagai, K.; Nagai, N.; Ohgami, K.; Satofuka, S.; Ozawa, Y.; Tsubota, K.; Ohno, S.; Oike, Y.; Ishida, S. Inhibition of choroidal neovascularization with an anti-inflammatory carotenoid astaxanthin. Investig. Ophthalmol. Vis. Sci. 2008, 49, 1679-1685.
76. Bennedsen, M.; Wang, X.; Willen, R.; Wadstrom, T.; Andersen, L.P. Treatment of H. pylori infected mice with antioxidant astaxanthin reduces gastric inflammation, bacterial load and modulates cytokine release by splenocytes. Immunol. Lett. 1999, 70, 185-189.
77. Yasui, Y.; Hosokawa, M.; Mikami, N.; Miyashita, K.; Tanaka, T. Dietary astaxanthin inhibits colitis and colitis-associated colon carcinogenesis in mice via modulation of the inflammatory cytokines. Chem. Biol. Interact. 2011, 193, 79-87.
78. Lee, S.J.; Bai, S.K.; Lee, K.S.; Namkoong, S.; Na, H.J.; Ha, K.S.; Han, J.A.; Yim, S.V.; Chang, K.; Kwon, Y.G.; et al. Astaxanthin inhibits nitric oxide production and inflammatory gene expression by suppressing I(kappa)B kinase-dependent NF-kappaB activation. Mol. Cells 2003, 16, 97-105.
79. Terazawa, S.; Nakajima, H.; Shingo, M.; Niwano, T.; Imokawa, G. Astaxanthin attenuates the UVB-induced secretion of prostaglandin E2 and interleukin-8 in human keratinocytes by interrupting MSK1 phosphorylation in a ROS depletion-independent manner. Exp. Dermatol. 2012, 21, S11-S17.
80. Chew, B.P.; Wong, M.W.; Park, J.S.; Wong, T.S. Dietary beta-carotene and astaxanthin but not canthaxanthin stimulate splenocyte function in mice. Anticancer Res. 1999, 19, 5223-5227.
81. Chew, B.P.; Mathison, B.D.; Hayek, M.G.; Massimino, S.; Reinhart, G.A.; Park, J.S. Dietary astaxanthin enhances immune response in dogs. Vet. Immunol. Immunopathol. 2011, 140, 199-206.
82. Jyonouchi, H.; Sun, S.; Iijima, K.; Gross, M.D. Antitumor activity of astaxanthin and its mode of action. Nutr. Cancer 2000, 36, 59-65.
83. Kurihara, H.; Koda, H.; Asami, S.; Kiso, Y.; Tanaka, T. Contribution of the antioxidative property of astaxanthin to its protective effect on the promotion of cancer metastasis in mice treated with restraint stress. Life Sci. 2002, 70, 2509-2520.
84. Park, J.S.; Chyun, J.H.; Kim, Y.K.; Line, L.L.; Chew, B.P. Astaxanthin decreased oxidative stress and inflammation and enhanced immune response in humans. Nutr. Metab. (Lond.) 2010, 7, 18.
85. Balietti, M.; Giannubilo, S.R.; Giorgetti, B.; Solazzi, M.; Turi, A.; Casoli, T.; Ciavattini, A.; Fattorettia, P. The effect of astaxanthin on the aging rat brain: Gender-related differences in modulating inflammation. J. Sci. Food Agric. 2015, doi:10.1002/jsfa.7131.
86. Elmore, S. Apoptosis: A review of programmed cell death. Toxicol. Pathol. 2007, 35, 495-516.
87. Wu, H.J.; Pu, J.L.; Krafft, P.R.; Zhang, J.M.; Chen, S. The molecular mechanisms between autophagy and apoptosis: Potential role in central nervous system disorders. Cell. Mol. Neurobiol. 2015, 35, 85-99.
88. Nijhawan, D.; Honarpour, N.; Wang, X. Apoptosis in neural development and disease. Annu. Rev. Neurosci. 2000, 23, 73-87.
89. Shao, A.; Wang, Z.; Wu, H.; Dong, X.; Li, Y.; Tu, S.; Tang, J.; Zhao, M.; Zhang, J.; Hong, Y. Enhancement of Autophagy by Histone Deacetylase Inhibitor Trichostatin A Ameliorates Neuronal Apoptosis After Subarachnoid Hemorrhage in Rats. Mol. Neurobiol. 2014, doi:10.1007/s12035-014-8986-0
90. Kim, J.H.; Choi, W.; Lee, J.H.; Jeon, S.J.; Choi, Y.H.; Kim, B.W.; Chang, H.I.; Nam, S.W. Astaxanthin inhibits H2O2-mediated apoptotic cell death in mouse neural progenitor cells via modulation of P38 and MEK signaling pathways. J. Microbiol. Biotechnol. 2009, 19, 1355-1363.
91. Dong, L.Y.; Jin, J.; Lu, G.; Kang, X.L. Astaxanthin attenuates the apoptosis of retinal ganglion cells in db/db mice by inhibition of oxidative stress. Mar. Drugs 2013, 11, 960-974.
92. Guo, S.X.; Zhou, H.L.; Huang, C.L.; You, C.G.; Fang, Q.; Wu, P.; Wang, X.G.; Han, C.M. Astaxanthin attenuates early acute kidney injury following severe burns in rats by ameliorating oxidative stress and mitochondrial-related apoptosis. Mar. Drugs 2015, 13, 2105-2123.
93. Lu, Y.P.; Liu, S.Y.; Sun, H.; Wu, X.M.; Li, J.J.; Zhu, L. Neuroprotective effect of astaxanthin on H(2)O(2)-induced neurotoxicity in vitro and on focal cerebral ischemia in vivo. Brain Res. 2010, 1360, 40-48.
94. Ikeda, Y.; Tsuji, S.; Satoh, A.; Ishikura, M.; Shirasawa, T.; Shimizu, T. Protective effects of astaxanthin on 6-hydroxydopamine-induced apoptosis in human neuroblastoma SH-SY5Y cells. J. Neurochem. 2008, 107, 1730-1740.
95. Gomez-Lazaro, M.; Galindo, M.F.; Concannon, C.G.; Segura, M.F.; Fernandez-Gomez, F.J.; Llecha, N.; Comella, J.X.; Prehn, J.H.; Jordan, J. 6-hydroxydopamine activates the mitochondrial apoptosis pathway through p38 MAPK-mediated, p53-independent activation of Bax and PUMA. J. Neurochem. 2008, 104, 1599-1612.
96. Lee, D.H.; Kim, C.S.; Lee, Y.J. Astaxanthin protects against MPTP/MPP+ -induced mitochondrial dysfunction and ROS production in vivo and in vitro. Food Chem. Toxicol. 2011, 49, 271-280.
97. Liu, X.; Shibata, T.; Hisaka, S.; Osawa, T. Astaxanthin inhibits reactive oxygen species-mediated cellular toxicity in dopaminergic SH-SY5Y cells via mitochondria-targeted protective mechanism. Brain Res. 2009, 1254, 18-27.
98. Song, X.D.; Zhang, J.J.; Wang, M.R.; Liu, W.B.; Gu, X.B.; Lv, C.J. Astaxanthin induces mitochondria-mediated apoptosis in rat hepatocellular carcinoma CBRH-7919 cells. Biol. Pharm. Bull. 2011, 34, 839-844.
99. Song, X.; Wang, M.; Zhang, L.; Zhang, J.; Wang, X.; Liu, W.; Gu, X.; Lv, C. Changes in cell ultrastructure and inhibition of JAK1/STAT3 signaling pathway in CBRH-7919 cells with astaxanthin. Toxicol. Mech. Methods 2012, 22, 679-686.
100. Kavitha, K.; Kowshik, J.; Kishore, T.K.; Baba, A.B.; Nagini, S. Astaxanthin inhibits NF-kappaB and Wnt/beta-catenin signaling pathways via inactivation of Erk/MAPK and PI3K/Akt to induce intrinsic apoptosis in a hamster model of oral cancer. Biochim. Biophys. Acta 2013, 1830, 4433-4444.