The aim of this study was to investigate the effects of astaxanthin-enriched diet on blood pressure, cardiac hypertrophy, both vascular structure and function and superoxide ((*)O(2-)) production in spontaneously hypertensive rats (SHR). Twelve-week-old SHR were treated for 8 weeks with an astaxanthin-enriched diet (75 or 200 mg/kg body weight per day). Systolic blood pressure was monitorized periodically during the study by the tail cuff method. At the end of the study animals were sacrificed and heart, kidneys and aorta were removed. Left ventricular weight/body weight ratio was used as left ventricular hypertrophy index (LVH). Vascular function and structure were studied in conductance (aortic rings) and resistance (renal vascular bed) arteries. Also (*)O (2-) production was evaluated by lucigenin-enhanced chemiluminescence. Systolic blood pressure was lower in astaxanthin-treated groups than the control group from the first week of treatment, and LVH was significantly reduced. Astaxanthin improved endothelial function on resistance arteries, but had no effect on aorta. These effects were accompanied by a decrease in oxidative stress and improvements in NO bioavailability. Taken together, these results show that diet supplemented with astaxanthin has beneficial effects on hypertension, by decreasing blood pressure values, improving cardiovascular remodeling and oxidative stress.
Pharmacol Res. 2011 Jan;63(1):44-50
ALPHA-TOCOPHEROL AND ASTAXANTHIN DECREASE MACROPHAGE INFILTRATION, APOPTOSIS AND VULNERABILITY IN ATHEROMA OF HYPERLIPIDAEMIC RABBITS.
The composition of atherosclerotic plaques, not just macroscopical lesion size, has been implicated in their susceptibility to rupture and the risk of thrombus formation. By focusing on the quality of lipids, macrophages, apoptosis, collagen, metalloproteinase expression and plaque integrity, we evaluated the possible anti-atherosclerotic effect of the antioxidants alpha-tocopherol and astaxanthin in Watanabe heritable hyperlipidemic (WHHL) rabbits. Thirty-one WHHL rabbits were divided into three groups and were fed a standard diet, as controls (N =10), or a standard diet with the addition of 500 mg alpha-tocopherol per kg feed (N =11) or 100 mg astaxanthin per kg feed (N =10) for 24 weeks. We found that both antioxidants, particularly astaxanthin, significantly decreased macrophage infiltration in the plaques although they did not affect lipid accumulation. All lesions in the astaxanthin-treated rabbits were classified as early plaques according to the distribution of collagen and smooth muscle cells. Both antioxidants also improved plaque stability and significantly diminished apoptosis, which mainly occurred in macrophages, matrix metalloproteinase three expressions and plaque ruptures. Although neither antioxidant altered the positive correlations between the lesion size and lipid accumulation, the lesion size and apoptosis were only positively correlated in the control group. Astaxanthin and alpha-tocopherol may improve plaque stability by decreasing macrophage infiltration and apoptosis in this atherosclerotic setting. Apoptosis reduction by alpha-tocopherol and astaxanthin may be a new anti-atherogenic property of these antioxidants.
J Mol Cell Cardiol. 2004 Nov;37(5):969-78
CYTOPROTECTIVE ROLE OF ASTAXANTHIN AGAINST GLYCATED PROTEIN/IRON CHELATE-INDUCED TOXICITY IN HUMAN UMBILICAL VEIN ENDOTHELIAL CELLS.
Astaxanthin (ASX), a red carotenoid pigment with no pro-vitamin A activity, is a biological antioxidant that occurs naturally in a wide variety of plants, algae and seafoods. This study investigated whether ASX could inhibit glycated protein/iron chelate-induced toxicity in human umbilical-vein endothelial cells (HUVEC) by interfering with ROS generation in these cells. Glycated fetal bovine serum (GFBS) was prepared by incubating fetal bovine serum (FBS) with high-concentration glucose. Stimulation of cultured HUVECs with 50 mm 1 mL of GFBS significantly enhanced lipid peroxidation and decreased antioxidant enzyme activities and levels of phase II enzymes. However, preincubation of the cultures with ASX resulted in a marked decrease in the level of lipid peroxide (LPO) and an increase in the levels of antioxidant enzymes in an ASX concentration-dependent manner. These results demonstrate that ASX could inhibit LPO formation and enhance the antioxidant enzyme status in GFBS/iron chelate-exposed endothelial cells by suppressing ROS generation, thereby limiting the effects of the AGE-RAGE interaction. The results indicate that ASX could have a beneficial role against glycated protein/iron chelate-induced toxicity by preventing lipid and protein oxidation and increasing the activity of antioxidant enzymes.
Phytother Res. 2010 Jan;24(1):54-9
EFFECT OF ASTAXANTHIN ON HEPATOCELLULAR INJURY FOLLOWING ISCHEMIA/REPERFUSION.
This study investigated the effect of astaxanthin (ASX; 3,3-dihydroxybeta, beta-carotene-4,4-dione), a water-dispersible synthetic carotenoid, on liver ischemia-reperfusion (IR) injury. Astaxanthin (5 mg/kg/day) or olive oil was administered to rats via intragastric intubation for 14 consecutive days before the induction of hepatic IR. On the 15th day, blood vessels supplying the median and left lateral hepatic lobes were occluded with an arterial clamp for 60 min, followed by 60 min reperfusion. At the end of the experimental period, blood samples were obtained from the right ventricule to determine plasma alanine aminotransferase (ALT) and xanthine oxidase (XO) activities and animals were sacrificed to obtain samples of nonischemic and postischemic liver tissue. The effects of ASX on IR injury were evaluated by assessing hepatic ultrastructure via transmission electron microscopy and by histopathological scoring. Hepatic conversion of xanthine dehygrogenase (XDH) to XO, total GSH and protein carbonyl levels were also measured as markers of oxidative stress. Expression of NOS2 was determined by immunohistochemistry and Western blot analysis while nitrate/nitrite levels were measured via spectral analysis. Total histopathological scoring of cellular damage was significantly decreased in hepatic IR injury following ASX treatment. Electron microscopy of postischemic tissue demonstrated parenchymal cell damage, swelling of mitochondria, disarrangement of rough endoplasmatic reticulum which was also partially reduced by ASX treatment. Astaxanthine treatment significantly decreased hepatic conversion of XDH to XO and tissue protein carbonyl levels following IR injury. The current results suggest that the mechanisms of action by which ASX reduces IR damage may include antioxidant protection against oxidative injury.
Toxicology. 2010 Jan 12;267(1-3):147-53
DISODIUM DISUCCINATE ASTAXANTHIN (CARDAX) ATTENUATES COMPLEMENT ACTIVATION AND REDUCES MYOCARDIAL INJURY FOLLOWING ISCHEMIA/REPERFUSION.
Carotenoids are a naturally occurring group of compounds that possess antioxidant properties. Most natural carotenoids display poor aqueous solubility and tend to form aggregates in solution. Disodium disuccinate astaxanthin (DDA; Cardax) is a water-dispersible synthetic carotenoid that rapidly and preferentially associates with serum albumin, thereby preventing the formation of supramolecular complexes and facilitating its efficacy after parenteral administration. This study investigated the ability of DDA to reduce inflammation and myocardial injury in a rabbit model of ischemia/reperfusion. DDA (50 mg/kg/day) or saline was administered i.v. for 4 consecutive days before the initiation of the protocol for induction of myocardial ischemia/reperfusion. On the 5th day, rabbits underwent 30 min of coronary artery occlusion, followed by a 3-h reperfusion period. Myocardial infarct size, as a percentage of the area at risk, was calculated for both groups. Infarct size was 52.5 +/- 7.5% in the vehicle-treated (n = 9) and 25.8 +/- 4.7% in the DDA-treated (n = 9) animals (p < 0.01 versus vehicle; mean myocardial salvage = 51%). To evaluate the anti-inflammatory effects of DDA, complement activity was assessed at the end of reperfusion using a red blood cell lysis assay. DDA administration significantly reduced (p < 0.01) the activation of the complement system in the serum. The current results, coupled with the well established antioxidant ability of carotenoids, suggest that the mechanism(s) of action by which DDA reduces the tissue damage associated with reperfusion injury may include both antioxidant and anticomplement components.
J Pharmacol Exp Ther. 2005 Aug;314(2):686-92
CARDIOPROTECTION AND MYOCARDIAL SALVAGE BY A DISODIUM DISUCCINATE ASTAXANTHIN DERIVATIVE (CARDAX).
Cardioprotection in humans by carotenoids has been inferred from observational and epidemiologic studies, however, direct studies of cardioprotection and myocardial salvage by carotenoids are lacking. In the current study, intravenous (I.V.) pretreatment with a novel carotenoid derivative (disodium disuccinate astaxanthin; Cardax) was evaluated as a myocardial salvage agent in a Sprague-Dawley rat infarct model. Animals were dosed once per day I.V. by tail vein injection for 4 days at one of 3 doses (25, 50, and 75 mg/kg) prior to the infarct study carried out on day 5. The results were compared with control animals treated with saline vehicle. Thirty (30) minutes of occlusion of the left anterior descending (LAD) coronary artery was followed by 2 hours of reperfusion prior to sacrifice, a regimen which resulted in a mean infarct size (IS) as a percent (%) of the area at risk (AAR) of 59 +/- 3%. Area at risk was quantified by Patent blue dye injection, and infarct size (IS) was determined by triphenyltetrazolium chloride (TTC) staining. Cardax at 50 and 75 mg/kg for 4 days resulted in a significant mean reduction in IS/AAR to 35 +/- 3% (41% salvage) and 26 +/- 2% (56% salvage), respectively. Infarct size and myocardial salvage were significantly, and linearly, correlated with plasma levels of non-esterified, free astaxanthin at the end of reperfusion. These results suggest that parenteral Cardax may find utility in those clinical applications where pretreatment of patients at risk for myocardial infarction is performed.
Life Sci. 2004 May 28;75(2):215-24
ASTAXANTHIN VS PLACEBO ON ARTERIAL STIFFNESS, OXIDATIVE STRESS AND INFLAMMATION IN RENAL TRANSPLANT PATIENTS (XANTHIN): A RANDOMISED CONTROLLED TRIAL.
BACKGROUND: There is evidence that renal transplant recipients have
accelerated atherosclerosis manifest by increased cardiovascular morbidity and mortality. The high incidence of atherosclerosis is, in part, related to increased arterial stiffness, vascular dysfunction, elevated oxidative stress and inflammation associated with immunosuppressive therapy. The dietary supplement astaxanthin has shown promise as an antioxidant and anti-inflammatory therapeutic agent in cardiovascular disease. The aim of this trial is to investigate the effects of astaxanthin supplementation on arterial stiffness, oxidative stress and inflammation in renal transplant patients. METHOD AND DESIGN: This is a randomised, placebo controlled clinical trial. A total of 66 renal transplant recipients will be enrolled and allocated to receive either 12 mg/day of astaxanthin or an identical placebo for one-year. Patients will be stratified into four groups according to the type of immunosuppressant therapy they receive: 1) cyclosporine, 2) sirolimus, 3) tacrolimus or 4) prednisolone+/-azathioprine, mycophenolate mofetil or mycophenolate sodium. Primary outcome measures will be changes in 1) arterial stiffness measured by aortic pulse wave velocity (PWV), 2) oxidative stress assessed by plasma isoprostanes and 3) inflammation by plasma pentraxin 3. Secondary outcomes will include changes in vascular function assessed using the brachial artery reactivity (BAR) technique, carotid artery intimal medial thickness (CIMT), augmentation index (AIx), left ventricular afterload and additional measures of oxidative stress and inflammation. Patients will undergo these measures at baseline, six and 12 months. DISCUSSION: The results of this study will help determine the efficacy of astaxanthin on vascular structure, oxidative stress and inflammation in renal transplant patients. This may lead to a larger intervention trial assessing cardiovascular morbidity and mortality.
BMC Nephrol. 2008 Dec 18;9:17
ASTAXANTHIN PROTECTS NEURONAL CELLS AGAINST OXIDATIVE DAMAGE AND IS A POTENT CANDIDATE FOR BRAIN FOOD.
Astaxanthin (AST) is a powerful antioxidant that occurs naturally in a wide variety of living organisms. Based on the report claiming that AST could cross the brain-blood barrier, the aim of this study was to investigate the neuroprotective effect of AST by using an oxidative stress-induced neuronal cell damage system. The treatment with DHA hydroperoxide (DHA-OOH) or 6-hydroxydopamine (6-OHDA), either of which is a reactive oxygen species (ROS)-inducing neurotoxin, led to a significant decrease in viable dopaminergic SH-SY5Y cells by the MTT assay, whereas a significant protection was shown when the cells were pretreated with AST. Moreover, 100 nM AST pretreatment significantly inhibited intracellular ROS generation that occurred in either DHA-OOH- or 6-OHDA-treated cells. The neuroprotective effect of AST is suggested to be dependent upon its antioxidant potential and mitochondria protection; therefore, it is strongly suggested that treatment with AST may be effective for oxidative stress-associated neurodegeneration and a potential candidate for natural brain food.
Forum Nutr. 2009;61:129-35
ASTAXANTHIN INHIBITS GLUTAMATE RELEASE IN RAT CEREBRAL CORTEX NERVE TERMINALS VIA SUPPRESSION OF VOLTAGE-DEPENDENT CA(2+) ENTRY AND MITOGEN-ACTIVATED PROTEIN KINASE SIGNALING PATHWAY.
The purpose of this study was to examine the effect and mechanism of astaxanthin, a natural carotenoid, on endogenous glutamate release in nerve terminals of rat cerebral cortex (synaptosomes). Results showed that astaxanthin exhibited a dose-dependent inhibition of 4-aminopyridine (4-AP)-evoked release of glutamate. The effect of astaxanthin on the evoked glutamate release was prevented by chelating the intrasynaptosomal Ca(2+) ions and by the vesicular transporter inhibitor, but was insensitive to the glutamate transporter inhibitor. Astaxanthin decreased depolarization-induced increase in [Ca(2+)](C), whereas it did not alter the resting synaptosomal membrane potential or 4-AP-mediated depolarization. The effect of astaxanthin on evoked glutamate release was abolished by the N-, P- and Q-type Ca(2+) channel blockers, but not by the ryanodine receptor blocker or the mitochondrial Na(+)/Ca(2+) exchanger blocker. In addition, the inhibitory effect of astaxanthin on evoked glutamate release was prevented by the mitogen-activated protein kinase (MAPK) inhibitors PD98059 and U0126. Western blot analyses showed that astaxanthin significantly decreased the 4-AP-induced phosphorylation of MAPK, and this effect was blocked by PD98059. On the basis of these results, it was concluded that astaxanthin inhibits glutamate release from rat cortical synaptosomes through the suppression of presynaptic voltage-dependent Ca(2+) entry and MAPK signaling cascade.
J Agric Food Chem. 2010 Jul 28;58(14):8271-8
ASTAXANTHINE SECURED APOPTOTIC DEATH OF PC12 CELLS INDUCED BY BETA-AMYLOID PEPTIDE 25-35: ITS MOLECULAR ACTION TARGETS.
Astaxanthine (ASTx) is a novel carotenoid nutraceutical occurring in many crustaceans and red yeasts. It has potent antioxidant, photoprotective, hepatodetoxicant, and anti-inflammatory activities. Documented effect of ASTx on treatment of neurodegenerative disease is still lacking. We used the beta-amyloid peptide (Abeta) 25-35-treated PC12 model to investigate the neuron-protective effect of ASTx. The parameters examined included cell viability, caspase activation, and various apoptotic biomarkers that play their critical roles in the transduction pathways independently or synergistically. Results indicated that Abeta25-35 at 30 microM suppressed cell viability by 55%, whereas ASTx was totally nontoxic below a dose of 5.00 microM. ASTx at 0.1 microM protected PC12 cells from damaging effects of Abeta25-35 in several ways: (1) by securing the cell viability; (2) by partially down-regulating the activation of caspase 3; (3) by inhibiting the expression of Bax; (4) by completely eliminating the elevation of interleukin-1beta and tumor necrosis factor-alpha; (5) by inhibiting the nuclear translocation of nuclear factor kappaB; (6) by completely suppressing the phosphorylation of p38 mitogen-activated protein kinase; (7) by completely abolishing the calcium ion influx to effectively maintain calcium homeostasis; and (8) by suppressing the majority (about 75%) of reactive oxygen species production. Conclusively, ASTx may have merit to be used as a very potential neuron protectant and an anti-early-stage Alzheimer's disease adjuvant therapy.
J Med Food. 2010 Jun;13(3):548-56
DOWN-REGULATION OF IL-6 PRODUCTION BY ASTAXANTHIN VIA ERK-, MSK-, AND NF-KB-MEDIATED SIGNALS IN ACTIVATED MICROGLIA.
In this study, we investigated the effect of astaxanthin on IL-6 in activated microglial cells because excessive interleukin-6 (IL-6) production by activated brain microglia has been linked to many neurological disorders and proper regulation of IL-6 is critical for maintaining brain homeostasis. Astaxanthin inhibited lipopolysaccharide (LPS)-stimulated IL-6 mRNA and protein in BV-2 microglial cells. Moreover, LPS-induced p-IKK [alpha], p-I [kappa] B [alpha], and p-NF-[kappa] B p65 levels were all suppressed by astaxanthin. The translocation of p-NF-[kappa] B p65 from the cytosol into the nucleus and transcriptional activity were inhibited by astaxanthin. IL-6 expression and NF-[kappa] B transcriptional activation were inhibited by astaxanthin, as well as inhibitors of NF-B and MAPK in LPS-stimulated BV-2 microglial cells. Consistent with these findings, astaxanthin down-regulated the activation of p-extracellular signal-regulated kinase 1/2 (p-ERK1/2) and p-mitogen- and stress-activated protein kinase 1(p-MSK1), but not of p-c-jun N-terminal kinase (p-JNK). Astaxathin also decreased IL-6 mRNA and protein levels in LPS-stimulated primary microglial cells, RAW264.7 macrophages, and peritoneal macrophages. In addition, IL-6 suppression through astaxanthin-induced down-regulation of p-ERK1/2, p-MSK1, and p-NF-B p65 occurred in microglial cells stimulated with LPS or stromal derived factor (SDF)-1 [alpha]. Astaxathin also inhibited the secretion and mRNA expression of IL-6 in SDF-1 [alpha] -stimulated microglial cells. SDF-1 [alpha] -stimulated ERK1/2, MSK1, and NF-B p65 phosphorylation were reduced by astaxanthin. Therefore, our results suggest that astaxanthin regulates IL-6 production through a p-ERK1/2-MSK-1- and p-NF-B p65-dependent pathway in activated microglial cells.
Int Immunopharmacol. 2010 Dec;10(12):1560-72
ASTAXANTHIN REDUCES ISCHEMIC BRAIN INJURY IN ADULT RATS.
Astaxanthin (ATX) is a dietary carotenoid of crustaceans and fish that contributes to their coloration. Dietary ATX is important for development and survival of salmonids and crustaceans and has been shown to reduce cardiac ischemic injury in rodents. The purpose of this study was to examine whether ATX can protect against ischemic injury in the mammalian brain. Adult rats were injected intracerebroventricularly with ATX or vehicle prior to a 60-min middle cerebral artery occlusion (MCAo). ATX was present in the infarction area at 70-75 min after onset of MCAo. Treatment with ATX, compared to vehicle, increased locomotor activity in stroke rats and reduced cerebral infarction at 2 d after MCAo. To evaluate the protective mechanisms of ATX against stroke, brain tissues were assayed for free radical damage, apoptosis, and excitoxicity. ATX antagonized ischemia-mediated loss of aconitase activity and reduced glutamate release, lipid peroxidation, translocation of cytochrome c, and TUNEL labeling in the ischemic cortex. ATX did not alter physiological parameters, such as body temperature, brain temperature, cerebral blood flow, blood gases, blood pressure, and pH. Collectively, our data suggest that ATX can reduce ischemia-related injury in brain tissue through the inhibition of oxidative stress, reduction of glutamate release, and antiapoptosis. ATX may be clinically useful for patients vulnerable or prone to ischemic events.
FASEB J. 2009 Jun; 23(6):1958-68
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