Comparison of the effects of α-tocopherol, ubiquinone-10 and probucol at therapeutic doses on atherosclerosis in WHHL rabbits

Bräsen, Jan Hinrich; Koenig, Kai; Bach, H.L.; Kontush, Anatol; Heinle, H.; Witting, Paul K.; Ylä‐Herttuala, Seppo; Stocker, Roland; Beisiegel, Ulrike

doi:10.1016/s0021-9150(02)00023-0

Cited by 31 publications

(16 citation statements)

References 54 publications

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“…We suppose, therefore, that the reasons for this unanticipated great risk reduction include some antioxidant and anti-atherogenic actions 3, 4, 27) of probucol. The finding in second prevention may be suggested by the report 27) that probucol significantly decreased in vitro LDL oxidizability measured under typically strong oxidative conditions, and that long-term treatment with probucol had an For secondary prevention, the incidence of cardiovascular events was 27.0% in the exposed group and 64.3% in the unexposed group. An event-free survival curve for the secondary prevention group is given.…”

Section: Discussionmentioning

confidence: 88%

Long-Term Probucol Treatment Prevents Secondary Cardiovascular Events: a Cohort Study of Patients with Heterozygous Familial Hypercholesterolemia in Japan

Yamashita

HBujo

Arai

et al. 2008

JAT

100

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Section: Discussionmentioning

confidence: 88%

Long-Term Probucol Treatment Prevents Secondary Cardiovascular Events: a Cohort Study of Patients with Heterozygous Familial Hypercholesterolemia in Japan

Yamashita

HBujo

Arai

et al. 2008

JAT

100

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“…This interpretation is consistent with the observation that in apolipoprotein E Ϫ/Ϫ mice fed an atherogenic diet the aortic content of coenzyme Q also remains largely unchanged as lesions develop (541). However, supplementing these animals with large amounts of coenzyme Q, without and with additional vitamin E, decreases atherosclerosis (948,1053), although supplements at therapeutic concentrations do not inhibit atherosclerosis in LDL receptor-deficient rabbits (86), and even large amounts of coenzyme Q 10 do not inhibit intimal hyperplasia in balloon-injured rabbits (152).…”

Section: Nonproteinaceous Antioxidantsmentioning

confidence: 99%

Role of Oxidative Modifications in Atherosclerosis

Stocker¹,

Keaney²

2004

Physiological Reviews

Self Cite

2,249

1,756

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This review focuses on the role of oxidative processes in atherosclerosis and its resultant cardiovascular events. There is now a consensus that atherosclerosis represents a state of heightened oxidative stress characterized by lipid and protein oxidation in the vascular wall. The oxidative modification hypothesis of atherosclerosis predicts that low-density lipoprotein (LDL) oxidation is an early event in atherosclerosis and that oxidized LDL contributes to atherogenesis. In support of this hypothesis, oxidized LDL can support foam cell formation in vitro, the lipid in human lesions is substantially oxidized, there is evidence for the presence of oxidized LDL in vivo, oxidized LDL has a number of potentially proatherogenic activities, and several structurally unrelated antioxidants inhibit atherosclerosis in animals. An emerging consensus also underscores the importance in vascular disease of oxidative events in addition to LDL oxidation. These include the production of reactive oxygen and nitrogen species by vascular cells, as well as oxidative modifications contributing to important clinical manifestations of coronary artery disease such as endothelial dysfunction and plaque disruption. Despite these abundant data however, fundamental problems remain with implicating oxidative modification as a (requisite) pathophysiologically important cause for atherosclerosis. These include the poor performance of antioxidant strategies in limiting either atherosclerosis or cardiovascular events from atherosclerosis, and observations in animals that suggest dissociation between atherosclerosis and lipoprotein oxidation. Indeed, it remains to be established that oxidative events are a cause rather than an injurious response to atherogenesis. In this context, inflammation needs to be considered as a primary process of atherosclerosis, and oxidative stress as a secondary event. To address this issue, we have proposed an “oxidative response to inflammation” model as a means of reconciling the response-to-injury and oxidative modification hypotheses of atherosclerosis.

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“…In experimental and clinical studies, probucol has been reported to reduce intimal proliferation following balloon injury in animals [12,13] and to inhibit restenosis after coronary angioplasty with [14] and without [15] stent in humans. Probucol also dramatically retards atherosclerosis in hyperlipidemic animals [16][17][18] . Furthermore, probucol has been demonstrated to posse the capacity to attenuate inflammation in animal models of aging [19,20] , focal cerebral ischemia [8,9] and ischemic myocardial injury [21,22] , as well as in diabetic [23] and atherosclerotic rabbits [24] .…”

Section: Original Articlementioning

confidence: 99%

Probucol inhibits LPS-induced microglia activation and ameliorates brain ischemic injury in normal and hyperlipidemic mice

et al. 2016

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Aim: Increasing evidence suggests that probucol, a lipid-lowering agent with anti-oxidant activities, may be useful for the treatment of ischemic stroke with hyperlipidemia via reduction in cholesterol and neuroinflammation. In this study we examined whether probucol could protect against brain ischemic injury via anti-neuroinflammatory action in normal and hyperlipidemic mice. Methods: Primary mouse microglia and murine BV2 microglia were exposed to lipopolysaccharide (LPS) for 3 h, and the release NO, PGE2, IL-1β and IL-6, as well as the changes in NF-κB, MAPK and AP-1 signaling pathways were assessed. ApoE KO mice were fed a high-fat diet containing 0.004%, 0.02%, 0.1% (wt/wt) probucol for 10 weeks, whereas normal C57BL/6J mice received probucol (3, 10, 30 mg·kg -1 ·d -1 , po) for 4 d. Then all the mice were subjected to focal cerebral ischemia through middle cerebral artery occlusion (MCAO). The neurological deficits were scored 24 h after the surgery, and then brains were removed for measuring the cerebral infarct size and the production of pro-inflammatory mediators. Results: In LPS-treated BV2 cells and primary microglial cells, pretreatment with probucol (1, 5, 10 μmol/L) dose-dependently inhibited the release of NO, PGE2, IL-1β and IL-6, which occurred at the transcription levels. Furthermore, the inhibitory actions of probucol were associated with the downregulation of the NF-κB, MAPK and AP-1 signaling pathways. In the normal mice with MCAO, preadministration of probucol dose-dependently decreased the infarct volume and improved neurological function. These effects were accompanied by the decreased production of pro-inflammatory mediators (iNOS, COX-2, IL-1, IL-6). In ApoE KO mice fed a high-fat diet, pre-administration of 0.1% probucol significantly reduced the infarct volume, improved the neurological deficits following MCAO, and decreased the total-and LDL-cholesterol levels. Conclusion: Probucol inhibits LPS-induced microglia activation and ameliorates cerebral ischemic injury in normal and hyperlipidemic mice via its anti-neuroinflammatory actions, suggesting that probucol has potential for the treatment of patients with or at risk for ischemic stroke and hyperlipidemia.

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Comparison of the effects of α-tocopherol, ubiquinone-10 and probucol at therapeutic doses on atherosclerosis in WHHL rabbits

Cited by 31 publications

References 54 publications

Long-Term Probucol Treatment Prevents Secondary Cardiovascular Events: a Cohort Study of Patients with Heterozygous Familial Hypercholesterolemia in Japan

Long-Term Probucol Treatment Prevents Secondary Cardiovascular Events: a Cohort Study of Patients with Heterozygous Familial Hypercholesterolemia in Japan

Role of Oxidative Modifications in Atherosclerosis

Probucol inhibits LPS-induced microglia activation and ameliorates brain ischemic injury in normal and hyperlipidemic mice

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