Administration Of Probucol Research Articles

Probucol mitigates high-fat diet-induced cognitive and social impairments by regulating brain redox and insulin resistance.

Probucol has been utilized as a cholesterol-lowering drug with antioxidative properties. However, the impact and fundamental mechanisms of probucol in obesity-related cognitive decline are unclear. In this study, male C57BL/6J mice were allocated to a normal chow diet (NCD) group or a high-fat diet (HFD) group, followed by administration of probucol to half of the mice on the HFD regimen. Subsequently, the mice were subjected to a series of behavioral assessments, alongside the measurement of metabolic and redox parameters. Notably, probucol treatment effectively alleviates cognitive and social impairments induced by HFD in mice, while exhibiting no discernible influence on mood-related behaviors. Notably, the beneficial effects of probucol arise independently of rectifying obesity or restoring systemic glucose and lipid homeostasis, as evidenced by the lack of changes in body weight, serum cholesterol levels, blood glucose, hyperinsulinemia, systemic insulin resistance, and oxidative stress. Instead, probucol could regulate the levels of nitric oxide and superoxide-generating proteins, and it could specifically alleviate HFD-induced hippocampal insulin resistance. These findings shed light on the potential role of probucol in modulating obesity-related cognitive decline and urge reevaluation of the underlying mechanisms by which probucol exerts its beneficial effects.

Probucol treatment after traumatic brain injury activates BDNF/TrkB pathway, promotes neuroregeneration and ameliorates functional deficits in mice.

Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide, yet pharmacotherapies for TBI are currently lacking. Neuroregeneration is important in brain repair and functional recovery. In this study, probucol, a cholesterol-lowering drug with established safety profiles, was examined for its therapeutic effects and neuroregenerative actions in TBI. Male mice were subjected to the controlled cortical impact model of TBI, followed by daily administration of probucol. Neurological and cognitive functions were evaluated. Histological analyses of the neocortex and hippocampus were performed to detect the lesion, dendritic degeneration (microtubule-associated protein 2), synaptic density (synaptophysin), neurogenesis (doublecortin), brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) activation. Involvement of BDNF/TrkB pathway in probucol-mediated effects was examined in primary cultures of cortical neurons. Probucol reduced brain lesion volume, enhanced the recovery of body symmetry, improved motor function and attenuated memory dysfunction after TBI. Meanwhile, probucol promoted post-injury dendritic growth and synaptogenesis and increased hippocampal proliferating neuronal progenitor cells, along with the formation as well as the survival of newborn neurons. Moreover, probucol enhances BDNF expression and TrkB activation. In vitro, probucol promoted neurite outgrowth, which was inhibited by a selective TrkB antagonist ANA-12. Probucol enhanced functional restoration and ameliorated cognitive impairment after TBI by promoting post-injury neuronal remodelling and neurogenesis. Increased activation of BDNF/TrkB pathway by probucol, at least in part, contributed to the neuroregenerative effects of probucol. Together, it may be promising to repurpose probucol for TBI.

Sphingosine 1-Phosphate Signaling Is Involved in Impaired Blood-Brain Barrier Function in Ischemia-Reperfusion Injury.

Sphingosine 1-phosphate (S1P) is a major bioactive lipid mediator in the vascular and immune system. Here, we have shown that inhibition of S1P signaling prevents blood-brain barrier (BBB) dysfunction after ischemia both in vitro and in vivo. In the in vitro BBB models, oxygen-glucose deprivation and reoxygenation (OGD/R) enhanced the expression of an S1P synthesizing enzyme (Sphk1) and S1P transporters (Abca1, Spns2), increasing S1P in culture media. Inhibitors of Sphk1 (SKI-II) or Abca1 (probucol) attenuated the decrease in transendothelial electrical resistance and the increase in permeability caused by OGD/R. In the middle cerebral artery occlusion and reperfusion (MCAO/R) model of mice, probucol administration after MCAO operation reduced the infarction area and vascular leakage, preserving the integrity of tight junction proteins. Furthermore, MCAO/R caused activation of STAT3, a downstream mediator of S1P signaling, which was suppressed by postoperative probucol administration. Accordingly, S1P activated STAT3, both in cultured vascular endothelial cells and pericytes, and STAT3 signaling inhibitor (Stattic) protected BBB dysfunction in OGD/R-treated in vitro BBB models. These results suggest that inhibition of S1P signaling is a strategy to treat BBB impairment after cerebral ischemia and highlight the potential alternative use of probucol, a classical anti-hyperlipidemic drug, for emergency treatment of stroke.

Probucol induces the generation of lipid peroxidation products in erythrocytes and plasma of male cynomolgus macaques.

We previously reported that probucol, a lipid lowering agent, protected mice from malaria infection via depletion in plasma α-tocopherol. The antioxidant α-tocopherol in host circulation is necessary for the malaria parasites to protect themselves from oxidative stress in erythrocytes where high amounts of reactive oxygen species are generated. To assess the potential for the clinical application of probucol as an anti-malarial therapy, it was necessary to determine the effects of probucol by using primate experiments. Here we verified that probucol induces an α-tocopherol decrement in cynomolgus macaque erythrocytes and plasma. After 2 weeks of probucol administration at doses of 200 or 400 mg/kg/day, the α-tocopherol contents in erythrocytes tended to decrease. The contents of hydroxyoctadecadienoic acids and 7β-hydroxycholesterol, peroxidation products derived from linoleic acid and cholesterol, respectively, increased in erythrocytes. On the other hand, plasma α-tocopherol concentration showed a marginal decrement. Plasma lipid peroxidation products were transiently increased in the early stages of probucol administration. No adverse effects were observed throughout the experiment, although the dosage of probucol was higher than the clinical maximum dosage. Considering that malaria proliferates in erythrocytes, probucol-induced disruption of redox homeostasis in erythrocytes could be effective in the inhibition of parasite proliferation.

Oral administration of alcalase potato protein hydrolysate-APPH attenuates high fat diet-induced cardiac complications via TGF-β/GSN axis in aging rats.

Consumption of high fat diet (HFD) is associated with increased cardiovascular risk factors among elderly people. Aging and obesity induced-cardiac remodeling includes hypertrophy and fibrosis. Gelsolin (GSN) induces cardiac hypertrophy and TGF-β, a key cytokine, which induces fibrosis. The relationship between TGF-β and GSN in aging induced cardiac remodeling is still unknown. We evaluated the expressions of TGF-β and GSN in HFD fed 22 months old aging SD rats, followed by the administration of either probucol or alcalase potato protein hydrolysate (APPH). Western blotting and Masson trichrome staining showed that APPH (45 and 75 mg/kg/day) and probucol (500 mg/kg/day) treatments significantly reduced the aging and HFD-induced hypertrophy and fibrosis. Echocardiograph showed that the performance of the hearts was improved in APPH, and probucol treated HFD aging rats. Serum from all rats was collected and H9c2 cells were cultured with collected serums separately. The GSN dependent hypertrophy was inhibited with an exogenous TGF-β in H9c2 cells cultured in HFD+ APPH treated serum. Thus, we propose that along with its role in cardiac fibrosis, TGF-β also acts as an upstream activator of GSN dependent hypertrophy. Hence, TGF-β in serum could be a promising therapeutic target for cardiac remodeling in aging and/or obese subjects.

Antidepressant Effects of Probucol on Early-Symptomatic YAC128 Transgenic Mice for Huntington's Disease.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a trinucleotide expansion in the HD gene, resulting in an extended polyglutamine tract in the protein huntingtin. HD is traditionally viewed as a movement disorder, but cognitive and neuropsychiatric symptoms also contribute to the clinical presentation. Depression is one of the most common psychiatric disturbances in HD, present even before manifestation of motor symptoms. Diagnosis and treatment of depression in HD-affected individuals are essential aspects of clinical management in this population, especially owing to the high risk of suicide. This study investigated whether chronic administration of the antioxidant probucol improved motor and affective symptoms as well as hippocampal neurogenic function in the YAC128 transgenic mouse model of HD during the early- to mild-symptomatic stages of disease progression. The motor performance and affective symptoms were monitored using well-validated behavioral tests in YAC128 mice and age-matched wild-type littermates at 2, 4, and 6 months of age, after 1, 3, or 5 months of treatment with probucol (30 mg/kg/day via water supplementation, starting on postnatal day 30). Endogenous markers were used to assess the effect of probucol on cell proliferation (Ki-67 and proliferation cell nuclear antigen (PCNA)) and neuronal differentiation (doublecortin (DCX)) in the hippocampal dentate gyrus (DG). Chronic treatment with probucol reduced the occurrence of depressive-like behaviors in early- and mild-symptomatic YAC128 mice. Functional improvements were not accompanied by increased progenitor cell proliferation and neuronal differentiation. Our findings provide evidence that administration of probucol may be of clinical benefit in the management of early- to mild-symptomatic HD.

A Bioactive Peptide Ameliorates Diet‐induced Nonalcoholic Fatty Liver in Senescence Accelerated Mice Prone 8 (SAMP8)‐Genetic Ageing Model

Background & PurposesAging and high‐fat diet (HFD) hypernutrition represent two major risk factors for nonalcoholic fatty liver disease (NAFLD). To investigate the chemopreventive effects of bioactive compounds in fatty liver, our lab has successfully developed various dietary murine models for the past years. Considering special issues with drug administration in elderly subjects, we purposed in this present work to induce NAFLD in senescence‐accelerated mice prone 8 (SAMP8) specific strains with HFD (60% calories from fat) and evaluate a novel bioactive peptide (DIKTNKPVIF) synthesized from a well‐studied lipolysis‐activating potato protein hydrolysate (PH), for its efficacy to reduce HFD‐driven fat deposition and associated proinflammatory events responsible for NAFLD development in SAMP8 aging mice.Methods & ResultsFive groups of six‐month‐old SAMP8 mice (n=4, per group) were submitted to a fourteen‐week experimental study. After sacrifice at ten months of age, liver tissue from individual mouse was collected for histopathological analyses and immunoblot assay. In comparison to the normal chow‐fed control group (NC) with minor aging‐associated hepatic fat depot, HCO group upon the fourteen‐week HFD feeding without treatment displayed widespread hepatic fat droplets evidenced by histopathological analyses of their liver slides. In addition to HFD feeding, a concomitant treatment for the final eight weeks with intraperitoneal dose of the bioactive peptide (HPEP group; 15 mg/kg/d b.w.), oral PH supplementation (HPH group; 50 mg/kg/d b.w.) or oral administration of probucol (HRX group; 500 mg/kg/d b.w) reduced liver steatosis in HPEP, HPH and HRX respectively. Contrary to a very low level of AMPK (HCO vs NC, p<0.001), highly expressed hepatic inflammatory proteins such as p‐38 MAP Kinase, MMP‐9, TNF‐α, IL‐6 were found in HCO. Following the trends of other treatments, the peptide administration reactivated hepatic AMPK (HPEP vs HCO, p<0.05), while significantly downregulated proinflammatory marker p‐p38 and cytokines TNF‐α, FGF‐2.ConclusionsOur set of data show strong evidence for an anti‐steatosis effect of our ten‐amino‐acid peptide (DIKTNKPVIF) and its role to alleviate proinflammatory reaction associated with HFD‐induced hepatosteatosis development in elderly, through activation of AMPK signaling in parallel with the impediment of proinflammatory and mitogenic activities of p‐38 MAPK and FGF‐2. Similarly to PH, our peptide may be suggested as a preventive alternative for NAFLD in elderly subjects.Support or Funding InformationThis work was funded in part by grants from the Ministry of Science and Technology of Taiwan (MOST103‐2410‐H‐029‐037 and MOST104‐2410‐H‐029‐ 033‐MY2). SD (Faculte de Medecine et de Pharmacie, Universite d'Etat d'Haiti ‐ FMP UEH) was financially supported by Taiwan Ministry of Foreign Affairs (MOFA) Scholarship Program for the Republic of Haiti.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Bioactive Peptide Improves Diet-Induced Hepatic Fat Deposition and Hepatocyte Proinflammatory Response in SAMP8 Ageing Mice

Background/Aims: High-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD) poses therapeutic challenges in elderly subjects. Due to lack of efficient drug therapy, plant-based bioactive peptides have been studied as alternative strategy in NAFLD and for less toxicity in elderly. To mimic fatty liver in aging conditions, researchers highly commended the genetically engineered strains SAMP8 (senescence-accelerated mice prone 8). However, there is a paucity of reports about the anti-steatosis effects of bioactive peptides against fatty liver development under a combined action of high-fat diet exposure and aging process. This study was conducted to evaluate the activity of DIKTNKPVIF peptide synthesized from alcalase-generated potato protein hydrolysate (PH), on reducing HFD-driven and steatosis-associated proinflammatory reaction in ageing model. Methods: Five groups of six-month-old SAMP8 mice (n=4, each) were fed either a normal chow (NC group) for 14 weeks upon sacrifice, or induced with a 6-week HFD feeding, then treated without (HCO group) or with an 8-week simultaneous administration of peptide (HPEP group), protein (HPH group) or probucol (HRX group). Liver organs were harvested from each group for histological analysis and immunoblot assay. Results: In contrast to NC, extensive fat accumulation was visualized in the liver slides of HCO. Following the trends of orally administered PH, intraperitoneally injected peptide reduces hepatic fat deposition and causes at protein level, a significant decrease in HFD-induced proinflammatory mediators p-p38 MAPK, FGF-2, TNF-α, IL-6 with concomitant reactivation of AMPK. However, p-Foxo1 and PPAR-α levels were slightly changed. Conclusion: Oral supplementation of PH and intraperitoneal injection of derived bioactive peptide alleviate proinflammatory reaction associated with hepatosteatosis development in elderly subjects, through activation of AMPK.

Probucol attenuates hyperoxia-induced lung injury in mice

Hyperoxic lung injury is pathologically characterized by alveolar edema, interlobular septal edema, hyaline membrane disease, lung inflammation, and alveolar hemorrhage. Although the precise mechanism by which hyperoxia causes lung injury is not well defined, oxidative stress, epithelial cell death, and proinflammatory cytokines are thought to be involved. Probucol—a commercially available drug for treating hypercholesterolemia—has been suggested to have antioxidant and antiapoptotic effects. This study aimed to assess whether probucol could attenuate hyperoxic lung injury in mice. Mice were exposed to 95% O2 for 72 h, with or without pre-treatment with 130 μg/kg probucol intratracheally. Probucol treatment significantly decreased both the number of inflammatory cells in the bronchoalveolar lavage fluid and the degree of lung injury in hyperoxia-exposed mice. Probucol treatment reduced the number of cells positive for 8-hydroxyl-2′-deoxyguanosine or terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and suppressed NF-κB activation, Bax expression, and caspase-9 activation in lung tissues from hyperoxia-exposed mice. These results suggest that probucol can reduce oxidative DNA damage, apoptotic cell death, and inflammation in lung tissues. Intratracheal administration of probucol may be a novel treatment for lung diseases induced by oxidative stress, such as hyperoxic lung injury and acute respiratory distress syndrome.

Low molecular weight fucoidan ameliorates streptozotocin-induced hyper-responsiveness of aortic smooth muscles in type 1 diabetes rats

Ethnopharmacological relevanceLow molecular weight fucoidan (LMWF) was prepared from Laminaria japonica Areschoug, a popular seafood and medicinal plant consumed in Asia. Chinese have long been using it as a traditional medicine for curing hypertension and edema. Aim of the studyThis study was intent to investigate the possible beneficial effect of LMWF on hyper-responsiveness of aortic smooth muscles instreptozotocin (STZ)-induced type 1 diabetic rats. Materials and methodsSprague-Dawley rats were made diabetic by injection of STZ, followed by the administration of LMWF (50 or 100mg/kg/day) or probucol (100mg/kg/day) for 12 weeks. Body weight, blood glucose level, basal blood pressure, serum lipid profiles, oxidative stress, prostanoids production, and vasoconstriction response of endothelium-denuded aorta rings to phenylephrine were measured by Real time-PCR, Western blots, ELISA assay, and force myograph, respectively. ResultsLMWF (100mg/kg/day)-treated group showed robust improvements on STZ-induced body weight-loss, hypertension, and hyperlipidaemia as indicated by decreased serum level of total cholesterol, triglyceride, and low density lipoprotein cholesterol; while probucol, a lipid-modifying drug with antioxidant properties, displayed mild effects. In addition, LMWF appreciably ameliorated STZ-elicited hyper-responsiveness and oxidative stress in aortic smooth muscles as indicated by decreased superoxide level, increased glutathione content and higher superoxide dismutase activity. Furthermore, administration with LMWF dramatically prevented cyclooxygenase-2 stimulation and restored the up-regulation of thromboxane synthase and down-regulation of 6-keto-PGF1α (a stable metabolic product of prostaglandin I2) in the STZ-administered rats. ConclusionThis study demonstrates for the first time that LMWF can protect against hyperlipidaemia, hypertension, and hyper-responsiveness of aortic smooth muscles in type 1 diabetic rat via, at least in part, amelioration of oxidative stress and restoration of prostanoids levels in aortic smooth muscles. Therefore, LMWF can be a potential adjuvant treatment against cardiovascular complications in type 1 diabetes.

Probucol prevents atrial remodeling by inhibiting oxidative stress and TNF-α/NF-κB/TGF-β signal transduction pathway in alloxan-induced diabetic rabbits.

Diabetes mellitus (DM) is an independent risk factor for atrial fibrillation (AF). However, the underlying mechanisms for the increased propensity for AF in the setting of DM and the potential effects of probucol on atrial remodeling remain unclear. Eighty Japanese rabbits were randomly assigned to normal/control group (Control, n = 20), alloxan-induced diabetic group (DM, n = 20), probucol-treated group (Control-P, n = 20), and probucol-treated diabetic group (DM-P, n = 20). Rabbits in the DPR and CPR groups were orally administered probucol (1,000 mg/day) for 8 weeks. Serum and left atrial tissue malonaldehyde (MDA), superoxide dismutase (SOD), myeloperoxidase (MPO), and catalase (CAT) levels were assessed. Isolated Langendorff perfused rabbit hearts were prepared to evaluate atrial refractory effective period (AERP) and its dispersion (AERPD), interatrial conduction time (IACT), and vulnerability to AF. Atrial interstitial fibrosis was also evaluated. The mRNA expression levels of TNF-α and TLR4 were analyzed. The protein expressions of NF-κB, HSP70, TGF-β, and ERK in left atrial tissue were analyzed by Western blot. Probucol administration decreased the inducibility of AF in diabetic rabbits and attenuated atrial interstitial fibrosis. The DM-P rabbits exhibited significant alleviation of oxidative stress, evidenced by reduced serum and tissue MDA, compared with diabetic rabbits. Moreover, NF-κB, TGF-β, and HSP70 protein expression and TNF-α mRNA expression were significantly downregulated by probucol treatment in alloxan-induced diabetic rabbits. Probucol prevents atrial remodeling and suppresses AF development in alloxan-induced diabetic rabbits. Its inhibitory effects on oxidative stress, NF-κB, TGF-β, and TNF-α overexpression may contribute to its antiremodeling effects.

Scavenger Receptor BI and High-Density Lipoprotein Regulate Thymocyte Apoptosis in Sepsis

Thymocyte apoptosis is a major event in sepsis; however, how this process is regulated remains poorly understood. Septic stress induces glucocorticoids production which triggers thymocyte apoptosis. Here, we used scavenger receptor BI (SR-BI)-null mice, which are completely deficient in inducible glucocorticoids in sepsis, to investigate the regulation of thymocyte apoptosis in sepsis. Cecal ligation and puncture induced profound thymocyte apoptosis in SR-BI(+/+) mice, but no thymocyte apoptosis in SR-BI(-/-) mice because of lack of inducible glucocorticoids. Unexpectedly, supplementation of glucocorticoids only partly restored thymocyte apoptosis in SR-BI(-/-) mice. We demonstrated that high-density lipoprotein (HDL) is a critical modulator for thymocyte apoptosis. SR-BI(+/+) HDL significantly enhanced glucocorticoid-induced thymocyte apoptosis, but SR-BI(-/-) HDL had no such activity. Further study revealed that SR-BI(+/+) HDL modulates glucocorticoid-induced thymocyte apoptosis via promoting glucocorticoid receptor translocation, but SR-BI(-/-) HDL loses such regulatory activity. To understand why SR-BI(-/-) HDL loses its regulatory activity, we analyzed HDL cholesterol contents. There was 3-fold enrichment of unesterified cholesterol in SR-BI(-/-) HDL compared with SR-BI(+/+) HDL. Normalization of unesterified cholesterol in SR-BI(-/-) HDL by probucol administration or lecithin cholesteryl acyltransferase expression restored glucocorticoid-induced thymocyte apoptosis, and incorporating unesterified cholesterol into SR-BI(+/+) HDL rendered SR-BI(+/+) HDL dysfunctional. Using lckCre-GR(fl/fl) mice in which thymocytes lack cecal ligation and puncture-induced thymocyte apoptosis, we showed that lckCre-GR(fl/fl) mice were significantly more susceptible to cecal ligation and puncture-induced septic death than GR(fl/fl) control mice, suggesting that glucocorticoid-induced thymocyte apoptosis is required for protection against sepsis. The findings in this study reveal a novel regulatory mechanism of thymocyte apoptosis in sepsis by SR-BI and HDL.

RETRACTED: Probucol via inhibition of NHE1 attenuates LPS-accelerated atherosclerosis and promotes plaque stability in vivo

Activation of Na(+)/H(+) exchanger 1 (NHE1) by lipopolysaccharide (LPS) via Ca(2+)/calpain is responsible in vascular smooth muscle cell (VSMC) apoptosis and to the process of atherosclerosis. Probucol is a lipid-lowering drug which has an anti-atherosclerosis effect. The mechanism remains poorly understood. Here we hypothesized that probucol via inhibition of NHE1 in VSMCs attenuates LPS-accelerated atherosclerosis and promotes plaque stability. Our results revealed that treatment of VSMCs with LPS increased the NHE1 activity in a time-dependent manner, associated with the increased Ca(2+)i. Probucol inhibited the LPS-induced increase of NHE1 activity in a dose-dependent manner in VSMCs for 24-hour co-incubation, as well as the change of Ca(2+)i. In addition, LPS enhanced the calpain activity. Both probucol and calcium chelation of Ca(2+) abolished the LPS-induced increase of calpain activity. Treatment of VSMCs with LPS reduced the expression of Bcl-2 without altering the mRNA level. Probucol inhibited the LPS-reduced expression of Bcl-2 protein in VSMCs. Animal studies indicated administration of probucol suppressed LPS-accelerated apoptosis, atherosclerosis and plaque instability in Apoe(-/-) mice. In conclusion, probucol via inhibition of NHE1 attenuates atherosclerosis lesion growth and promotes plaque stability.

GW24-e3518 Probucol prevents atrial remodeling by inhibiting reactive oxygen species production and NF-kappaB activation in alloxan-induced diabetic rabbits

ObjectivesThis study sought to assess the effects of probucol on atrial remodelling and atrial fibrillation (AF) promotion in alloxan-induced diabetic rabbits and to elucidate the underlying mechanisms.Methods40 Japanese rabbits were...

Abstract 271: Scavenger Receptor Bi is a Key Determinant and HDL is a Critical Modulator of Thymocyte Apoptosis in Sepsis

Background- Thymocyte apoptosis is a major event in sepsis; however, how this process is regulated remains poorly understood. Methods and Results- We induced sepsis in scavenger receptor BI (SR-BI) null and wild type littermates with cecal ligation and puncture (CLP). CLP induced profound thymocyte apoptosis in SR-BI +/+ mice, but no thymocyte apoptosis in SR-BI -/- mice, indicating that SR-BI is a key determinant of thymocyte apoptosis in sepsis. SR-BI controlled inducible glucocorticoid (GC) generation during sepsis, which is required for triggering thymocyte apoptosis. Unexpectedly, supplementation with GC only partly restored thymocyte apoptosis in SR-BI -/- mice. We demonstrated that HDL is a critical modulator for thymocyte apoptosis. SR-BI +/+ HDL significantly enhanced GC-induced thymocyte apoptosis but SR-BI -/- HDL had no such activity. Further study revealed that SR-BI +/+ HDL modulates GC-induced thymocyte apoptosis via promoting glucocorticoid receptor translocation, but SR-BI -/- HDL loses such regulatory activity. To understand why SR-BI -/- HDL loses its regulatory activity, we analyzed HDL cholesterol contents and found that there was 3-fold enrichment of unesterified cholesterol in SR-BI -/- HDL compared with SR-BI +/+ HDL. Importantly, normalization of unesterified cholesterol in SR-BI -/- HDL by probucol administration restored GC-induced thymocyte apoptosis both in vitro and in vivo , and incorporating unesterified cholesterol into SR-BI +/+ HDL rendered SR-BI +/+ HDL dysfunctional. Conclusions- The findings in this study reveal a previously unrecognized regulatory mechanism of thymocyte apoptosis in sepsis, involving SR-BI as a key determinant and HDL as a critical modulator.

EFFECT OF PROBUCOL ON ATRIAL ELECTROPHYSIOLOGICAL CHANGES AND INDUCIBILITY OF ATRIAL FIBRILLATION IN ALLOXAN-INDUCED DIABETIC RABBITS

ObjectivesTo investigate the effects of probucol on AF promotion in alloxan-induced diabetic rabbits.MethodsTwenty alloxan-induced diabetic rabbits were examined. Ten of these were treated with probucol at a dose of 1000...

Development of a Novel Model of Hypertriglyceridemic Acute Pancreatitis in Hamsters

The aim of the present study was to develop a model of hypertriglyceridemic (HTG) acute pancreatitis and to investigate the effects of probucol in this model. Hamsters were fed a high-fat diet (HFD) or a normal diet for 3 weeks. Probucol was added at 1% to the HFD in the treated group. Pancreatitis was induced by 7 peritoneal injections of cerulein to the normal and HFD hamster groups. The severity of the pancreatitis and whole body oxidative stress were assessed. The HFD induced severe HTG (>1000 mg/dL) in the hamsters. A more severe pancreatitis was observed in the HFD group. The HFD did not influence plasma-reduced glutathione level, but there was a significant increase after 1% probucol was provided in the diet. Plasma malonaldehyde levels in the HFD group were significantly higher than the normal chow group, whereas probucol administration significantly decreased plasma hydrogen peroxide and malonaldehyde levels. We also found that probucol significantly reduced levels of amylase and lipase in the plasma and pathological scores in pancreatic tissue. This study presents a novel model of severe HTG acute pancreatitis, and our results support the potential therapeutic application of probucol in HTG acute pancreatitis.

Probucol therapy improves long-term (>10-year) survival after complete revascularization: A propensity analysis

Objective Probucol has anti-atherosclerotic properties and has been shown to reduce post-angioplasty coronary restenosis. However, the effect of probucol therapy on long-term (>10 years) outcome following coronary revascularization is less well established. Accordingly, we sought to determine if probucol therapy at the time of complete coronary revascularization reduces mortality in patients with coronary artery disease (CAD). Methods We collected data from 1694 consecutive patients who underwent complete revascularization (PCI and/or bypass surgery). Mortality data were compared between patients administered probucol and those not administered probucol at the time of revascularization. A propensity score (PS) was calculated to evaluate the effects of variables related to decisions regarding probucol administration. The association of probucol use and mortality was assessed using 3 Cox regression models, namely, conventional adjustment, covariate adjustment using PS, and matching patients in the probucol and no-probucol groups using PS. Results In the pre-match patients, 231 patients were administered probucol (13.6%). During follow-up [10.2 (SD, 3.2) years], 352 patients died (including 113 patients who died of cardiac-related issues). Probucol use was associated with significant decrease in all-cause death (hazard ratio [HR], 0.65; P = 0.036 [conventional adjustment model] and HR, 0.57; P = 0.008 [PS adjusted model]). In post-match patients ( N = 450, 225 matched pair), the risk of all-cause mortality was significantly lower in the probucol group than in the no-probucol group (HR, 0.45; P = 0.002). Conclusion In CAD patients who had undergone complete revascularization, probucol therapy was associated with a significantly reduced risk of all-cause mortality.

Combinatorial Effect of Probucol and Cilostazol in Focal Ischemic Mice with Hypercholesterolemia

Hypercholesterolemia may increase stroke risk by accelerating atherosclerosis, narrowing the luminal diameter in cerebral vessels, and disrupting both vascular endothelial and smooth muscle function. In the present study, we investigated the beneficial effects of combinatorial therapy with probucol and cilostazol on focal cerebral ischemia with hypercholesterolemia. Apolipoprotein E (ApoE) knockout (KO) mice were fed a high-fat diet with or without 0.5% probucol and/or 0.2% cilostazol for 10 weeks. Probucol alone and probucol and cilostazol significantly decreased total, low-density lipoprotein, and high-density lipoprotein cholesterol, whereas cilostazol did not affect the plasma cholesterol levels in ApoE KO mice. Administration of probucol alone and cilostazol alone significantly decreased atherosclerotic lesion area in the aorta, with a significant decrease evident using combinatorial administration. Middle cerebral artery occlusion resulted in significantly larger infarct volumes in ApoE KO mice fed 10 weeks of high-fat diet compared with those in ApoE KO mice fed a regular diet. The infarct volume was reduced significantly using probucol alone or cilostazol alone and even was reduced significantly by their combinatorial administration. Consistent with a larger infarct size, the combinatorial therapy prominently improved neurological function. The combinatorial administration increased cerebral blood flow during ischemia. Expression of endothelial nitric oxide synthase and adiponectin in the cortex were decreased by high-fat diet but were elevated by combinatorial treatment. Adiponectin expression colocalized within the cerebral vascular endothelium. The data suggest that the combination of probucol and cilostazol prevents cerebrovascular damage in focal cerebral ischemic mice with hypercholesterolemia by up-regulation of endothelial nitric oxide synthase and adiponectin.

Impact of short-duration administration of N-acetylcysteine, probucol and ascorbic acid on contrast-induced cytotoxicity

The best pharmaceutical prevention of contrast-medium-induced nephropathy for emergency procedures remains unknown. The aim of this study was to examine the impact of short-duration antioxidant pretreatment on contrast-medium-induced cytotoxicity. Human embryonic kidney cells were treated with three different contrast media: ionic ioxitalamate, non-ionic low-osmolar iopromide, and iso-osmolar iodixanol. The doses and durations of pretreatment with antioxidants were 2 mM/L N-acetylcysteine for 15 minutes, 40 µM/L probucol for 30 minutes, and 30 µM/L ascorbic acid for 30 minutes. A supplementary dose of 2 mM/L N-acetylcysteine was administered 12 hours after contrast medium treatment. Cell viability was determined by tetrazolium MTT assay. All three contrast media caused significant reduction of cell viability at 24 hours (p<0.001). In the groups receiving iopromide or iodixanol, N-acetylcysteine pretreatment significantly improved cell viability compared with no N-acetylcysteine pretreatment (p<0.001). In the group receiving ioxitalamate, N-acetylcysteine pretreatment followed by a supplementary dose of N-acetylcysteine at 12 hours rather than N-acetylcysteine pretreatment alone significantly improved cell viability compared with no N-acetylcysteine pretreatment (p=0.038). Probucol or ascorbic acid pretreatment was unable to reduce cell death caused by the three contrast media. Short-duration pretreatment with N-acetylcysteine significantly reduced contrast-medium-induced cytotoxicity. These findings provide new insight into the prevention of contrast-medium-induced nephropathy in clinical emergency scenarios.