Evaluating the impact of adjunctive istradefylline on the cumulative dose of levodopa-containing medications in Parkinson's disease: study protocol for the ISTRA ADJUST PD randomized, controlled study.

BACKGROUND: Levodopa remains the most effective symptomatic treatment for Parkinson's disease (PD) more than 50 years after its clinical introduction. However, the onset of motor complications can limit pharmacological intervention with levodopa, which can be a challenge when treating PD patients. Clinical data suggest using the lowest possible levodopa dose to balance the risk/benefit. Istradefylline, an adenosine A2A receptor antagonist indicated as an adjunctive treatment to levodopa-containing preparations in PD patients experiencing wearing off, is currently available in Japan and the US. Preclinical and preliminary clinical data suggested that adjunctive istradefylline may provide sustained antiparkinsonian benefits without a levodopa dose increase; however, available data on the impact of istradefylline on levodopa dose titration are limited. The ISTRA ADJUST PD study will evaluate the effect of adjunctive istradefylline on levodopa dosage titration in PD patients. METHODS: This 37-week, multicenter, randomized, open-label, parallel-group controlled study in PD patients aged 30-84 years who are experiencing the wearing-off phenomenon despite receiving levodopa-containing medications ≥ 3 times daily (daily dose 300-400 mg) began in February 2019 and will continue until February 2022. Enrollment is planned to attain 100 evaluable patients for the efficacy analyses. Patients will receive adjunctive istradefylline (20 mg/day, increasing to 40 mg/day) or the control in a 1:1 ratio, stratified by age, levodopa equivalent dose, and presence/absence of dyskinesia. During the study, the levodopa dose will be increased according to symptom severity. The primary study endpoint is the comparison of the cumulative additional dose of levodopa-containing medications during the treatment period between the adjunctive istradefylline and control groups. Secondary endpoints include changes in efficacy rating scales and safety outcomes. DISCUSSION: This study aims to clarify whether adjunctive istradefylline can reduce the cumulative additional dose of levodopa-containing medications in PD patients experiencing the wearing-off phenomenon, and lower the risk of levodopa-associated complications. It is anticipated that data from ISTRA ADJUST PD will help inform future clinical decision-making for patients with PD in the real-world setting. TRIAL REGISTRATION: Japan Registry of Clinical Trials, jRCTs031180248 ; registered 12 March 2019.

Myelin-oligodendrocyte glycoprotein antibody-positive encephalitis in a patient with Sturge-Weber syndrome.

Sturge-Weber syndrome (SWS) is a rare congenital disorder associated with systemic vascular malformations characterized by port-wine stains, epilepsy, and glaucoma. Patients with SWS can develop stroke-like symptoms such as hemiparesis. We report a case of a 63-year old woman with SWS who developed left-sided hemiparesis and was finally diagnosed with myelin-oligodendrocyte glycoprotein (MOG) antibody-positive encephalitis. Brain magnetic resonance imaging (MRI) revealed right-dominant bilateral leptomeningeal enhancement, thickened dura mater, and a cerebellar lesion. Cerebrospinal fluid (CSF) examination showed pleocytosis. Both serum and CSF proved positive for MOG antibodies. The patient recovered immediately after intravenous methylprednisolone administration. SWS and MOG antibody-positive encephalitis share similar clinical findings of stroke-like symptoms and leptomeningeal enhancement on MRI. However, MOG antibody-positive encephalitis is highly steroid-responsive in most cases. If a patient with SWS develops stroke-like symptoms accompanied by abnormal CSF findings or subtentorial lesions, testing for MOG antibodies should be considered.

Impact of Istradefylline on Levodopa Dose Escalation in Parkinson's Disease: ISTRA ADJUST PD Study, a Multicenter, Open-Label, Randomized, Parallel-Group Controlled Study.

INTRODUCTION: A higher levodopa dose is a risk factor for motor complications in Parkinson's disease (PD). Istradefylline (IST) is used as adjunctive treatment to levodopa in PD patients with off episodes, but its impact on levodopa dose titration remains unclear. The objective of this study was to investigate the effect of IST on levodopa dose escalation in PD patients with wearing-off. METHODS: This was a multicenter, open-label, randomized, parallel-group controlled study (ISTRA ADJUST PD) in which PD patients experiencing wearing-off (n = 114) who were receiving levodopa 300-400 mg/day were randomized to receive IST or no IST (control). Levodopa dose was escalated according to clinical severity. The primary endpoint was cumulative additional levodopa dose, and secondary endpoints were changes in symptom rating scales, motor activity determined by a wearable device, and safety outcomes. RESULTS: The cumulative additional levodopa dose throughout 37 weeks and dose increase over 36 weeks were significantly lower in the IST group than in the control group (both p < 0.0001). The Movement Disorder Society Unified Parkinson's Disease Rating Scale Part I and device-evaluated motor activities improved significantly from baseline to 36 weeks in the IST group only (all p < 0.05). Other secondary endpoints were comparable between the groups. Adverse drug reactions (ADRs) occurred in 28.8% and 13.2% of patients in the IST and control groups, respectively, with no serious ADRs in either group. CONCLUSION: IST treatment reduced levodopa dose escalation in PD patients, resulting in less cumulative levodopa use. Adjunctive IST may improve motor function more objectively than increased levodopa dose in patients with PD. TRIAL REGISTRATION: Japan Registry of Clinical Trials: jRCTs031180248.

Super MI sensor: recent advances of amorphous wire and CMOS-IC magneto-impedance sensor.

We indicate that the Magneto-Impedance sensor using amorphous wires has reached a new stage to view "Super MI sensor technology" based on three main advantageous factors of (i) micro sized head and micro power consumption chip, (ii) ultra-high sensitivity micro magnetic sensor with 1 pico-Tesla resolution at the room temperature without any electromagnetic shielding, and (iii) ultra-quick response magnetic sensor with GHz operation. We summarize systematically the magneto-impedance technology with the basic principle and mechanisms of three advantageous features for constitution of various high performance new sensor devices such as the electronic compass chip for mobile phones and smart phones and portable sensors for the magneto-encephalography, the magneto-spinography, and various bio-cell magnetic measurements. Possibility of new application to MI antenna in magnetic telecommunications is also discussed.

Differential levels of alpha-synuclein, beta-amyloid42 and tau in CSF between patients with dementia with Lewy bodies and Alzheimer's disease.

BACKGROUND: The clinical diagnosis of dementia with Lewy bodies (DLB) is made on the basis of consensus criteria; however, the sensitivity of the criteria is relatively low. There are no generally accepted biomarkers to distinguish DLB from other dementias. Here the utility of quantification of alpha-synuclein, beta-amyloid42 (Abeta42) and tau in the CSF of patients with DLB, Alzheimer's disease (AD) and other dementias was examined. METHODS: 86 patients were divided into three age and sex matched groups: DLB (n=34), AD (n=31) and other dementias (n=21). Two patients with alpha-synuclein gene (SNCA) duplication were also examined. Abeta and tau were quantified using an ELISA kit. A modified sandwich ELISA was developed which enables the sensitive quantification of CSF alpha-synuclein. RESULTS: Total and phosphorylated tau levels as well as Abeta40/42 and tau/Abeta42 ratios were significantly higher in AD patients than in patients with DLB (p<0.01) and other dementias (p<0.01). CSF alpha-synuclein levels in DLB patients were significantly lower than those in patients with AD (p<0.05) and other dementias (p<0.01). CSF alpha-synuclein level correlated with the Abeta42 level in DLB patients (p=0.01, r=0.43). Two patients with SNCA duplication exhibited relatively low levels of CSF alpha-synuclein. CONCLUSIONS: The study suggests that reduced levels of CSF alpha-synuclein in DLB may reflect the accumulation of alpha-synuclein with Lewy pathology in the brain and that quantification of CSF alpha-synuclein helps in the differentiation of DLB from AD and other dementias in combination with Abeta42 and tau analysis.

Generation of a human induced pluripotent stem cell line derived from a Parkinson's disease patient carrying SNCA duplication.

Parkinson's disease (PD) is a devastating movement disorder with an unknown etiology. Multiplications of the SNCA gene cause the autosomal dominant form of familial PD as well as missense mutations of the gene. We established and characterized a human induced pluripotent stem cell (iPSC) line from a PD patient carrying SNCA duplication. The iPSC line displayed a capacity to differentiate into midbrain dopaminergic neurons affected in PD. The iPSC line will be useful for disease modeling applications.

[A case report of primary central nervous system lymphoma preceded by cerebral and cerebellar lesion diminishing spontaneously: consideration of two brain biopsy at the onset and after two years].

A 57-year-old man suffered a generalized seizure. Brain MRI showed a Gadolinium (Gd) enhanced lesion with massive edema in the left frontal lobe. He received in a brain biopsy a diagnosis of ganglioglioma, probable. After two weeks from the biopsy, brain MRI showed spontaneous remmision of the lesion. Eighteen months after his seizure, a follow-up brain MRI showed a new lesion in the left cerebellar peduncle. However, the lesion also improved spontaneously. After 2 years from the onset, a follow-up examination showed a new lesion in the corpus callosum. At that time even though high dose corticosteroid was given with the diagnosis of multiple sclerosis, the lesion enlarged progressively and uveitis occurred at the same time. He received in the second biopsy a diagnosis of diffuse large B cell lymphoma We report a case of primary central nervous system lymphoma preceded by cerebral and cerebellar lesion diminishing spontaneously, with consideration of two brain biopsy at the onset and after two years.

[A case of scirrhous gastric cancer with peritoneal dissemination acquiring stable disease over three years by treatment with oral anticancer drug S-1].

A 71-year-old male, who complicated of abdominal distension, was diagnosed as scirrhous gastric cancer. We treated him with the oral anticancer drug S-1 and achieved long-term stable disease over three years.

Targeting the enhanced ER stress response in Marinesco-Sjögren syndrome.

BACKGROUND AND OBJECTIVE: Marinesco-Sjögren syndrome (MSS) is an autosomal recessive infantile-onset disorder characterized by cataracts, cerebellar ataxia, and progressive myopathy caused by mutation of SIL1. In mice, a defect in SIL1 causes endoplasmic reticulum (ER) chaperone dysfunction, leading to unfolded protein accumulation and increased ER stress. However, ER stress and the unfolded protein response (UPR) have not been investigated in MSS patient-derived cells. METHODS: Lymphoblastoid cell lines (LCLs) were established from four MSS patients. Spontaneous and tunicamycin-induced ER stress and the UPR were investigated in MSS-LCLs. Expression of UPR markers was analyzed by western blotting. ER stress-induced apoptosis was analyzed by flow cytometry. The cytoprotective effects of ER stress modulators were also examined. RESULTS: MSS-LCLs exhibited increased spontaneous ER stress and were highly susceptible to ER stress-induced apoptosis. The inositol-requiring protein 1α (IRE1α)-X-box-binding protein 1 (XBP1) pathway was mainly upregulated in MSS-LCLs. Tauroursodeoxycholic acid (TUDCA) attenuated ER stress-induced apoptosis. CONCLUSION: MSS patient-derived cells exhibit increased ER stress, an activated UPR, and susceptibility to ER stress-induced death. TUDCA reduces ER stress-induced death of MSS patient-derived cells. The potential of TUDCA as a therapeutic agent for MSS could be explored further in preclinical studies.

HSF1 and constitutively active HSF1 improve vascular endothelial function (heat shock proteins improve vascular endothelial function).

We have been examining the role of heat shock factor 1 (HSF1) in the pleiotropic effects of statins. In parallel studies, we found that statin induces the nuclear translocation of HSF1 and that a decoy oligonucleotide encoding the heat shock element inhibits the statin-induced expression of heat shock protein 70, endothelial nitric oxide synthase (eNOS) and thrombomodulin. Also, in vascular endothelial cells, increases in the expression of human HSF1 corresponded with elevated steady-state levels of eNOS and thrombomodulin and reduced levels of endothelin-1 and plasminogen activator inhibitor-1. We also found that heat shock proteins induced eNOS and thrombomodulin expression and reduced PAI-1 and ET-1 expression. In particular, a combination of HSP70 and HSP90 strongly induced eNOS expression and reduced PAI-1 expression. In the current studies, we generated a constitutively active form of HSF1 and found that it is more effective than the wild-type HSF at inducing thrombomodulin and eNOS expression and decreasing endothelin-1 and plasminogen activator inhibitor-1 expression. These results show that the wild-type and constitutively active forms of HSF1 induce anticoagulation and relaxation factors in vascular endothelial cells and could therefore be used to treat cardiovascular disease.

Proteinase 3-antineutrophil cytoplasmic antibody-positive ulcerative colitis presenting with abducens neuropathy.

A 72-year-old man with ulcerative colitis (UC) presented with complete left abducens nerve palsy. Although MRI showed no significant changes, cerebrospinal fluid analysis revealed pleocytosis and elevated protein and interleukin (IL)-6 levels. His serum proteinase 3-antineutrophil cytoplasmic antibody (PR3-ANCA) level was also elevated to 31.1 U/mL, but granulomatosis with polyangiitis was not observed. On the basis of the diagnosis of autoimmune cranial neuropathy, he was treated with steroid therapy. While tapering steroid therapy, his serum PR3-ANCA levels; cerebrospinal fluid findings, including IL-6 levels; and symptoms improved. Serum PR3-ANCA could be a useful parameter of neurological disorders associated with ANCA-positive UC.

Alamandine reduces leptin expression through the c-Src/p38 MAP kinase pathway in adipose tissue.

OBJECTIVE: Obesity is associated with an increased risk of diabetes mellitus, hypertension, and renal dysfunction. Angiotensin 1-7 and alamandine are heptameric renin angiotensin system peptide hormones. Further, alamandine levels increase with renal dysfunction. In the cardiovascular system, angiotensin 1-7 and alamandine produce similar improvements and counterbalance angiotensin II in regulating vascular function. We aimed to determine whether the effect of alamandine on leptin expression and secretion in adipocytes was similar to that of angiotensin 1-7. APPROACH AND RESULTS: We studied isolated peri-renal visceral adipose tissue and peri-renal isolated visceral adipocytes from male Wistar rats. Angiotensin II from 0.01 to 10nM had no effect on leptin expression. Angiotensin 1-7 (1 nM) increased leptin secretion and expression, whereas alamandine (1 nM) decreased leptin secretion and expression in adipose tissue and isolated adipocytes and reduced blood leptin levels in vivo. These effects were mediated by Gq, c-Src, p38 mitogen-activated protein, and IκB activation. Additionally, alamandine induced nitric oxide expression via inducible nitric oxidase synthase and plasminogen activator inhibitor 1 expression in adipose tissue and isolated adipocytes. CONCLUSIONS: Angiotensin 1-7 and alamandine produced opposing effects on leptin expression and secretion in adipose tissue. This result suggests that the action of Mas (angiotensin 1-7 receptor) and Mas-related G-protein coupled receptor D in adipocytes exhibited opposing actions similar to angiotensin II type 1 and type 2 receptors.

Anhedonia and its correlation with clinical aspects in Parkinson's disease.

Anhedonia is one of the non-motor symptoms observed in the Parkinson's disease (PD). However, there is no clear relationship between anhedonia and its correlation with other symptoms of PD. The aim of this study is to evaluate the characteristics of anhedonia and its correlation with clinical aspects of PD in a relatively large cohort. We enrolled 318 patients with PD and 62 control subjects for this study. Patients and subjects were tested using the Snaith-Hamilton Pleasure Scale Japanese version and the Beck Depression Inventory 2nd edition for the assessment of anhedonia and depression. We also investigated the correlation among clinical aspects of PD, anhedonia, and depression in patients with PD. The Snaith-Hamilton Pleasure Scale Japanese version and the Beck Depression Inventory 2nd edition scores were significantly higher in patients with PD than in control subjects (p=0.03 and p=0.0006, respectively). All PD patients with anhedonia had a significantly higher score on the unified Parkinson's disease rating scale (UPDRS) parts I and II compared to PD patients without anhedonia. Additionally, all PD patients with depression scored significantly higher on UPDRS part I-IV than PD patients without depression. The patients with anhedonia and without depression had mild motor severity and their treatment was relatively low dosage. These results suggest that anhedonia and depression are slightly linked, but not the same. PD patients with only anhedonia may be closely linked apathy found in untreated early stages of PD.

Simvastatin induces heat shock factor 1 in vascular endothelial cells.

Statins not only reduce serum cholesterol but they also improve vascular endothelial function independent of their lipid-lowering effects. However, except for the mechanism of nitric oxide induction via calveolin, the physiologic basis for the pleiotropic effect of statins remains unknown. In the present study, we investigated the relationship between the effects of statins on vascular endothelial cell function and heat shock proteins. We found that, in vascular endothelial cells, simvastatin increased the steady-state levels of heat shock proteins 90 and 70, and heme oxygenase-1 and caused the nuclear translocation of heat shock factor 1. A decoy oligonucleotide encoding the heat shock element inhibited statin-induced expression of heat shock protein 70, endothelial nitric oxide synthase, and thrombomodulin. This decoy oligonucleotide also inhibited the ability of statin to reduce endothelin-1 and plasminogen activator inhibitor-1 expression. These results indicate that statins improve vascular endothelial function via heat shock factor 1, which may contribute to their ability to improve cardiovascular disease.

Transcriptional stimulation of the eNOS gene by the stable prostacyclin analogue beraprost is mediated through cAMP-responsive element in vascular endothelial cells: close link between PGI2 signal and NO pathways.

Beraprost sodium (BPS), an orally active prostacyclin analogue, has been reported to be beneficial in the treatment of primary pulmonary hypertension and obstructive peripheral arterial disease. Although BPS was originally described for its effects on platelet aggregation and vasodilatory response, the effect on endothelial cells has been poorly understood. In this study, we examined the effects of BPS on the eNOS gene expression in mouse aorta and cultured human and bovine aortic endothelial cells. Treatment of these cells with BPS increased the eNOS expression as assessed by Northern blots, Western blots, and NO production by NO-specific fluorescence (DAF2-DA) and by the Griess method. Standard mRNA decay assays showed that BPS increases the stability of eNOS mRNA. In addition, BPS increased the promoter activity of the human eNOS gene, as determined by luciferase assays of the eNOS promoter gene. Progressive 5'-deletion and site-specific mutation analyses defined the BPS-responsive sequences as cAMP-responsive elements (CRE) located at -733 and -603. By using the oligonucleotide probe containing this CRE sequence in electrophoretic mobility shift assays, we showed that the phosphorylated form of CRE-binding protein is a major constituent of the complex in BPS-treated cells. Western blot analyses indicate that BPS but not endogenous prostacyclin phosphorylates CRE-binding protein. The presence of functional CRE sites within human eNOS promoter may represent a novel mechanism for regulating eNOS gene expression.

Mitochondrial reactive oxygen species and c-Src play a critical role in hypoxic response in vascular smooth muscle cells.

OBJECTIVE: Thickened atherosclerotic plaques are prone to be hypoxic because of poor perfusion. In this study, we tested (a) whether reactive oxygen species (ROS) and c-Src play roles in hypoxic induction of HIF-1alpha protein and PAI-1 gene expression in the rabbit aortic smooth muscle cell line C2/2 cells and primary cultures of rat aortic smooth muscle cells, and (b) how mitochondria act on the hypoxia-induced signaling mechanism. METHODS AND RESULTS: Hypoxic exposure of C2/2 cells increased H2O2 generation, c-Src phosphorylation, HIF-1alpha protein expression, and PAI-1 gene expression. Catalase, a scavenger of H2O2, inhibited the hypoxia-induced ROS generation and PAI-1 gene expression. Src kinase inhibitors PP1 and PP2 inhibited hypoxia-induced HIF-1alpha protein and PAI-1 gene expression. Ablation of mitochondrial respiration by rotenone abolished hypoxia-induced ROS generation, c-Src phosphorylation, HIF-1alpha protein expression, and PAI-1 gene expression. CONCLUSION: Induction of HIF-1alpha protein and PAI-1 gene expression in response to hypoxia was regulated by ROS production and c-Src activation in vascular smooth muscle cells. Mitochondria linked the hypoxic signal to c-Src, which in turn led to HIF-1alpha protein and PAI-1 gene expression. These results provide evidence that hypoxia induces the ROS-mediated and c-Src-dependent signaling cascades which are closely associated with angiogenesis and thrombosis in atherosclerotic vasculature.

A Japanese multicenter survey characterizing pain in Parkinson's disease.

BACKGROUND: Pain is a frequent, troublesome symptom of PD but is under-recognized and poorly understood. AIM: We characterized pain prevalence, severity, and location in PD, to better understand its pathophysiology and improve diagnosis and treatment. SUBJECTS AND METHODS: A cross-sectional controlled study was conducted at 19 centers across Japan. A total of 632 subjects with Mini-Mental State Examination scores ≥24 were enrolled, including 324 PD patients and 308 controls. Sex and mean age did not differ between the two groups. Demographic and clinical data were collected. Pain was assessed using questionnaires, the SF-36v2 bodily pain scale, and a body illustration for patients to indicate the location of pain in 45 anatomical areas. RESULTS: Pain prevalence in the PD group was 78.6%, significantly higher than in controls (49.0%), as was its severity. There was no correlation between SF-36v2 score and motor scores, such as Unified Parkinson's Disease Rating Scale III or Hoehn & Yahr scores. Pain distribution was similar between groups, predominantly in the lower back, followed by the gluteal region, lower legs, thighs, posterior neck, and shoulders. CONCLUSION: Pain is a significant problem in the Japanese PD population and we discuss its pathophysiology.

[Ischemic changes and blood coagulation abnormalities as complications of pneumococcal meningitis].

One explanation for cerebral infarctions that occur as a complication of pneumococcal meningitis is blood coagulation abnormalities. We investigated the clinical features, laboratory test results, magnetic resonance imaging (MRI) findings, and pathological features of 10 patients with pneumococcal meningitis between 2006 and 2013 to examine the abnormal findings that may be associated with prognosis. Five patients (50%) that had Glasgow Outcome Scale scores between 1 and 4 were classified as the poor outcome group. In this group, the MRI revealed a high signal intensity on the diffusion-weighted image (DWI), and there was an abnormal signal along the cerebral cortex and Virchow-Robin spaces, which were characterized pathologically by ischemic changes. The plasma thrombin-antithrombin complex (TAT) levels showed greater differences between the poor and good prognosis groups than platlet and D-dimer levels; this suggested that high plasma TAT levels indicate a poor prognosis.

Angiotensin II Reduces Lipoprotein Lipase Expression in Visceral Adipose Tissue via Phospholipase C ß4 Depending on Feeding but Increases Lipoprotein Lipase Expression in Subcutaneous Adipose Tissue via c-Src.

Metabolic syndrome is characterized by visceral adiposity, insulin resistance, high triglyceride (TG)- and low high-density lipoprotein cholesterol-levels, hypertension, and diabetes-all of which often cause cardiovascular and cerebrovascular diseases. It remains unclear, however, why visceral adiposity but not subcutaneous adiposity causes insulin resistance and other pathological situations. Lipoprotein lipase (LPL) catalyzes hydrolysis of TG in plasma lipoproteins. In the present study, we investigated whether the effects of angiotensin II (AngII) on TG metabolism are mediated through an effect on LPL expression. Adipose tissues were divided into visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) for comparison. AngII accelerated LPL expression in SAT but, on the contrary, suppressed its expression in VAT. In both SAT and VAT, AngII signaled through the same type 1 receptor. In SAT, AngII increased LPL expression via c-Src and p38 MAPK signaling. In VAT, however, AngII reduced LPL expression via the Gq class of G proteins and the subsequent phospholipase C ß4 (PLCß4), protein kinase C ß1, nuclear factor κB, and inducible nitric oxide synthase signaling pathways. PLCß4 small interfering RNA experiments showed that PLCß4 expression is important for the AngII-induced LPL reduction in VAT, in which PLCß4 expression increases in the evening and falls at night. Interestingly, PLCß4 expression in VAT decreased with fasting, while AngII did not decrease LPL expression in VAT in a fasting state. In conclusion, AngII reduces LPL expression through PLCß4, the expression of which is regulated by feeding in VAT, whereas AngII increases LPL expression in SAT. The different effects of AngII on LPL expression and, hence, TG metabolism in VAT and SAT may partly explain their different contributions to the development of metabolic syndrome.

Effect of cerivastatin on endothelial dysfunction and aortic CD36 expression in diabetic hyperlipidemic rats.

A mutation of the CD36 gene that encodes a fatty acid transporter has been reported to play a role in insulin resistance in spontaneously hypertensive rat (SHR). Statins reduce circulating cholesterol and triglyceride concentrations. The objective of this study was to determine the role of CD36 and the significance of statin therapy in insulin-resistance syndromes. We determined the isometric relaxation induced by acetylcholine or lecithinized superoxide dismutase (SOD) in aortas obtained from Otsuka Long Evans Tokushima Fatty (OLETF) rats, a model of insulin resistance and dyslipidemia, and normal control (Long Evans Tokushima Otsuka; LETO) rats with or without cerivastatin treatment. We also determined the effect of cerivastatin on aortic expression of CD36 and PPARgamma. The CD36 genotype and microsatellite markers on chromosome 4 were also determined. The relaxation induced by acetylcholine and lecithinized SOD were attenuated in OLETF rats but restored by a low dose of cerivastatin without significant changes in serum cholesterol. These relaxations were also restored by a high dose of cerivastatin with significant reductions in serum cholesterol and triglyceride. Cerivastatin increased the aortic expression of CD36 and PPARgamma mRNA in both LETO and OLETF rats. However, the basal level of CD36 mRNA and the increase in CD36 mRNA in response to cerivastatin were significantly lower in OLETF rats than in LETO rats. Although the abnormal CD36 genotype reported in SHR was not found in OLETF rats, the microsatellite markers of D4Rat151 and D4Rat115 differed between OLETF and LETO rats. In conclusion, insulin resistance in OLETF rats may be partially due to an altered expression of CD36. Increased aortic expression of CD36 in response to cerivastatin could explain the reduction in serum triglyceride concentrations with statin therapy and may have pronounced beneficial effects in insulin-resistance syndromes.