ABSTRACT
Objective To investigate the phosphorylation of tau protein and the effect of atorvastatin on tau protein phosphorylation in hypercholesteremic mouse hippocampus. Methods Male Kunming mice were randomly divided into normal control group, hypercholesteremia group, and low-dose atorvastatin treatment group (8mg·kg-1·d-1), middle-dose group (15mg·kg-1·d-1),and high-dose group (20mg·kg-1·d-1) with five mice in each group. The hypercholesteremia mouse model was induced by cholesterol-enriched diets. The expression level of tau protein phosphorylation in mouse hippocampus was detected by Western blot and immunohistochemistry methods. The activities of mitogen-activated protein kinase (MAPK) and cyelin dependent kinase 5 (Cdk-5) were measured by liquid scintillation counting of the hippocampus incorporated radioactivity and immunoprecipetation activity assay respectively. Results In hypercholesteremic group, the expression level of tau protein phosphorylation in mouse hippocampus was significantly increased(F=14.761,P＜0.01)as compared with control group, and so were MAPK activity and Cdk-5 activity(all P＜0.01). Atorvastatin treatment group showed the decreased expression level of tau protein phosphorylation at ser396/404 site in low-dose group (F=6.349,P＜0.05),middle-dose group (F=10.283,P＜0.01) and high-dose group (F=10.511,P＜0.01) as compared with hypercholesteremia mouse group. The activities of MAPK and Cdk-5 were decreased along with the increasing atorvastatin doses. Conclusions Hypercholesteremia induces tau protein hyperphosphorylation in mouse hippocampus. Abnormal cholesterol metabolism may play an important role in the pathology process of neurodegeneration in brain. Atorvastatin might inhibit tau protein hyperphosphorylation by inhibiting the activations of MAPK and Cdk-5 in brain, atorvastatin may have the protect effect for tau protein.
ABSTRACT
BACKGROUND: The quantitative measurements based on magnetic resonance imaging (MRI) have been vastly used in evaluating the therapeutic efficacy on multiple sclerosis (MS).OBJ ECTIVE: To determine whether the effect of IFNB-1b on brain atrophy of MS could be shown with analysis of MRI measurement.DESIGN: Randomized controlled observation.SETTING : Center for Neurological Diseases, Utano National Hospital.PARTICIPANTS: Totally 188 patients with MS, including 55 males and 133 females aged from 16-59 years, averagely(36±11) years, from Center for Neurological Diseases, UtanoNational Hospital from January to December 1998 were enrolled. Inclusive criteria: ①according to Poser RR type criteria were considered as having MS for enrollment, ②Expanded Disability Status Scale (EDSS) score of 7.0 or less, ③at least 1 relapse in the past year or at least 2 relapses in the past two years prior to enrollment, but no relapse for 30 days before enrollment, stable neurological state for at least 1 month and negative results of the IFNB-1b needle-prick test, and ④they all knew the detected items and agreed. In the included patients, there were 148 cases of optic nerves and spinal cord type and 40 cases of classical type.METHODS: ①Drug treatment: All the patients were treated with IFNB-1b injectable preparation (provided by Japanese Pharmaceuticals Company). According to the different injected dosage, the patients were divided into low-dosage group (n =93) and high-dosage group (n =95), given with 1.6 million U and 8 million U of IFNB-1b subcutaneously on alternate days for 2 years. ②MRI examination: The patients received MRI in lesion site (optic nerves, cerebrum, cerebellum, brainstem, and spinal cord). T1 and T2-weighted axial MRI scan were performed by a single neurologist. The area of the MS lesions in T2-weighted images was summed slice by slice for a total lesion area and was recorded as mm2. Third ventricle, lateral ventricle width and brain width were measured and expressed by atrophy rate. ③Neurologic impairment examination: Neurologic impairment was evaluated with Kurtzke EDSS (from 0 point to 10 points, 0 point as normal, the higher score represented severe condition). ④Analysis of related factors: Correlation analysis was performed in brain atrophy condition and T2 focus area with EDSS score in 148 MS patients with typical MS. At the same time,correlation analysis was conducted between variance (age, progress, relapse rate, T2 focus area and EDSS score) and brain atrophy.MAIN OUTCOME MEASURES: ①Comparison of brain atrophy in patients of the two groups, and ②analysis of related factors of brain atrophy measurements.RESULTS: Totally 188 patients were involved in the result analysis. ①Outcome of brain atrophy comparison in the two groups: In classical type MS the rates of atrophy measures in high-dosage group were 2.84%, 3.15%, and 1.3% in lateral ventricle width, third ventricle width and brain width, respectively, and significantly lower than those in low-dosage group (4.09%, 5.36% and 1.97%, P ＜ 0.01). In optic nerve and spinal cord type MS patients, the rates of brain atrophy were 0.9%, 1.55% and 0.6% in lateral ventricle width, third ventricle width and brain width, respectively in high-dosage group, and there was no significant difference as compared with the low-dosage group (1.65%, 1.75% and 0.7%, P ＜0.05). ②There was significant correlation of lateral ventricle width, T2 focus area and EDSS score in classical MS patients (r =0.33,0.27, P ＜ 0.01 ). There was significant correlation of third ventricle width, T2 focus area and EDSS score (r=0.31,0.29, P ＜ 0.05). There was significant correlation of brain width, T2 focus area and EDSS score (r =0.11,0.14, P ＜0.05). There was significant correlation of baseline EDSS score and T2 focus area with lateral ventricle width (r =0.23,0.33, P ＜ 0.05). The other baseline variables failed to show a significant contribution to the process.CONCLUSION: The effects of IFNB-1b on brain atrophy were positive and significant differences were also found between both high- and low-dosage groups. This brain atrophy measurement provides an independent MRI confirmation of a therapy and dose effect of IFNB-1b for MS.