Metformin restores cognitive dysfunction and histopathological deficits in an animal model of sporadic Alzheimer's disease.

Background: Metformin has been introduced as a neuroprotective agent in recent years. Here we evaluate the therapeutic effects of metformin in sporadic mouse model of Alzheimer's disease (SAD). Methods: AD was induced by streptozotocin (STZ, 0.5 mg/kg) on days 1 and 3. Metformin (MET, 200 mg/kg per day) was used for two weeks. Novel objective recognition (NOR) and Barnes Maze test were used to test the learning and memory. Nissl staining was used as s histological method for counting the dying neurons in different regions of hippocampus. Immunofluorescence staining against glial fibrillary acidic protein (GFAP), ionized calcium binding adaptor molecule 1 (Iba1) and NeuN were used to visualize reactive astrocytes, microglia and neurons, respectively. Results: In NOR test, the discrimination indices in the STZ group were significantly lower than the control and treatment groups. Goal sector/non-goal sector (GS/NGS) ratio index in Barnes maze was increased in metformin group compared to other groups. The number of dying neurons was increased by SAD and metformin reduced it. GFAP level was increased in CA1, CA3 and cortex of STZ group and reversed following the treatment. Iba1 level was significantly higher in STZ group in CA3 and cortex regions compared to Control and decreased by metformin in CA3 and cortex. Counting NeuN+ cells demonstrated significant reduction of neurons in DG+CA1 and CA3 after SAD induction. Significance: Metformin decreased inflammatory cells and reactive astrocytes as well as the dying neurons in the hippocampus region and the cortex in SAD, and improved the cognitive performance.

Characterizing of Four Common BCR-ABL Kinase Domain Mutations (T315I, Y253H, M351T and E255K) in Iranian Chronic Myelogenous Leukemia Patients With Imatinib Resistance.

BACKGROUND: Chronic myelogenous leukemia (CML) is a kind of hematopoietic stem-cell cancer. A significant number of CML patients who do not achieve an acceptable response to therapy, show acquired resistance against Imatinib. One of the most considerable causes of resistance against Imatinib as the first line of therapy, are BCR-ABL kinase domain mutations. OBJECTIVES: One of the most considerable causes of resistance against Imatinib as the first line of therapy, are BCR-ABL kinase domain mutations. PATIENTS AND METHODS: The study was performed on 39 CML patients with Imatinib resistance. Basic hematologic parameters in blood samples were checked to identify hematologic response. To identify molecular response, BCR-ABL/ABL ratio was assessed by Real-time PCR. The ABL kinase domain amplification was performed by PCR. Restriction fragment length polymorphism (RFLP) was performed to detect four common mutations (T315I, Y253H, E255K and M351T). Finally the results were approved by direct sequencing. RESULTS: In this study, the Y253H mutation, detected by RFLP method and confirmed by direct sequencing, was the prevalent ABL kinase domain mutation in these 39 CML patients. The G250E, V379I and L384M mutations were found in three different cases with failure molecular response. CML patients with these four ABL kinase domain mutations cannot achieve major molecular response (MMR). In addition, complete hematologic response (CHR) was observed only in the V379I mutated case and not in other mutated patients. CONCLUSIONS: Identification of ABL kinase domain mutations may be used as a proper and useful method for improving therapeutic strategies, avoiding delay in treatment and excessive expenditure in CML patients with Imatinib resistance.

Identification of CYP2C9 and VKORC1 polymorphisms in Iranian patients who are under warfarin therapy.

BACKGROUND: Although catalytic properties of different genetic polymorphisms of VKORC1 and CYP2C9 products have been identified, there is limited study available regarding warfarin dose requirement in Iranian patient population. This study investigates the impact of these polymorphisms on 115 patients, referred to Payvand Clinical and Specialty Laboratory for determining the appropriate dose of warfarin. RESULTS of the study may be applicable to individuals who are under warfarin therapy to avoid warfarin resistance or intolerance. SUBJECTS AND METHODS: PT-INR test was utilized as a screening method. Genotyping were performed for VKORC1 and CYP2C9 using PCR method. Statistical analyses including unpaired t-test or ANOVA and regression were done using SPSS. RESULTS: VKORC1 GA was the most common genotype of VKORC1 allele among the study samples, with a rate of 57.4%. In CYP2C9 variant, 20% and 14.8% of subjects carried CYP2C9*1/*2 and CYP2C9*1/*3 genotyping, respectively. By contrast, the WT *1/*1 genotype was more abundant and dominant. The high frequency of VKORC1 (_1639) GA genotype (57.4%), was significant versus for the rest of the cohort (42.6%). In addition, a significant relationship was found between CYP2C9*1 and drug dose (P>0.021). CONCLUSION: In this study, samples were characterized by higher frequencies of CYP2C9*1 and VKORC1 G/A, determined as higher warfarin taking doses. The results showed a significant relationship of the VCORC1 and CYP2C9 polymorphisms with warfarin sensitivity and severe side effects. Estimating right doses of warfarin to prescribe can help to reduce the risk of over- or under-anticoagulation and subsequently, the risk of thromboembolism or bleeding.