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en Targeting Altered Mitochondrial Biogenesis in the Brain of Diabetic Rats: Potential Effect of Pioglitazone and Exendin-4 بیوشیمی Biochemistry مقالات اصلی Original Article <div style="text-align: justify;">Background:Neuroprotective mechanisms triggered by peroxisome proliferator-activated receptor-gamma agonist: pioglitazone (PIO) and glucagon-like peptide 1 analog: exendin-4 (Ex-4) in neurological diseases were reported, but whether mitochondrial biogenesis is involved or not in their neuro-protective mechanisms in type 1 Diabetes Mellitus (T1DM); has not been studied before. To bridge this gap, we investigated the effect of PIO and Ex-4 on brain mitochondrial biogenesis in streptozotocin-induced diabetes in rats. Methods:Seven weeks after induction of diabetes in rats, serum fasting glucose and insulin were measured in studied groups. The brain was removed for histological analysis and assessment of: mitochondrial complexes I and II, ATP, H2O2, brain derived neurotrophic factor (BDNF), cytochrome c and hemeoxygenase (HO)-1 activity, and relative gene expression of the nuclear factor; Nrf2and the apoptotic markers: bax& bcl2and mitochondrial biogenesis markers; peroxisome proliferator–activated receptor γ coactivator (PGC) 1-α and sirtuin 1 (SIRT-1) and AMP-activated protein kinase (AMPK) and c-Jun-N-terminal kinase (JNK) proteins. Results:Brain in untreated rats showed neurodegeneration area and significantly rising H2O2and JNK, up-regulation of bax, down-regulation of bcl2. These changes were paralleled with significant reduction in Nrf2, HO-1, BDNF, complex I, II and ATP and SIRT-1/ PGC1-αexpression. PIO and Ex-4 significantly improved the reported changes. Combined modality showed better improvement relative to each drug alone. Conclusions:PIO and Ex-4 may have neuroprotective effects in T1DM, via targeting altered mitochondrial biogenesis probably due to modulation of brain SIRT-1signaling, improvement of oxidative stress and equilibrating the balance between pro-apoptotic and anti-apoptotic mediators.</div> Brain derived neurotrophic factor, Diabetic neurodegeneration, Exendin-4, oxidative stress, PGC1-α. 287 300 http://rbmb.net/browse.php?a_code=A-10-310-1&slc_lang=en&sid=1 Ola Mostafa Tork ola.m.tork@kasralainy.edu.eg 100319475328460017364 100319475328460017364 No MedicalPhysiology department, Faculty of Medicine, Cairo University. & Basic Medical ScienceDepartment,College ofMedicine,PrincessNourah BintAbdulrahman University Laila Ahmed Rashed lailaahmedrashed@gmail.com 100319475328460017365 100319475328460017365 No Medical Biochemistry department, Faculty of Medicine, Cairo University. Nermeen Bakr Sadek Nermeen.B.Sadek@kasralainy.edu.eg 100319475328460017366 100319475328460017366 No MedicalPhysiology department, Faculty of Medicine, Cairo University. Marwa Sayed Abdel-Tawab marwa.amar@med.bsu.edu.eg 100319475328460017367 100319475328460017367 Yes Medical Biochemistry, Faculty of Medicine, Beni-Suef University.