targeting altered mitochondrial biogenesis in the brain of diabetic rats: potential effect of pioglitazone and exendin-4

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.