Targeting Altered Mitochondrial Biogenesis in the Brain of Diabetic Rats: Potential Effect of Pioglitazone and Exendin-4

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.

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.

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.

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.