Nrf1 and Nrf2 Knockdown Effect in Anxiety-related Behavior and Mitochondrial Function

Introduction: Nuclear factor, erythroid-derived 2, -like2 (Nrf2) and Nuclear erythroid 2-related factor 1 (Nrf1) stand as two important regulators of antioxidant defense system. Materials and Methods: Small interfering RNA (siRNA) targeting Nrf1 and Nrf2 (Nrf1&2) was injected in dorsal third ventricle of adult male albino Wistar rats. Anxiety-related behaviors and protein level of mitochondrial biogenesis, apoptotic marker factors and also electron transport chain (ETC), Citrate synthase (CS) and Malate dehydrogenase (MDH) enzymes activity in three brain regions: hippocampus, prefrontal cortex, and amygdala were evaluated. Results: Nrf1&2-silenced rats induced anxiety-like behaviors compared to the control group. The level of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1) protein increased in those three regions. Although Nrf1&2-silencing decreased MDH activity in hippocampus and prefrontal cortex, the activity of CS was increased in all three mentioned areas. However, Nrf1&2 silencing had no effect in complex I and II-III activity, but complex IV activity was increased, particularly in amygdala. Furthermore, Bax/Bcl2 ratio and cleavage of caspase-3 was increased in all mentioned areas of the brain in Nrf1&2-silenced group. Conclusion: In conclusion, the presented data evaluated the complexity of mitochondrial functions and Nrf1 and Nrf2 in rat’s brain and points to mitochondrial crucial role in oxidative stress, energy metabolism, and behavior.