Hesperetin ameliorates diabetes-associated anxiety and depression-like behaviors in rats via activating Nrf2/ARE pathway

Diabetes-associated affective disorders are of wide concern, and oxidative stress plays a vital role in the pathological process. This study was to investigate the cerebroprotective effects of hesperetin against anxious and depressive disorders caused by diabetes, exploring the potential mechanisms related to activation of Nrf2/ARE pathway. Streptozotocin-induced diabetic rats were intragastrically administrated with hesperetin (0, 50, and 150 mg/kg) for 10 weeks. Forced swimming test, open field test, and elevated plus maze were used to evaluate the anxiety and depression-like behaviors of rats. The brain was collected for assays of Nrf2/ARE pathway. Moreover, high glucose-cultured SH-SY5Y cells were used to further examine the neuroprotective effects of hesperetin and underlying mechanisms. Hesperetin showed anxiolytic and antidepressant effects in diabetic rats according to the behavior tests, and increased p-Nrf2 in cytoplasm and Nrf2 in nucleus followed by elevations in mRNA levels and protein expression of glyoxalase 1 (Glo-1) and gamma-glutamylcysteine synthetase (gamma-GCS) in brain, known target genes of Nrf2/ARE signaling. Moreover, hesperetin attenuated high glucose-induced neuronal damages through activation of the classical Nrf2/ARE pathway in SH-SY5Y cells. Further study indicated that PKC inhibition or GSK-3 beta activation pretreatment attenuated even abolished the effect of hesperetin on the protein expression of Glo-1 and gamma-GCS in high glucose-cultured SH-SY5Y cells. In summary, hesperetin ameliorated diabetes-associated anxiety and depression-like behaviors in rats, which was achieved through activation of the Nrf2/ARE pathway. Furthermore, an increase in nuclear Nrf2 phosphorylation from PKC activation and GSK-3 beta inhibition contributed to the activation of Nrf2/ARE pathway by hesperetin.