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 γ-glutamylcysteine synthetase (γ-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-3β activation pretreatment attenuated even abolished the effect of hesperetin on the protein expression of Glo-1 and γ-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-3β inhibition contributed to the activation of Nrf2/ARE pathway by hesperetin.

中文翻译：

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橙皮素通过激活 Nrf2/ARE 通路改善大鼠糖尿病相关的焦虑和抑郁样行为。

糖尿病相关的情感障碍受到广泛关注，氧化应激在病理过程中起着至关重要的作用。本研究旨在探讨橙皮素对糖尿病引起的焦虑和抑郁障碍的脑保护作用，探索与激活Nrf2/ARE通路相关的潜在机制。用橙皮素（0、50 和 150 mg/kg）灌胃给予链脲佐菌素诱导的糖尿病大鼠 10 周。采用强迫游泳试验、旷场试验、高架十字迷宫等方法评价大鼠的焦虑和抑郁样行为。收集大脑用于 Nrf2/ARE 通路的测定。此外，高糖培养的 SH-SY5Y 细胞用于进一步检查橙皮素的神经保护作用和潜在机制。根据行为测试，橙皮素在糖尿病大鼠中显示出抗焦虑和抗抑郁作用，并增加细胞质中的 p-Nrf2 和细胞核中的 Nrf2，随后乙二醛酶 1（Glo-1）和 γ-谷氨酰半胱氨酸合成酶（γ -GCS）在大脑中，已知 Nrf2/ARE 信号传导的靶基因。此外，橙皮素通过激活 SH-SY5Y 细胞中的经典 Nrf2/ARE 通路来减轻高糖诱导的神经元损伤。进一步的研究表明，PKC抑制或GSK-3β活化预处理减弱甚至消除了橙皮素对高糖培养的SH-SY5Y细胞中Glo-1和γ-GCS蛋白表达的影响。总之，橙皮素改善了大鼠糖尿病相关的焦虑和抑郁样行为，这是通过激活 Nrf2/ARE 通路实现的。