School of Environment Science and Spatial Informatics, China University of Mining and Technology, Xuzhou 221116, Jiangsu Province, China; Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, 101 Shanghai Road, Xuzhou 221116, Jiangsu Province, China; Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, Huaiyin Normal University, Huaian 223300, China; Jiangsu Key Laboratory for Eco-Agricultural Biotechnology around Hongze Lake, Huaiyin Normal University, Huaian 223300, China; School of Life Sciences, Huaiyin Normal University, Huaian 223300, China.
Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, 101 Shanghai Road, Xuzhou 221116, Jiangsu Province, China; College of Health Sciences, Jiangsu Normal University, 101 Shanghai Road, Xuzhou 221116, Jiangsu Province, China.
J Hazard Mater. 2018 Apr 5;347:390-402. doi: 10.1016/j.jhazmat.2018.01.008. Epub 2018 Jan 8.
Evidence indicates that oxidative stress is the central pathological feature of 2, 2´, 4, 4´-tetrabromodiphenyl ether (BDE-47)-induced neurotoxicity. Protein kinase C delta (PKCδ), an oxidative stress-sensitive kinase, can be proteolytically cleaved to yield a catalytically active fragment (PKCδ-CF) that is involved in various neurodegenerative disorders. Here, we showed that BDE-47 treatment increased ROS, malondialdehyde, and protein carbonyl levels in the mouse hippocampus. In turn, excessive ROS induced caspase-3-dependent PKCδ activation and stimulated NF-κB p65 nuclear translocation, resulting in inflammation in the mouse hippocampus. These changes caused learning and memory deficits in BDE-47-treated mice. Treatment with Z-DEVD-fmk, a caspase-3 inhibitor, or N-acetyl-L-cysteine, an antioxidant, blocked PKCδ activation and subsequently inhibited inflammation, thereby improving learning and memory deficits in BDE-47-treated mice. Our data further showed that activation of ROS-PKCδ signaling was associated with DJ-1 downregulation, which exerted neuroprotective effects against oxidative stress induced by different neurotoxic agents. Adeno-associated viral vector-mediated DJ-1 overexpression in the hippocampus effectively inhibited excessive ROS production, suppressed caspase-3-dependent PKCδ cleavage, blunted inflammation and ultimately reversed learning and memory deficits in BDE-47-treated mice. Taken together, our results demonstrate that DJ-1 plays a pivotal role in BDE-47-induced neurotoxic effects and learning and memory deficits.
证据表明，氧化应激是 2,2′,4,4′-四溴二苯醚（BDE-47）诱导神经毒性的中心病理特征。蛋白激酶 C 德尔塔（PKCδ）是一种氧化应激敏感激酶，可被蛋白水解切割生成具有催化活性的片段（PKCδ-CF），参与各种神经退行性疾病。在这里，我们表明 BDE-47 处理增加了小鼠海马体中的 ROS、丙二醛和蛋白质羰基水平。反过来，过量的 ROS 诱导 caspase-3 依赖性 PKCδ 激活，并刺激 NF-κB p65 核易位，导致小鼠海马体炎症。这些变化导致 BDE-47 处理的小鼠出现学习和记忆缺陷。用 caspase-3 抑制剂 Z-DEVD-fmk 或抗氧化剂 N-乙酰-L-半胱氨酸处理，阻断了 PKCδ 的激活，随后抑制了炎症，从而改善了 BDE-47 处理的小鼠的学习和记忆缺陷。我们的数据进一步表明，ROS-PKCδ 信号的激活与 DJ-1 的下调有关，DJ-1 对不同神经毒性剂诱导的氧化应激具有神经保护作用。腺相关病毒载体介导的 DJ-1 在海马体中的过表达有效地抑制了过量的 ROS 产生，抑制了 caspase-3 依赖性 PKCδ 切割，减轻了炎症，并最终逆转了 BDE-47 处理的小鼠的学习和记忆缺陷。总之，我们的结果表明 DJ-1 在 BDE-47 诱导的神经毒性作用和学习记忆缺陷中发挥关键作用。
