Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China.
Sanhome Pharmaceutical Limited Company, Nanjing, China.
J Cell Mol Med. 2019 Sep;23(9):6343-6354. doi: 10.1111/jcmm.14522. Epub 2019 Jul 18.
Protein kinase C (PKC) shows a neuronal protection effect in neurodegenerative diseases. In this study, we test whether berberine has a positive effect on the activity of PKC in quinolinic acid (QA)-induced neuronal cell death. We used intrastriatal injections of QA mice model to test the effect of berberine on motor and cognitive deficits, and the PKC signalling pathway. Treatment with 50 mg/kg b.w of berberine for 2 weeks significantly prevented QA-induced motor and cognitive impairment and related pathologic changes in the brain. QA inhibited the phosphorylation of PKC and its downstream molecules, GSK-3β, ERK and CREB, enhanced the glutamate level and release of neuroinflammatory cytokines; these effects were attenuated by berberine. We used in vivo infusion of Go6983, a PKC inhibitor to disturb PKC activity in mice brain, and found that the effect of berberine to reverse motor and cognitive deficits was significantly reduced. Moreover, inhibition of PKC also blocked the anti-excitotoxicity effect of berberine, which is induced by glutamate in PC12 cells and BV2 cells, as well as anti-neuroinflammatory effect in LPS-stimulated BV2 cells. Above all, berberine showed neuroprotective effect against QA-induced acute neurotoxicity by activating PKC and its downstream molecules.
蛋白激酶 C（PKC）在神经退行性疾病中表现出神经元保护作用。在这项研究中，我们测试了小檗碱是否对喹啉酸（QA）诱导的神经元细胞死亡中 PKC 的活性有积极影响。我们使用纹状体注射 QA 建立小鼠模型，以测试小檗碱对运动和认知功能障碍以及 PKC 信号通路的影响。用 50mg/kg bw 的小檗碱治疗 2 周，可显著预防 QA 诱导的运动和认知障碍以及大脑相关的病理变化。QA 抑制了 PKC 及其下游分子 GSK-3β、ERK 和 CREB 的磷酸化，增加了谷氨酸水平和神经炎症细胞因子的释放；小檗碱减弱了这些作用。我们使用体内灌流 Go6983（一种 PKC 抑制剂）来干扰小鼠大脑中的 PKC 活性，发现小檗碱逆转运动和认知障碍的作用明显减弱。此外，抑制 PKC 也阻断了小檗碱在 PC12 细胞和 BV2 细胞中对抗谷氨酸诱导的兴奋性毒性以及在 LPS 刺激的 BV2 细胞中的抗炎作用。总之，小檗碱通过激活 PKC 及其下游分子，对 QA 诱导的急性神经毒性表现出神经保护作用。
