Department of Neurosurgery, Private Buhara Hospital, Erzurum, Turkey.
Department of Biochemistry, Faculty of Veterinary Medicine, Atatürk University, Erzurum, Turkey.
Neurotoxicology. 2020 Dec;81:137-146. doi: 10.1016/j.neuro.2020.10.001. Epub 2020 Oct 7.
In the present study, the protective effects of quercetin on peripheral neurotoxicity caused by vincristine, which is used effectively in the treatment of various types of cancers, were investigated by using different techniques. In the study, for 12 days, male Sprague Dawley rats were given 25 and 50 mg/kg doses of quercetin orally and were administered a 0.1 mg/kg dose of vincristine (a total cumulative dose of 1.2 mg/kg) intraperitoneally 30 min later. The protein levels of nuclear factor erythroid 2-related factor-2 (Nrf2), heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase-1 (NQO1), glial fibrillary acidic protein (GFAP), and nuclear factor kappa B (NF-κB) were measured with ELISA; the immunopositivity of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and caspase 3 were determined with immunohistochemistry; the mRNA transcript levels of double-stranded RNA-activated protein kinase (PKR)-like ER kinase (PERK), inositol-requiring enzyme-1 (IRE1), activating transcription factor-6 (ATF-6), glucose-regulated protein 78 (GRP78), Bcl-2-associated X protein (Bax), B-cell lymphoma-2 (Bcl-2), caspase 3, protein kinase B1/2 (Akt-1/2), and forkhead box transcription factor, class O1 (FOXO1) were determined with RT-PCR. The reduction of Nrf2 levels and HO-1 and NQO1 activities in the sciatic nerve tissue, the increase in the levels of 8-OHdG, and the increase in the levels of GFAP and NF-κB caused by vincristine was observed to cause oxidative stress, oxidative DNA damage, neuronal cell damage, and inflammation, respectively. Additionally, vincristine was determined to cause ER stress and apoptosis by increasing PERK, IRE1, ATF-6, and GRP78 and caspase 3 and Bax expressions and by decreasing Bcl-2 expressions. Vincristine causing Akt inhibition also shows that it prevents neuronal survival. However, quercetin was determined to relieve oxidative stress, oxidative DNA damage, neuronal cell damage, inflammation, ER stress, and apoptosis caused by vincristine and enable Akt activation. These results show that in rats, quercetin may have a protective effect against peripheral neurotoxicity caused by vincristine.
在本研究中，使用不同的技术研究了槲皮素对长春新碱引起的周围神经毒性的保护作用，长春新碱有效用于治疗各种类型的癌症。在研究中，12 天内，雄性 Sprague Dawley 大鼠口服给予 25 和 50mg/kg 的槲皮素，并在 30 分钟后腹膜内给予 0.1mg/kg 的长春新碱（总累积剂量为 1.2mg/kg）。使用 ELISA 测量核因子红细胞 2 相关因子 2（Nrf2）、血红素加氧酶 1（HO-1）、NAD（P）H 醌氧化还原酶 1（NQO1）、神经胶质纤维酸性蛋白（GFAP）和核因子 κB（NF-κB）的蛋白水平；用免疫组织化学法测定 8-羟基-2'-脱氧鸟苷（8-OHdG）和半胱氨酸蛋白酶 3 的免疫阳性率；用 RT-PCR 测定双链 RNA 激活蛋白激酶（PKR）样内质网激酶（PERK）、肌醇需求酶 1（IRE1）、激活转录因子 6（ATF-6）、葡萄糖调节蛋白 78（GRP78）、B 细胞淋巴瘤-2 相关 X 蛋白（Bax）、B 细胞淋巴瘤-2（Bcl-2）、半胱氨酸蛋白酶 3、蛋白激酶 B1/2（Akt-1/2）和叉头框转录因子，O1 类（FOXO1）的 mRNA 转录水平。长春新碱引起坐骨神经组织中 Nrf2 水平降低，HO-1 和 NQO1 活性降低，8-OHdG 水平升高，GFAP 和 NF-κB 水平升高，分别导致氧化应激、氧化 DNA 损伤、神经元细胞损伤和炎症。此外，长春新碱通过增加 PERK、IRE1、ATF-6 和 GRP78 以及半胱氨酸蛋白酶 3 和 Bax 的表达和降低 Bcl-2 的表达，导致内质网应激和细胞凋亡。长春新碱抑制 Akt 的产生也表明它阻止神经元存活。然而，槲皮素被确定可缓解长春新碱引起的氧化应激、氧化 DNA 损伤、神经元细胞损伤、炎症、内质网应激和细胞凋亡，并激活 Akt。这些结果表明，在大鼠中，槲皮素可能对长春新碱引起的周围神经毒性具有保护作用。
