Protective effect of edaravone on chlorpyrifos-induced brain injury in rats and its mechanism

doi:10.12047/j.cjap.6223.2022.024

Abstract

Abstract: Objective: To investigate the protective effect of edaravone on chlorpyrifos-induced neuronal apoptosis and its mitochondrial mechanism. Methods: Under the principle of randomization and double-blindness, the rats were divided into control group, chlorpyrifos group, and edaravone group (n=6). The rats in edaravone group were treated with edaravone (10 mg/1.6 ml/kg, ip.) 1 h after chlorpyrifos injection. After continuous injection of chlorpyrifos and edaravone for 28 days, the learning and memory abilities of the rats were tested by open field and water maze tests. The rat brain tissue was collected after cardiac perfusion, and the neuronal damage in the hippocampus of the brain was detected by HE staining and the mitochondrial and nuclear damage were observed by transmission electron microscopy. The contents of Na⁺-K⁺-ATPase and ATP were measured to evaluate mitochondrial damage. The expression of mitochondrial fission protein DRP1 and phosphorylation at Ser 637 of DRP1 were determined by immunohistochemistry and immunoblotting. Results: Compared with the control group, the total movement distance and average speed of the rats in the chlorpyrifos group were decreased significantly within 3 minutes of the open field test (P＜0.01), and the escape latency within 1 minute of the water maze test was prolonged significantly. The number of platform crossings was reduced significantly (P＜0.01), the activity of ATPase in brain tissue was decreased significantly (P＜0.01) , the content of ATP and the phosphorylation level of Ser637 of mitochondrial DRP1 were decreased significantly (P＜0.05, P＜0.01). After edaravone treatment, the total movement distance and average speed of rats in the open field test were increased (P＜0.05), the latency in the water maze test was decreased, and the number of crossing platforms was increased (P＜0.01), brain pathological sections showed that nerve cells were arranged neatly, nucleus and mitochondrial damage was significantly improved, the activity of ATPase in brain tissue was increased (P＜0.01), the levels of ATP and mitochondrial DRP1 Ser637 phosphorylation increased (P＜0.05, P＜0.01).Conclusion: Edaravone alleviates chlorpyrifos-induced brain injury in rats by promoting the phosphorylation of DRP1 at Ser637.

Key words: chlorpyrifos, edaravone, dynamin-related protein 1(DRP1), mitochondrial, rat

CLC Number:

LIN Pei-yao, SONG Ying, QIN Dong-xu, LU Dong-ze, FAN Xyu-li. Protective effect of edaravone on chlorpyrifos-induced brain injury in rats and its mechanism[J]. CJAP, 2022, 38(2): 163-168.

References

[1] Caughlan A, Newhouse K, Namgung U, et al. Chlorpyrifos induces apoptosis in rat cortical neurons that is regulated by a balance between p38 and ERK/JNK MAP kinases[J]. Toxicol Sci, 2004, 78(1): 125-134.
[2] Wang T, Zhao L, Liu M, et al. Oral intake of hydrogen-rich water ameliorated chlorpyrifos-induced neurotoxicity in rats[J]. Toxicol Appl Pharmacol, 2014, 280(1): 169-176.
[3] Brasil FB, de Almeida FJS, Luckachaki MD, et al. Pinocembrin pretreatment counteracts the chlorpyrifos-induced HO-1 downregulation, mitochondrial dysfunction, and inflammation in the SH-SY5Y cells[J]. Metab Brain Dis, 2021, 36(8): 2377-2391.
[4] Jiang Y, He Y, Li W, et al. Exposure to chlorpyrifos leads to spindle disorganization and mitochondrial dysfunction of porcine oocytes during in vitro maturation[J]. Theriogenology, 2021, 173: 249-260.
[5] Li W, Ehrich M. Transient alterations of the blood-brain barrier tight junction and receptor potential channel gene expression by chlorpyrifos[J]. J Appl Toxicol, 2013, 33(10): 1187-1191.
[6] Ubaid Ur Rahman H, Asghar W, Nazir W, et al. A comprehensive review on chlorpyrifos toxicity with special reference to endocrine disruption: Evidence of mechanisms, exposures and mitigation strategies[J]. Sci Total Environ, 2021, 755(2): 142649.
[7] Germain M, Mathai JP, McBride HM, et al. Endoplasmic reticulum BIK initiates DRP1 regulated remodelling of mitochondrial cristae during apoptosis[J]. EMBO J, 2015, 24: 1546-1556.
[8] Ismail H, Shakkour Z, Tabet M, et al. Traumatic brain injury: Oxidative stress and novel anti-oxidants such as mitoquinone and edaravone[J]. Antioxidants(Basel), 2020, 9(10): 943-943.
[9] Hussein RM, Mohamed WR, Omar HA.A neuroprotective role of kaempferol against chlorpyrifos-induced oxidative stress and memory deficits in rats via GSK3β-Nrf2 signaling pathway[J]. Pestic Biochem Physiol, 2018, 152: 29-37.
[10] Hernandez CM, Beck WD, Naughton SX, et al. Repeated exposure to chlorpyrifos leads to prolonged impairments of axonal transport in the living rodent brain[J]. Neurotoxicology, 2015, 47: 17-26.
[11] Liu J, Jiang Y, Zhang G, et al. Protective effect of edaravone on blood-brain barrier by affecting NRF-2/HO-1 signaling pathway[J]. Exp Ther Med, 2019, 18(4): 2437-2442.
[12] Sarkar B, Dhiman M, Mittal S, et al. Curcumin revitalizes Amyloid beta(25-35)-induced and organophosphate pesticides pestered neurotoxicity in SH-SY5Y and IMR-32 cells via activation of APE1 and Nrf2[J]. Metab Brain Dis, 2017, 32(6): 2045-2061.
[13] 宋英, 寿丽蒙, 陈曼婷. 依达拉奉减轻毒死蜱诱导的PC12细胞损伤[J]. 浙江工业大学学报, 2016, 44(6): 654-659.
[14] Xu MY, Wang P, Sun YJ, et al. Joint toxicity of chlorpyrifos and cadmium on the oxidative stress and mitochondrial damage in neuronal cells[J].Food Chem Toxicol, 2017, 103: 246-252.
[15] 苏艳红, 袁乾坤, 肖蓉, 等. 抗阻训练对增龄大鼠骨骼肌线粒体功能的影响[J]. 中国应用生理学杂志, 2020, 36(2): 165-170.
[16] 李帅, 张炳东. 细胞凋亡途径的研究进展 [J]. 山东医药, 2017, 57(37): 103-106.
[17] Wu X, Luo J, Liu H, et al. Recombinant adiponectin peptide ameliorates brain injury following intracerebral hemorrhage by suppressing astrocyte-derived inflammation via the inhibition of Drp1-mediated mitochondrial fission[J]. Transl Stroke Res, 2020, 11(5): 924-939.
[18] Song Y, Bei Y, Xiao Y, et al. Edaravone, a free radical scavenger, protects neuronal cells' mitochondria from ischemia by inactivating another new critical factor of the 5-lipoxygenase pathway affecting the arachidonic acid metabolism[J]. Brain Res, 2018, 1690: 96-104.
[19] Shou L, Bei Y, Song Y, et al. Nrf2 mediates the protective effect of edaravone after chlorpyrifos-induced nervous system toxicity[J]. Environ Toxicol, 2019, 34(5): 626-633.
[20] 包晓辰, 方以群, 马骏, 等. 依达拉奉对小鼠肺型氧中毒的保护作用及其机制[J]. 中国应用生理学杂志, 2020, 36(1): 73-76.