Gene xxx (xxxx) xxx Please cite this article as: Ahmet Yardım, Gene, https://doi.org/10.1016/j.gene.2020.145239 Available online 15 October 2020 0378-1119/© 2020 Elsevier B.V. All rights reserved. Silymarin alleviates docetaxel-induced central and peripheral neurotoxicity by reducing oxidative stress, infammation and apoptosis in rats Ahmet Yardım a , Sefa Kucukler b , Selçuk ¨ Ozdemir c , Selim Çomaklı d , Cuneyt Caglayan e, * , Fatih Mehmet Kandemir b, * , Hamit Çelik f a Department of Neurosurgery, Private Buhara Hospital, Erzurum, Turkey b Department of Biochemistry, Faculty of Veterinary Medicine, Atatürk University, 25240 Erzurum, Turkey c Department of Genetics, Faculty of Veterinary Medicine, Atatürk University, 25240 Erzurum, Turkey d Department of Pathology, Faculty of Veterinary Medicine, Atatürk University, 25240 Erzurum, Turkey e Department of Biochemistry, Faculty of Veterinary Medicine, Bingol University, 12000 Bingol, Turkey f Department of Neurology, Private Buhara Hospital, Erzurum, Turkey A R T I C L E INFO Keywords: Apoptosis Docetaxel Infammation Oxidative stress Peripheral neurotoxicity Silymarin ABSTRACT Docetaxel (DTX) is a chemotherapeutic agent used in the treatment of various malignancies but is often asso- ciated with central and peripheral neurotoxicity. The aim of this study was to investigate the neuroprotective effect of silymarin (SLM) against DTX-induced central and peripheral neurotoxicities in rats. Rats received 25 and 50 mg/kg body weight SLM orally for seven consecutive days after receiving a single injection of 30 mg/kg body weight DTX on the frst day. SLM signifcantly decreased brain lipid peroxidation level and ameliorated brain glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activities in DTX-administered rats. SLM attenuated levels of nuclear factor kappa B (NF-κB), tumor necrosis factor-α (TNF-α), glial fbrillary acidic protein (GFAP) and activity of p38α mitogen-activated protein kinase (p38α MAPK) whereas caused an increase in levels of neural cell adhesion molecule (NCAM) in the brain and sciatic nerve of DTX- induced rats. In addition, SLM improved the histological structure of the brain and sciatic nerve tissues and decreased the expression of c-Jun N-terminal kinase (JNK) in the sciatic nerve whereas increased cyclic AMP response element binding protein (CREB) expression in the brain induced by DTX. Additionally, SLM markedly up-regulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and B-cell lymphoma-2 (Bcl-2) and downregulated the expression of Bcl-2 associated X protein (Bax) in the brain and sciatic nerve tissues of DTX-induced rats. Our results show that SLM can protect DTX-induced brain and sciatic nerve injuries by enhancing the antioxidant defense system and suppressing apoptosis and infammation. 1. Introductıon Docetaxel (DTX) is an effcient taxane group chemotherapeutic drug commonly used for the treatment of several type of cancers such as prostate cancer, head and neck cancer, ovarian cancer, metastatic breast cancer, gastric cancer, non-small cell lung cancer and brain metastasis (Ghoochani et al., 2016; Kim et al., 2018; Bas and Naziroglu, 2019). Despite its broad chemotherapeutic spectrum, peripheral neurotoxicity is a common side effect in DTX-induced chemotherapy (Cervellini et al., 2010; Kim et al., 2018). DTX treatment has been reported to have severe dose-limiting adverse effects causing brain toxicity in experimental an- imals and humans (Fushida et al., 2016; Ataizi et al., 2019). DTX leads to the accumulation of microtubules in the cell through reverse binding to microtubules and disrupting the microtubular networking in the cells, thus causing cell death (Miltenburg and Boogerd, 2014). Several studies show that DTX toxicity is triggered by overgeneration of reactive oxygen Abbreviations: Bax, Bcl-2 associated X protein; B.wt, Body weight; CAT, Catalase; CNS, central nervous system; CREB, cyclic AMP response element binding protein; DTX, Docetaxel; ELISA, Enzyme-linked immunosorbent assay; GFAP, Glial fbrillary acidic protein; GPx, Glutathione peroxidase; GSH, Glutathione; JNK, c- Jun N-terminal kinase; MDA, Malondialdehyde; NCAM, Neural cell adhesion molecule; NF-κB, Nuclear Factor Kappa B; Nrf-2, Nuclear factor erythroid 2-related factor 2; OH-1, Heme oxygenase-1; p38α MAPK, p38α mitogen-activated protein kinase; ROS, Reactive oxygen species; SLM, Silymarin; SOD, Superoxide dismut- ase; TNF-α, Tumor Necrosis Factor-α. * Corresponding authors. E-mail addresses: ccaglayan@bingol.edu.tr (C. Caglayan), fmehmet.kandemir@atauni.edu.tr (F.M. Kandemir). Contents lists available at ScienceDirect Gene journal homepage: www.elsevier.com/locate/gene https://doi.org/10.1016/j.gene.2020.145239 Received 8 June 2020; Received in revised form 22 September 2020; Accepted 11 October 2020