Contents lists available at ScienceDirect European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar Full length article Preventive effect of silymarin-loaded chitosan nanoparticles against global cerebral ischemia/reperfusion injury in rats Akbar Hajizadeh Moghaddam a,* , Seyed Reza Mokhtari Sangdehi a , Mojtaba Ranjbar b , Vahid Hasantabar c a Department of Biology, Faculty of Basic Sciences, University of Mazandaran, Babolsar, Iran b Faculty of Biotechnology, Amol University of Special Modern Technologies, Amol, Iran c Department of Organic Polymer Chemistry, Faculty of Chemistry, University of Mazandaran, Babolsar, Iran ARTICLE INFO Keywords: Ischemia/reperfusion Silymarin-loaded chitosan nanoparticles Depression Oxidative stress Inflammation Bioavailability ABSTRACT Chitosan-based polymeric nanocarrier has been utilized as a novel drug delivery device in recent years due to its prominent role in the treatment of central nervous system disorders. The aim of this study was to investigate the anti-oxidative and anti-inflammatory effects of silymarin-loaded chitosan nanoparticles (SM–CS–NPs) on rat model of global cerebral ischemia/reperfusion (I/R). All rats were randomly distributed into four groups: Control, I/R, SM and SM–CS–NPs. Oral administration of SM and SM–CS–NPs was started 14 days prior to bilateral common carotid artery occlusion (BCCAO). Depressive-like behaviors, infarct volume, some oxidative stress markers and inflammatory factors were assessed after induction of I/R. SM–CS–NPs pretreatment sig- nificantly ameliorated depressive-like behaviors and infarct volume after I/R. SM–CS–NPs also significantly decreased the levels of malondialdehyde (MDA), and expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), and significantly increased the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GRx), and glutathione (GSH) levels in I/R brain. The current study demonstrated that SM–CS–NPs pretreatment effectively prevents oxidative and inflammatory damage in the brain caused by I/R, and it can be considered as a useful pretreatment to attenuate the negative effects of I/R. 1. Introduction Brain ischemic disease is one of the primary causes of disability and mortality, which is a major challenge to public health (Godinho et al., 2018). This developing disorder is usually caused by a transient or permanent reduction in cerebral blood flow (Xue et al., 2017). Studies have shown that there is a link between oxidative stress and the pro- duction of reactive oxygen species acting as a source of injury (Allen and Bayraktutan, 2009). Patients who survive I/R or hypoxia com- monly develop cognitive deficit and depression. The impairments are strongly correlated with damage to various cortical regions including disturbances of attention deficits, disability, social problems and post- stroke depression (Godinho et al., 2018). Although the exact mechan- isms of behavioral disorders remain unclear, IR-induced oxidative stress in the brain has been shown to play a critical role in the progression of cognitive impairment. In addition, the oxidative stress, as a source of injury to biological molecules that leads to toxicity and degeneration of the neuron, is one of the major contributing factors to the development of depressive disorders (Nabavi et al., 2018). In addition to oxidative stress, inflammation can play a pivotal role in damaging brain tissue. The inflammatory response following I/R is a well-known event that involves the activation of astrocyte and microglial which react by se- creting cytokines, such as TNF-α and IL-6 (Liu et al., 2017). However, there are very limited clinically effective therapies to improve functional outcomes associated with I/R. Consequently, there is a pressing need to identify new safe and effective drugs to treat I/R (Godinho et al., 2018). Flavonoids and polyphenols are one of the most important groups of natural antioxidants available in human diets. SM is composed of several isomer flavonolignans. Silybin is the chief active constituent in SM mixture that shows anti-oxidant activity and exerts anti-inflammatory effect (Surai, 2015; Turgut et al., 2008). Previous studies showed that inhibition of TNF-α and IL-6 mediates the anti- inflammatory effect of SM (Hou et al., 2010; Stolf et al., 2017). Nevertheless, poor bioavailability of SM is the main factor limiting its https://doi.org/10.1016/j.ejphar.2020.173066 Received 13 December 2019; Received in revised form 1 March 2020; Accepted 10 March 2020 * Corresponding author. E-mail addresses: a.hajizadeh@umz.ac.ir (A.H. Moghaddam), reza.mokhtari1100@gmail.com (S.R. Mokhtari Sangdehi), ranjbarmf@gmail.com (M. Ranjbar), vahidhasantabar@yahoo.com (V. Hasantabar). European Journal of Pharmacology 877 (2020) 173066 0014-2999/ © 2020 Elsevier B.V. All rights reserved. T