Neuroscience Letters 480 (2010) 206–210 Contents lists available at ScienceDirect Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet Neuroprotective effect of silymarin in 6-hydroxydopamine hemi-parkinsonian rat: Involvement of estrogen receptors and oxidative stress Tourandokht Baluchnejadmojarad a,∗ , Mehrdad Roghani b , Mehdi Mafakheri a a Department of Physiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran b Department of Physiology, School of Medicine and Medicinal Plant Research Center, Shahed University, Tehran, Iran article info Article history: Received 18 February 2010 Received in revised form 10 June 2010 Accepted 13 June 2010 Keywords: Silymarin 6-Hydroxydopamine Parkinson’s disease Estrogen receptor Oxidative stress abstract This study examined neuroprotective effect of silymarin (SM) in a model of Parkinson’s disease (PD). Uni- lateral intrastriatal 6-hydroxydopamine (6-OHDA)-lesioned rats were pretreated i.p. with SM (100 and 200 mg/kg) 1 h before neurotoxin injection. Fulvestrant was used to evaluate the involvement of estro- gen receptors. Net apomorphine-induced rotations and number of Nissl-stained neurons of substantia nigra pars compacta (SNC) were counted in addition to measurement of oxidative stress markers. SM administration only at a dose of 200 mg/kg attenuated the rotational behavior in 6-OHDA-lesioned rats and protected the neurons of SNC against its toxicity and fulvestrant partially attenuated this beneficial effect of SM. In addition, pretreatment with SM at a dose of 200 mg/kg significantly decreased the 6- OHDA-induced thiobarbituric acid reactive substances (TBARS) formation. SM exhibits a dose-dependent neuroprotective effect against 6-OHDA toxicity, partly through attenuating oxidative stress and via an estrogenic pathway. © 2010 Elsevier Ireland Ltd. All rights reserved. Parkinson’s disease (PD) is a neuropathological disorder involving the degeneration of dopaminergic neurons in the substantia nigra with debilitating motor disturbances [24,34]. Oxidative stress, low glutathione levels, DNA damage and iron deposition has been reported as the main causes of dopaminergic neurons degeneration in PD [11,15,25]. Oxidative stress not only destroys the dopamin- ergic neurons, but it also compromises mitochondrial oxidative phosphorylation, leading to decreased energy output and eventu- ally to secondary cell death [6]. Although great advances have been made in development of agents to treat PD, none yet address the underlying problem asso- ciated with it, i.e. the progressive loss of dopaminergic neurons [3,19,36]. Among natural products, silymarin (SM), classified within the group of flavonolignans and isolated from milk thistle plant Silybum marianum [21], routinely used to treat liver disorders [14], could prevent lipid peroxidation [8,33], promote regener- ative processes, stabilize cell membranes, and possibly through binding to an estradiol binding site, may stimulate the synthesis of ribosomal RNAs [4,29,30]. SM can also increase antioxidative enzyme levels [31]. Neuroprotective effect of SM on oxidative stress in rat brain has already been reported [18]. Furthermore, SM through inhibiting glial cell monoamine oxidase (MAO) or ∗ Corresponding author at: Department of Physiology, School of Medicine, Iran University of Medical Sciences, Shaheed Hemmat Expressway, P.O. Box: 14155- 6183, Tehran, Iran. Tel.: +98 21 88058709; fax: +98 21 88058719. E-mail address: tmojarad@yahoo.com (T. Baluchnejadmojarad). scavenging peroxide products may be useful to attenuate oxida- tive neuronal damage associated with various neurodegenerative diseases [16]. SM could also lower damage to dopaminergic neu- rons through inhibiting lipopolysaccharide-induced activation of microglia and reducing production of inflammatory mediators [35]. SM due to its estrogenic activity [26] prevents bone loss in ovariectomized rats and shows mild proliferative effects in uterus [10]. Silymarin is capable of binding to cytosolic estrogen receptors and this binding is exclusive to the estrogen receptor  (ER). Treatment of ovariectomized rats with SM or estradiol may allow differentiation of biological effects mediated by the ER or ER [26]. In addition, in vitro and in vivo studies have described estrogen’s protective effects against amyloid  peptide (A)-induced toxicity [12] and mitochondria toxins such as N- methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP) [7]. One of the important points regarding SM is that it is a safe herbal product, since no health hazards or side effects are known in conjunction with the proper administration of designed therapeutic dosages [17]. This study was conducted to investigate for the first time the possible neuroprotective effect of SM administration in an early model of Parkinson’s disease in rat and to evaluate the related involvement of estrogenic pathway and oxidative stress. Adult male Wistar rats (250–300 g; n = 80) (Pasteur’s Insti- tute, Tehran) were housed in a temperature-controlled colony room under light/dark cycle with food and water available ad libitum. Procedures involving animals were conducted in con- formity with NIH guidelines for the care and use of laboratory animals. Only rats not showing any biased rotational behavior 0304-3940/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2010.06.038