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Neuroprotective Effect of Apocynin Nitrone in Oxygen Glucose Deprivation-Treated SH-SY5Y Cells and Rats with Ischemic Stroke

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Neuroprotective Effect of Apocynin Nitrone in Oxygen Glucose Deprivation-Treated SH-SY5Y Cells and Rats with Ischemic Stroke Liu et al Tropical Journal of Pharmaceutical Research August 2016; 15 (8): 1681-1689 ISSN: 1596-5996 (print); 1596-9827 (electronic) © Pharmacotherapy Group, Faculty of Pharmacy, University of Benin, Benin City, 300001 Nigeria. All rights reserved. Available online at http://www.tjpr.org http://dx.doi.org/10.4314/tjpr.v15i8.13 Original Research Article Neuroprotective effect of apocynin nitrone in oxygen glucose deprivation-treated SH-SY5Y cells and rats with ischemic stroke Wu Liu1, Guo-Shuai Feng1,2, Yang Ou1, Jun Xu3, Zai-Jun Zhang1, Gao-Xiao Zhang1, Ye-Wei Sun1, Sha Li4 and Jie Jiang1,5* 1Institute of New Drug Research, College of Pharmacy, Jinan University, Guangzhou 510632, 2Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, 3College of Pharmacy, Jinan University, Guangzhou 510632, 4Department of Pharmaceutics, College of Pharmacy, Jinan University, Guangzhou 510632, 5Dongguan Institute of Jinan University, Dong Guan 523808, China *For correspondence: Email: [email protected]; Tel: +86-20-8522-2156; Fax: +86-20-8522-4766 Received: 12 December 2015 Revised accepted: 2 July 2016 Abstract Purpose: To investigate the neuroprotective potential of apocynin nitrone (AN-1), a nitrone analogue of apocynin, in rat brain tissue as a novel candidate for ischemic stroke treatment. Methods: In vitro neuroprotection of AN-1 was studied in SH-SY5Y cells treated with oxygen glucose deprivation (OGD). Cell viability was measured using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H- tetrazolium bromide (MTT) assay, and intracellular reactive oxygen species (ROS) level was investigated using flow cytometry. The protection of AN-1 in cerebral ischemia-reperfusion (I/R) rats was evaluated by cerebral infarct area and neurological deficit score. Oxidative stress of the ischemic hemisphere was assessed by malondialdehyde (MDA), glutathione (GSH) and superoxide dismutase (SOD) levels. Results: In OGD-treated SH-SY5Y cells, AN-1 reduced cell death and ROS level. In I/R rats, AN-1 exerted potential protection against neurological deficit by reducing infarction area, decreasing neurological deficit score and relieving oxidative stress. AN-1 exhibited stronger action than its parent compound apocynin in vitro, but the two had similar effects in vivo. In addition, AN-1 demonstrated efficacy close to or higher than the positive reference Edaravone® both in vitro and in vivo. Furthermore, AN-1 showed lower toxicity than apocynin in vitro. Conclusion: The results suggest that AN-1 may be a potential neuroprotective agent for the treatment of ischemic stroke in human. Keywords: Apocynin nitrone, Cerebral ischemia-reperfusion injury, Neuroprotection, Reactive oxygen species, Oxidative stress Tropical Journal of Pharmaceutical Research is indexed by Science Citation Index (SciSearch), Scopus, International Pharmaceutical Abstract, Chemical Abstracts, Embase, Index Copernicus, EBSCO, African Index Medicus, JournalSeek, Journal Citation Reports/Science Edition, Directory of Open Access Journals (DOAJ), African Journal Online, Bioline International, Open-J-Gate and Pharmacy Abstracts INTRODUCTION cell death [1,2]. It is one of the leading causes of death and disability worldwide. However, few Ischemic stroke is a disturbance caused by therapeutic methods or drugs have adequate occlusion of the cerebral vasculature, which lead effects in the clinical treatment of ischemic stroke to decreased delivery of glucose and oxygen to [2,3]. Timely recanalization of cerebral artery the brain, disruption of the ionic equilibrium and vessels and reintroduction of blood flow allow calcium homeostasis, excitotoxicity and eventual ischemic stroke-induced impairments to be Trop J Pharm Res, August 2016; 15(8): 1681 Liu et al arrested and reversed, thus, it is considered as human neuroblastoma cell line (SH-SY5Y) an efficient therapy [3]. In ischemic cerebral treated by oxygen glucose deprivation (OGD) injury, besides the ischemic infarction, the followed by reoxygenation was used for test in reperfusion after ischemia brings oxidative injury vitro, and rats with cerebral I/R caused by middle induced by reactive oxygen species (ROS) as cerebral artery occlusion (MCAO) were studied in well, which might cause delayed neuronal death vivo. For comparison, Edaravone® (Eda), a [3]. To prevent irreversible ischemic injury, powerful free-radical scavenger often used in neuroprotection is essential [2-4]. In ischemia- cerebral I/R injury studies [17,18], was used as a reperfusion (I/R), superoxide anion is one of the positive reference, and the parent Apo was most important ROS, as it contributes to included as a control compound. oxidative injury in the progress of ischemic stroke [5]. NADPH oxidase (NOX) can effectively EXPERIMENTAL generate superoxide anion, which further interacts with nitric oxide to form peroxynitrite, Chemicals and reagents another key reactive species accounting for neuronal death [6]. NOX is a major mediator 3-(4,5-dimethylthiazol-2-yl)-2,5- involved in I/R-induced neuronal death. Thus, diphenyltetrazolium bromide (MTT), dimethyl NOX inhibitors or genetic deletion of NOX have sulfoxide (DMSO), triphenyltetrazolium chloride potential as treatments for ischemic injury due to (TTC) and 2',7'-dichlorofluorescein diacetate stroke [7,8]. (DCFH-DA) were obtained from Sigma-Aldrich (St. Louis, MO, USA). Dulbecco's Modified Eagle Medium (DMEM), fetal blood serum (FBS) and Apocynin (Apo, 4-hydroxy-3-methoxyacetophe- penicillin-streptomycin solution (100×) were none), a natural compound in the root of supplied by Gibco (Shanghai, China). Assay kits Picrorhiza kurroa Royle, is able to specifically for glutathione (GSH), malondialdehyde (MDA) block the activity of NOX by preventing the and superoxide dismutase (SOD) were provided transfer of its cytosolic subunit to membrane [7]. by Nanjing Jiancheng Bioengineering Institute In previous researches, Apo was reported to (Nanjing, China). All other reagents were improve ischemic infarction and show purchased from Sigma-Aldrich unless stated neuroprotection against middle cerebral artery otherwise. occlusion (MCAO)-induced impairments in wild- type rodent models but not in NOX2-deficient Cell culture under normal and OGD condition mice [7,8]. However, Tang et al reported that the therapeutic dose range of Apo was quite narrow Under normal condition, the human in experimental stroke [9]. Hence, new apocynin neuroblastoma cell line SH-SY5Y (purchased analogues were designed and synthesized in our from ATCC) was maintained in DMEM containing lab to explore promising candidates in treating 10 % FBS and supplemented with 100 U/mL ischemic stroke [10]. penicillin and 100 g/mL streptomycin in a humidified atmosphere containing 5 % CO2 at 37 Nitrones were originally developed as free radical ºC. Under OGD condition, the cells were trapping agents in free radical chemistry [11]. incubated in glucose-free DMEM at 37 ºC in a tri- Recently, it was discovered that nitrones gas incubator with 95 % N2 and 5 % CO2. protected biological systems against oxidative stress induced impairments [11-14]. Nitrones Cell protection effect by MTT assay have been tested as therapeutic agents for The cell protection effect of the tested agents various diseases, including stroke [11,12]. In light was measured by MTT assy. All compounds of the neuroprotective activity of both apocynin including AN-1 were dissolved in DMSO and and nitrones, we synthesized apocynin nitrone freshly prepared before use (final culture (AN-1) by conjugating apocynin with a nitrone concentration of DMSO < 0.1 %). SH-SY5Y cells moiety at the ortho position of its phenolic were dispensed in 96-well plate at a density of 1 hydroxyl group [10]. × 105 cells per well. After 24 h incubation under normal condition (5 % CO2 at 37 ºC), cells were In previous studies, AN-1 showed relatively good treated with the tested agents for 8 h under OGD NADPH oxidase inhibition and activity against condition, and the cells were continuously oxidative injury both in vitro and in vivo, cultured for an additional 12 h under normal compared with its parent apocynin [15,16]. In this condition. A 10 µl aliquot of 0.5 % MTT solution work, AN-1 was further studied for its efficacy on was added to each well followed by 4 h of ischemic stroke through neuroprotective incubation. Then, the medium was discarded and investigation. To evaluate the efficacy of AN-1, 100 μl of DMSO was added to each well to Trop J Pharm Res, August 2016; 15(8): 1682 Liu et al dissolve the formazan. The optical density of Following this, the incision was closed and each well was measured at 570 nm using a penicillin was given intraperitoneally to prevent microplate reader (Spectra MAX 340, Molecular inflammation. Two hours after occlusion, Apo, Devices Co, CA, USA). Cell viability was Eda and AN-1 were administered via the tail expressed as a percentage of the value of vein. Five minutes later, the suture was removed control cells. to restore blood flow. Sham-operated rats were manipulated similarly, except MCA was not Intracellular ROS assay occluded. Regional cerebral blood flow (rCBF) was monitored by laser-Doppler flowmeter SH-SY5Y cells were seeded on 6-well plates at a (Periflux System 5000, Perimed Inc.) with a density of 5 × 105 cells/well, and OGD insult was flexible probe over the skull. rCBF was measured generated as described above. After 1 h of OGD before ischemia, during MCAO and after insult, cells were washed with phosphate- reperfusion. Animals
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