title: Neuroprotection by Combined Administration with Maslinic Acid, a Natural Product from Olea europaea, and MK-801 in the Cerebral Ischemia Model.
abstract: Glutamate-mediated excitotoxicity is a major cause of ischemic brain damage. MK-801 confers neuroprotection by attenuating the activation of the N-methyl-d-aspartate (NMDA) receptor, but it failed in clinical use due to the short therapeutic window. Here we aim to investigate the effects of maslinic acid, a natural product from Olea europaea, on the therapeutic time window and dose range for the neuroprotection of MK-801. Rats were administered with maslinic acid intracerebroventricularly and cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) followed by reperfusion. MK-801 was administered at 1 h, 2 h, 3 h and 4 h after ischemia, respectively. The cerebral infarct volume was determined by 2,3,5-Triphenyltetrazolium chloride (TTC) staining, neuronal damage was assessed by Haematoxylin Eosin (H&amp;E) staining, and the expression of glial glutamate transporters and glial fibrillary acidic protein (GFAP) was evaluated by immunohistochemistry and Western blot post-ischemia. Results showed that the presence of maslinic acid extended the therapeutic time window for MK-801 from 1 h to 3 h. Co-treatment of maslinic acid and MK-801 at a subthreshold dosage obviously induced neuroprotection after ischemia. The combination of these two compounds improved the outcome in ischemic rats. Moreover, maslinic acid treatment promoted the expression of GLT-1 and GFAP post-ischemia. These data suggest that the synergistic effect of maslinic acid on neurological protection might be associated with the improvement of glial function, especially with the increased expression of GLT-1. The combination therapy of maslinic acid and MK-801 may prove to be a potential strategy for treating acute ischemic stroke.
authors.affiliation: Institute of Translational Medicine, Nanchang University, 1299 Xuefu Avenue, Nanchang 330001, China. qianyisong@ncu.edu.cn.
authors.forename: Yisong
authors.initials: Y
authors.lastname: Qian
authors.affiliation: Department of Physiology, China Pharmaceutical University, 24 Tongjiaxiang Street, Nanjing 210009, China. txzgrace@gmail.com.
authors.forename: Xuzhen
authors.initials: X
authors.lastname: Tang
authors.affiliation: Department of Human Anatomy and Cell Science, University of Manitoba, 745 Bannatyne Avenue, Winnipeg, MB R3E 0J9, Canada. guan.teng@gmail.com.
authors.forename: Teng
authors.initials: T
authors.lastname: Guan
authors.affiliation: Department of Physiology, China Pharmaceutical University, 24 Tongjiaxiang Street, Nanjing 210009, China. phy.lym@gmail.com.
authors.forename: Yunman
authors.initials: Y
authors.lastname: Li
authors.affiliation: Center for Drug Discovery, China Pharmaceutical University, 24 Tongjiaxiang Street, Nanjing 210009, China. hbsun2000@yahoo.com.
authors.forename: Hongbin
authors.initials: H
authors.lastname: Sun
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000008:administration & dosage* / Q000494:pharmacology; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D050491:Glutamate Plasma Membrane Transport Proteins / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000494:pharmacology; D031658:Olea / Q000737:chemistry*; D051381:Rats; D014315:Triterpenes / Q000008:administration & dosage* / Q000494:pharmacology; D009828:Oleanolic Acid / Q000031:analogs & derivatives
chemical_list: D016291:Dizocilpine Maleate; D005904:Glial Fibrillary Acidic Protein; D050491:Glutamate Plasma Membrane Transport Proteins; D018696:Neuroprotective Agents; D014315:Triterpenes; C412811:maslinic acid; D009828:Oleanolic Acid
keywords: GLT-1; MK-801; cerebral ischemia; maslinic acid