title: Anti-inflammatory and protective effects of MT-031, a novel multitarget MAO-A and AChE/BuChE inhibitor in scopolamine mouse model and inflammatory cells.
abstract: Previous study demonstrated that the novel multitarget compound, MT-031 preserved in one molecule entity the beneficial properties of its parent drugs, rasagiline and rivastigmine, and exerted high dual potencies of monoamine oxidase-A (MAO-A) and cholinesterase (ChE) inhibition in acute-treated mice and neuroprotective effects against H2O2-induced neurotoxicity in human neuroblastoma SH-SY5Y cells. The present study aimed to further investigate the anti-inflammatory and protective effects of MT-031 in scopolamine mouse model and inflammatory cell cultures. Our findings demonstrated that once daily chronic administration of MT-031 (5-10 mg/kg) to mice antagonized scopolamine-induced memory and cognitive impairments, displayed brain selective MAO-A and AChE/BuChE inhibition, increased the levels of striatal dopamine (DA), serotonin (5-HT) and norepinephrine and prevented the metabolism of DA and 5-HT. In addition, MT-031 upregulated mRNA expression levels of Bcl-2, the neurotrophic factors, (e.g., brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) and nerve growth factor (NGF)), the antioxidant enzyme catalase and the anti-inflammatory cytokine, neurotrophic tyrosine kinase receptor (Ntrk), and down-regulated the mRNA expression levels of the pro-inflammatory interleukin (IL)-6 in scopolamine-induced mice. In accordance, MT-031 was shown to reduce reactive oxygen species accumulation, increase the levels of anti-inflammatory cytokines, IL-10 and decrease the levels of the pro-inflammatory cytokines, IL-1β, IL-6, IL-17 and interferon-gamma (IFN-γ) in activated mouse splenocytes and microglial cells. Taken together, these pharmacological properties of MT-031 can be of clinical importance for developing this novel multitarget compound as a novel drug candidate for the treatment of Alzheimer's disease.
authors.affiliation: Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Alon
authors.initials: A
authors.lastname: Rabinovich
authors.affiliation: Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel; Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Nash
authors.affiliation: Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel; Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Dan
authors.initials: D
authors.lastname: Frenkel
authors.affiliation: Institute of New Drug Research, Jinan University College of Pharmacy, Guangzhou, China.
authors.forename: Yuqiang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Moussa B H
authors.initials: MBH
authors.lastname: Youdim
authors.affiliation: Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. Electronic address: worly@tx.technion.ac.il.
authors.forename: Orly
authors.initials: O
authors.lastname: Weinreb
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000378:metabolism; D002478:Cells, Cultured; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000008:administration & dosage*; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D012601:Scopolamine / Q000633:toxicity*
chemical_list: D000893:Anti-Inflammatory Agents; D002800:Cholinesterase Inhibitors; D018836:Inflammation Mediators; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; D012601:Scopolamine; D008995:Monoamine Oxidase; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: Anti-inflammation; Cholinesterase inhibition; Monoamine oxidase-A inhibition; Multitarget drug; Scopolamine mouse model