Anti-inflammatory and protective effects of MT-031, a novel multitarget MAO-A and AChE/BuChE inhibitor in scopolamine mouse model and inflammatory cells. (February 2017)

• Record Type: Journal Article
• Authors: Liu, Wei; Rabinovich, Alon; Nash, Yuval; Frenkel, Dan; Wang, Yuqiang; Youdim, Moussa B.H.; Weinreb, Orly
• Is Part Of: Neuropharmacology. Volume 113:Part A(2017)
• Page Start: 445
• Page End: 456
• Publication Date: 2017-02
• Subjects: Cholinesterase inhibition -- Monoamine oxidase-A inhibition -- Multitarget drug -- Scopolamine mouse model -- Anti-inflammation; ACh acetylcholine -- AChE acetylcholinesterase -- AChEIs acetylcholinesterase inhibitors -- AD Alzheimer's disease -- Bcl-2 B-cell lymphoma 2 -- BDNF Brain-derived neurotrophic factor -- GDNF Glial cell line-derived neurotrophic factor -- ChE cholinesterase -- DOPAC 3, 4-dihydroxyphenylacetic acid -- DA dopamine -- HPLC high performance liquid chromatography -- HVA homovanillic acid -- 5-HIAA 5-hydroxyindoleacetic acid -- IL Interleukin -- IFN-γ Interferon-gamma -- LPS Lipopolysaccharide -- MAO monoamine oxidase -- 3-MT 3-methoxytyramine -- NE noradrenaline -- NGF neurotrophic growth factor -- Ntrk neurotrophic tyrosine kinase receptor -- OS oxidative stress -- ROS reactive oxygen species -- RT-PCR real-time reverse transcription polymerase chain reaction -- 5-HT serotonin; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2016.10.028
• Languages: English
• ISSNs: 0028-3908

Abstract

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 H2 O2 -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. Highlights: MT-031 is a novel hybrid molecule of rasagiline and rivastigmine. This anti-AD drug candidate is a brain AChE/BuChE and MAO-A inhibitor. MT-031 antagonized scopolamine-induced memory and cognitive impairments in mice. MT-031 exerted protection/anti-inflammation in scopolamine-induced mice. Anti-inflammatory effects of MT-031 were shown in anti-CD3 and LPS-activated cells.