Anti-inflammatory and protective effects of MT-031, a novel multitarget MAO-A and AChE/BuChE inhibitor in scopolamine mouse model and inflammatory cells
Introduction
Alzheimer's disease (AD) is a neurological disease, consider as a progressive disorder of dementia and impaired cognitive and mental functions (Alzheimer's Association, 2015, Katzman, 1986, McCarty, 2006). In addition to the two major neuropathological hallmarks of the disease, namely the neurofibrillary tangles and amyloid beta (Aβ) plaques (Hardy and Selkoe, 2002, Octave, 2005), AD is characterized by a consistent deficit in cholinergic neurotransmission, particularly in the basal forebrain (Schliebs, 2005). Moreover, accumulating evidence indicated that many cytotoxic signals in the AD brain such as, oxidative stress (OS), inflammation and excessive bio-metals (e.g. iron, zinc, and copper) at the sites of the neurodegeneration can initiate neuronal death processes (Aisen and Davis, 1994, Joseph et al., 2005, Octave, 2005, Rogers and Lahiri, 2004). Thus, it is likely reasonable to conclude that novel AD therapeutic strategy will require multitarget drug treatment to address the varied pathological aspects of this disease.
A vast studies considered to develop and design multitarget-directed ligands towards targeting AD complex etiological pathways (Buccafusco and Terry, 2000, Weinstock et al., 2000, Youdim, 2010, Zheng et al., 2005). Recently, we have designed and synthesized a new series of multitarget compounds, by amalgamating the neuroprotective/neurorescue active N-propargyl moiety of the monoamine oxidase (MAO)-B inhibitor/anti-Parkinson's drug, rasagiline (Youdim, 2003) to the methyl-amino-position of the acetylcholinesterase (AChE) inhibitor/anti-AD drug, rivastigmine (Weinstock et al., 1994), aiming to develop new therapy for AD (Liu et al., 2016). The use of the multitarget-directed ligand strategy to combine rasagiline and rivastigmine in order to create a series of rasagiline-rivastigmine hybrids, MT compounds, attained to achieve simultaneously inhibition of MAO/ChE inhibitory activities, antioxidant activity and neuroprotective properties. Among MT series, MT-031 (Fig. 1A) exerted the higher dual potency of MAO-A and ChE inhibition than other compounds and found to increase the striatal levels of dopamine (DA), serotonin (5-HT) and norepinephrine (NE), and prevent the metabolism of DA and 5-HT in acute-treated mice (Liu et al., 2016). Additionally, MT-031 exerted neuroprotective/antioxidant effects against H2O2 in human neuroblastoma SH-SY5Y cells (Liu et al., 2016).
In the present study, we have further examined the anti-inflammatory and protective effects of the multitarget ligand, MAO-A/ChE inhibitor, MT-031 in mice-treated with scopolamine-induced amnesia, which is widely referred as a model simulating human dementia in general and AD in particular (Joshi and Parle, 2006). In addition, the anti-inflammatory and protective effects of MT-031 were explored in mouse splenocytes and microglial cells.
Section snippets
Materials
The MD-TM Mobile Phase, for analysis of monoamines and metabolites in high performance liquid chromatography (HPLC) system, was purchased from Thermo Fisher Scientific Inc. (Waltham, MA, USA). Bradford reagent and the monoamines: DA, homovanilic acid (HVA), 3,4-dihydroxyphenylacetic acid (DOPAC), 5-HT, 5-hydroxyindoleacetic acid (5-HIAA) and NE were purchased from Sigma Chemical Co. (St Louis, MO, USA). For the MAO activity assay, phenylethylamine HCl, trans-2-phenylcyclopropylamine HCl (TCP),
Chronic MT-031 treatment attenuated anxiety-like behavior and cognitive deficits
Open field test, a commonly used assay of general locomotors activity and willingness of rodents to explore novel environment, offers also to assess depression or anxiety-related behavior (Christmas and Maxwell, 1970, Prut and Belzung, 2003). Administration of MT-031 (10 mg/kg) to mice for 2 weeks significantly increased the number of entries (Fig. 2A) and the duration of moving time to the central area (Fig. 2B), compared to vehicle-treated animals, in the open field test. In accordance,
Discussion
In the present study, the protective effect of MT-031 was examined in scopolamine-induced memory loss in mice (Henderson and Sherriff, 1991, Mahmoodi et al., 2010). We have demonstrated that MT-031 treatment prevented cognitive deficits induced by scopolamine and improved spatial learning and memory, compared with vehicle-treated mice, as examined in Y-maze task and Morris water maze test. These results may be attributed to the ability of MT-031 to increase the levels of amines, such as NE,
Conclusions
Nowadays, designing multiple-target ligands is referred as a novel and most adequate therapeutic approach for multi-pathological disorders, such as neurodegenerative diseases (Buccafusco and Terry, 2000, Youdim, 2010). Current study supports MT-031 as a novel multi-functional and anti-AD drug candidate, based on its selective inhibition of MAO-A activity, dual inhibition of AChE/BuChE enzyme activities and the wide range of neuroprotective activities, including anti-oxidant effect, clearing ROS
Acknowledgements
The authors gratefully acknowledge the support of Rappaport Family Research Institute, Technion-Israel Institute of Technology (Haifa, Israel).
References (63)
- et al.
Inflammation and Alzheimer's disease
Neurobiol. Aging
(2000) - et al.
Effect of rivastigmine on scopolamine-induced memory impairment in rats
Eur. J. Pharmacol.
(1999) Effect of a carboxy-terminal fragment of the Alzheimer's amyloid precursor protein on expression of proinflammatory cytokines in rat glial cells
Life Sci.
(1997)- et al.
A comparison of the effects of some benzodiazepines and other drugs on aggressive and exploratory behaviour in mice and rats
Neuropharmacology
(1970) - et al.
Reversion of age-related recognition memory impairment by iron chelation in rats
Neurobiol. Aging
(2008) - et al.
Treating inflammation by blocking interleukin-1 in humans
Semin. Immunol.
(2013) - et al.
Nerve growth factor metabolic dysfunction in Alzheimer's disease and Down syndrome
Trends Pharmacol. Sci.
(2014) - et al.
Design, synthesis and evaluation of novel dual monoamine-cholinesterase inhibitors as potential treatment for Alzheimer's disease
Neuropharm
(2016) - et al.
Inhibitory avoidance memory deficit induced by scopolamine: interaction of cholinergic and glutamatergic systems in the ventral tegmental area
Neurobiol. Learn Mem.
(2010) Toward prevention of Alzheimer disease–potential nutraceutical strategies for suppressing the production of amyloid beta peptides
Med. Hypotheses
(2006)
Developments of a water-maze procedure for studying spatial learning in the rat
J. Neurosci. Methods
Anti-inflammatory properties of pro-inflammatory interferon-gamma
Int. Immunopharmacol.
Amyloid precursor protein (APP) metabolites APP intracellular fragment (AICD), Abeta42, and Tau in Nuclear Roles
J. Biol. Chem.
Correlation of brain levels of 9-amino-1,2,3,4-tetrahydroacridine (THA) with neurochemical and behavioral changes
Eur. J. Pharmacol.
The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review
Eur. J. Pharmacol.
Acetylcholinesterase inhibitors effects on oncostatin-M, interleukin-1 beta and interleukin-6 release from lymphocytes of Alzheimer's disease patients
Exp. Gerontol.
Acetylcholinesterase inhibitors used in treatment of Alzheimer's disease prevent glutamate neurotoxicity via nicotinic acetylcholine receptors and phosphatidylinositol 3-kinase cascade
Neuropharmacology
A novel cholinesterase and brain-selective monoamine oxidase inhibitor for the treatment of dementia comorbid with depression and Parkinson's disease
Prog. Neuropsychopharmacol. Biol. Psychiatry
Design, synthesis, and evaluation of novel bifunctional iron-chelators as potential agents for neuroprotection in Alzheimer's, Parkinson's, and other neurodegenerative diseases
Bioorg Med. Chem.
Inflammatory mechanisms in Alzheimer's disease: implications for therapy
Am. J. Psychiatry
2015 Alzheimer's disease facts and figures
Alzheimer's Dementia
Multiple central nervous system targets for eliciting beneficial effects on memory and cognition
J. Pharmacol. Exp. Ther.
New approaches to developing antidepressants by enhancing monoaminergic neurotransmission
Expert Opin. Investig. Drugs
Genomic sequence for human prointerleukin 1 beta: possible evolution from a reverse transcribed prointerleukin 1 alpha gene
Nucleic Acids Res.
Serotonin function and the mechanism of antidepressant action. Reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan
Arch. Gen. Psychiatry
gamma-Secretase component presenilin is important for microglia beta-amyloid clearance
Ann. Neurol.
Behavioral and psychological signs and symptoms of dementia: implications for research and treatment. Proceedings of an international consensus conference. Lansdowne, Virginia, April 1996
Int. Psychogeriatr.
Nerve growth factor: two receptors, multiple functions
Bioessays
Reduced tissue levels of noradrenaline are associated with behavioral phenotypes of the TgCRND8 mouse model of Alzheimer's disease
Neuropsychopharmacology
Scara1 deficiency impairs clearance of soluble amyloid-beta by mononuclear phagocytes and accelerates Alzheimer's-like disease progression
Nat. Commun.
Novel multifunctional neuroprotective iron chelator-monoamine oxidase inhibitor drugs for neurodegenerative diseases. In vivo selective brain monoamine oxidase inhibition and prevention of MPTP-induced striatal dopamine depletion
J. Neurochem.
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