Elsevier

Neuropharmacology

Volume 113, Part A, February 2017, Pages 445-456
Neuropharmacology

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

https://doi.org/10.1016/j.neuropharm.2016.10.028Get rights and content

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.

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.

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)

  • R. Morris

    Developments of a water-maze procedure for studying spatial learning in the rat

    J. Neurosci. Methods

    (1984)
  • H. Muhl et al.

    Anti-inflammatory properties of pro-inflammatory interferon-gamma

    Int. Immunopharmacol.

    (2003)
  • G. Multhaup et al.

    Amyloid precursor protein (APP) metabolites APP intracellular fragment (AICD), Abeta42, and Tau in Nuclear Roles

    J. Biol. Chem.

    (2015)
  • J.A. Nielsen et al.

    Correlation of brain levels of 9-amino-1,2,3,4-tetrahydroacridine (THA) with neurochemical and behavioral changes

    Eur. J. Pharmacol.

    (1989)
  • L. Prut et al.

    The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review

    Eur. J. Pharmacol.

    (2003)
  • M. Reale et al.

    Acetylcholinesterase inhibitors effects on oncostatin-M, interleukin-1 beta and interleukin-6 release from lymphocytes of Alzheimer's disease patients

    Exp. Gerontol.

    (2005)
  • Y. Takada-Takatori et al.

    Acetylcholinesterase inhibitors used in treatment of Alzheimer's disease prevent glutamate neurotoxicity via nicotinic acetylcholine receptors and phosphatidylinositol 3-kinase cascade

    Neuropharmacology

    (2006)
  • M. Weinstock et al.

    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

    (2003)
  • H. Zheng et al.

    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.

    (2005)
  • P.S. Aisen et al.

    Inflammatory mechanisms in Alzheimer's disease: implications for therapy

    Am. J. Psychiatry

    (1994)
  • Alzheimer's Association

    2015 Alzheimer's disease facts and figures

    Alzheimer's Dementia

    (2015)
  • J.J. Buccafusco et al.

    Multiple central nervous system targets for eliciting beneficial effects on memory and cognition

    J. Pharmacol. Exp. Ther.

    (2000)
  • F.P. Bymaster et al.

    New approaches to developing antidepressants by enhancing monoaminergic neurotransmission

    Expert Opin. Investig. Drugs

    (2003)
  • B.D. Clark et al.

    Genomic sequence for human prointerleukin 1 beta: possible evolution from a reverse transcribed prointerleukin 1 alpha gene

    Nucleic Acids Res.

    (1986)
  • P.L. Delgado et al.

    Serotonin function and the mechanism of antidepressant action. Reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan

    Arch. Gen. Psychiatry

    (1990)
  • D. Farfara et al.

    gamma-Secretase component presenilin is important for microglia beta-amyloid clearance

    Ann. Neurol.

    (2011)
  • S. Finkel

    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.

    (1996)
  • J.M. Frade et al.

    Nerve growth factor: two receptors, multiple functions

    Bioessays

    (1998)
  • B.M. Francis et al.

    Reduced tissue levels of noradrenaline are associated with behavioral phenotypes of the TgCRND8 mouse model of Alzheimer's disease

    Neuropsychopharmacology

    (2012)
  • D. Frenkel et al.

    Scara1 deficiency impairs clearance of soluble amyloid-beta by mononuclear phagocytes and accelerates Alzheimer's-like disease progression

    Nat. Commun.

    (2013)
  • S. Gal et al.

    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.

    (2005)
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