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Methyl Yellow: A Potential Drug Scaffold for Parkinson's Disease

Authors

  • Dr. Werner J. Geldenhuys,

    Corresponding author
    1. Neurotherapeutics Emphasis Group, Department of Pharmaceutical Sciences, Northeast Ohio Medial University (NEOMED), College of Pharmacy, 4209 State Route 44, Rootstown, OH 44272 (USA)
    • Werner J. Geldenhuys, Neurotherapeutics Emphasis Group, Department of Pharmaceutical Sciences, Northeast Ohio Medial University (NEOMED), College of Pharmacy, 4209 State Route 44, Rootstown, OH 44272 (USA)===

      Mi Hee Lim, Department of Chemistry and Life Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109 (USA)===

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  • Dr. Akiko Kochi,

    1. Department of Chemistry and Life Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109 (USA)
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  • Li Lin,

    1. Neurotherapeutics Emphasis Group, Department of Pharmaceutical Sciences, Northeast Ohio Medial University (NEOMED), College of Pharmacy, 4209 State Route 44, Rootstown, OH 44272 (USA)
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  • Dr. Vijaykumar Sutariya,

    1. Department of Pharmaceutical Sciences, University of South Florida, 12901 Bruce B. Downs Blvd., MDC 30, Tampa, FL 33612 (USA)
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  • Dr. Dean E. Dluzen,

    1. Neurotherapeutics Emphasis Group, Department of Pharmaceutical Sciences, Northeast Ohio Medial University (NEOMED), College of Pharmacy, 4209 State Route 44, Rootstown, OH 44272 (USA)
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  • Prof. Cornelis J. Van der Schyf,

    1. Department of Pharmaceutical Sciences, Idaho State University, 921 S. 8th Avenue, Pocatello, ID 83209 (USA)
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  • Prof. Mi Hee Lim

    Corresponding author
    1. Department of Chemistry and Life Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109 (USA)
    2. Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), 50 UNIST-gil, Eonyan-eup, Ulju-gun, Ulsan 689-798 (Republic of Korea)
    • Werner J. Geldenhuys, Neurotherapeutics Emphasis Group, Department of Pharmaceutical Sciences, Northeast Ohio Medial University (NEOMED), College of Pharmacy, 4209 State Route 44, Rootstown, OH 44272 (USA)===

      Mi Hee Lim, Department of Chemistry and Life Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109 (USA)===

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Abstract

Parkinson's disease (PD) is an age-related neurodegenerative disease affecting movement. To date, there are no currently available therapeutic agents which can prevent or slow disease progression. Here, we evaluated an azobenzene derivative, methyl yellow (MY), as a potential drug scaffold for PD; its inhibitory activity toward monoamine oxidase B (MAO-B) as well as drug-like properties were investigated. The inhibitory effect of MY on MAO activity was determined by a MAO enzyme inhibition assay. In addition, the in vitro properties of MY as a drug candidate (e.g., blood–brain barrier (BBB) permeability, serum albumin binding, drug efflux through P-glycoprotein (P-gp), drug metabolism by P450, and mitochondrial toxicity) were examined. In vivo effectiveness of MY was also evaluated in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Parkinsonian mouse model. MY selectively inhibited MAO-B in a dose-dependent and reversible manner. MY was BBB-permeable, bound relatively weakly to serum albumin, was an unlikely substrate for both systems of P-gp and P450, and did not cause mitochondrial toxicity. Results from the MPTP Parkinsonian mouse model indicated that, upon treatment with MY, neurotoxicity induced by MPTP was mitigated. Investigations of MY demonstrate its inhibitory activity toward MAO-B, compliant properties for drug consideration, and its neuroprotective capability in the MPTP Parkinsonian mouse model. These data provide insights into potential use, optimization, and new design of azobenzene derivatives for PD treatment.

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