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N-Methyl-(R) Salsolinol and the Enzymes Catalyzing its Synthesis and Metabolism in Parkinson’s Disease

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Handbook of Neurotoxicity

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Abstract

Salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline) is an endogenous catechol isoquinoline detected in the human brain. It is produced by the nonenzymatic Pictet-Spengler reaction as the racemic mixture. However, a novel enzyme, (R)salsolinol synthase, was isolated from the human brain, which catalyzes the enantio-specific synthesis of (R)salsolinol from dopamine and acetaldehyde or keto acids. R-Salsolinol is N-methylated by (R)salsolinol N-methyltransferase (N-MT) into 2(N)-methyl-(R)salsolinol [NM-(R)Sal], which is oxidized by an oxidase sensitive to semicarbazide. NM-(R)Sal induces cell death in the dopaminergic cells of the rat substantia nigra after the systemic administration. The behavioral and pathological changes in rats were quite similar to those in other animal models of Parkinson’s disease, using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or 6-hydroxydopamine. In cellular experiments, NM-(R)Sal binds to type A monoamine oxidase and induces apoptosis through activation of mitochondrial death signaling. Furthermore, NM-(R)Sal levels increase in the cerebrospinal fluid from parkinsonian patients, and the activity of its synthesizing neural (R)Sal N-MT is significantly higher in the lymphocytes prepared from parkinsonian patients than in control. The enantioselective neurotoxicity of NM-(R)Sal suggests that the enzymes related to the synthesis of this toxin might be associated with the etiology for PD. This chapter reviews the role of N-methylated isoquinolines and enzymes catalyzing N-methylation of small molecules in the pathogenesis of Parkinson’s disease.

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Abbreviations

CSF:

The cerebrospinal fluid

DA:

Dopamine

DMDHIQ+ :

1,2-dimethyl-6,7-dihydroxyisoquinolinium ion

IQ:

Isoquinoline

IVF:

Intraventricular fluid

MAO-A and MAO-B:

Type A and B monoamine oxidase

MPTP:

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

NM-(R)Sal:

N-methyl-(R)salsolinol

N-MT:

N-methyltransferase

Norsal:

Norsalsolinol

PD:

Parkinson’s disease

ROS and RNS:

Reactive oxygen and nitrogen species

Sal:

Salsolinol

Sal-1-CA:

Salsolinol-1-carboxylic acid

SAM:

S-adenosyl-l-methionine

SN:

Substantia nigra

TH:

Tyrosine hydroxylase

TIQ:

1,2,3,4-tetrahydroisoquinoline

β-CB:

β-carboline

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Acknowledgment

This work is supported by The Research Funding for Longevity Sciences (23-2) from National Center for Geriatrics and Gerontology (NCGG), Japan.

Declaration of Approval from the Ethical Committee

The Ethical Committee of Iwate Medical University, Aichi Medical University, National Institute for Longevity Science, and Neurological Clinic (Dr. H. Narabayashi) approved the protocol for the examination of the CSF samples and lymphocytes and of the IVF. The patients were fully informed about the risk and the benefits of the examination.

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Authors and Affiliations

  1. Department of Neurosciences, Gifu International Institute of Biotechnology, 1-1 Nakafudogaoka, Kakamigahara Gifu, 504-0838, Japan

    Makoto Naoi

  2. Department of Cognitive Brain Science, National Research Center for Geriatrics and Gerontology, Obu Aichi, 474-8511, Japan

    Wakako Maruyama

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  1. Makoto Naoi
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  2. Wakako Maruyama
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Correspondence to Makoto Naoi .

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Editors and Affiliations

  1. Department of Biomedical Sciences, East Tennessee State University, Johnson City, Tennessee, USA

    Richard M. Kostrzewa

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Naoi, M., Maruyama, W. (2014). N-Methyl-(R) Salsolinol and the Enzymes Catalyzing its Synthesis and Metabolism in Parkinson’s Disease. In: Kostrzewa, R. (eds) Handbook of Neurotoxicity. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5836-4_10

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