Localization of N-methyl-norsalsolinol within rodent and human brain

Michael DeCuypere, Vassilios N. Kalabokis, Ruyi Hao, Dorothy Schroeder, Duane D. Miller, Mark S. LeDoux*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

The isoquinoline derivative N-methyl-6,7-dihydroxytetrahydroisoquinoline (N-methyl-norsalsolinol) is present in normal human brain and has been identified in the cerebrospinal fluid of patients with Parkinson's disease (PD). Endogenously, N-methyl-norsalsolinol may be derived from dopamine by condensation with aldehydes or α-ketoacids. In vitro experiments suggest that N-methyl-norsalsolinol is neurotoxic. In this study, high-performance liquid chromatography with electrochemical detection (HPLC-EC) was used to determine N-methyl-norsalsolinol concentrations in mouse, rat, normal human, and PD brain. In addition, a monoclonal antibody was generated against N-methyl-norsalsolinol and used to determine the cellular localization of N-methyl-norsalsolinol in brain. With HPLC-EC, N-methyl-norsalsolinol was detected in all regions of rodent and human brain subjected to analysis. In rodent brains, N-methyl-norsalsolinol tissue concentrations were similar among frontal cortex, ventral midbrain, striatum, hippocampus, and cerebellum. Conversely, in normal human control brains, N-methyl-norsalsolinol was concentrated in the substantia nigra and striatum. In comparison to normal human controls, N-methyl-norsalsolinol levels were significantly lower in the substantia nigra and caudate nuclei from PD patients, a finding possibly related to the death of nigrostriatal dopaminergic neurons. N-methyl-norsalsolinol immunoreactivity colocalized with a general neuronal marker (neuron-specific enolase) and a monoaminergic marker (tyrosine hydroxylase) but not with a glial marker (glial fibrillary acidic protein). The widespread neuronal localization of N-methyl-norsalsolinol in several mammalian species suggests that, in isolation, this compound is a "weak" neurotoxin. However, endogeneously derived N-methyl-norsalsolinol could contribute to the pathobiology of PD in genetically predisposed individuals after years of accumulation in dopaminergic neurons.

Original languageEnglish (US)
Pages (from-to)2543-2552
Number of pages10
JournalJournal of Neuroscience Research
Volume86
Issue number11
DOIs
StatePublished - Aug 15 2008
Externally publishedYes

Keywords

  • N-methyl-norsalsolinol
  • Parkinson's disease
  • Substantia nigra pars compacta
  • Tetrahydroisoquinoline
  • Tyrosine hydroxylase

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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