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Localization of N ‐methyl‐norsalsolinol within rodent and human brain
Author(s) -
DeCuypere Michael,
Kalabokis Vassilios N.,
Hao Ruyi,
Schroeder Dorothy,
Miller Duane D.,
LeDoux Mark S.
Publication year - 2008
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.21691
Subject(s) - substantia nigra , striatum , human brain , dopaminergic , monoaminergic , neurotoxicity , dopamine , neurotoxin , chemistry , cerebellum , hippocampus , biology , microbiology and biotechnology , neuroscience , medicine , biochemistry , toxicity , serotonin , receptor
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. © 2008 Wiley‐Liss, Inc.