title: Localization of N-methyl-norsalsolinol within rodent and human brain.
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 alpha-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.
authors.affiliation: Departments of Neurology and Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: DeCuypere
authors.forename: Vassilios N
authors.initials: VN
authors.lastname: Kalabokis
authors.forename: Ruyi
authors.initials: R
authors.lastname: Hao
authors.forename: Dorothy
authors.initials: D
authors.lastname: Schroeder
authors.forename: Duane D
authors.initials: DD
authors.lastname: Miller
authors.forename: Mark S
authors.initials: MS
authors.lastname: LeDoux
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry / Q000502:physiology*; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D010300:Parkinson Disease / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012490:Salsoline Alkaloids / Q000032:analysis* / Q000378:metabolism*
chemical_list: D012490:Salsoline Alkaloids; C020784:norsalsolinol