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

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.