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.