ISSN:
1471-4159
Source:
Blackwell Publishing Journal Backfiles 1879-2005
Topics:
Medicine
Notes:
Abstract: To examine whether simple β-carbolines induce parkinsonian-like symptoms in vivo via N-methylation, the simple β-carbolines norharman (NH), 2-mono-N-methylated norharmanium cation (2-MeNH+), and 9-mono-N′-methylnorharman (9-MeNH) were systematically administered to C57BL/6 mice for 7 days. These substances induced bradykinesia with reduction of locomotion activity. NH or 2-MeNH+ decreased dopamine (DA) contents to 50–70% of values in controls in the striatum and midbrain. 9-MeNH potently decreased not only DA but also serotonin content in various regions. Immunohistochemical examination revealed that the numbers of tyrosine hydroxylase (TH)-positive cells in the substantia nigra pars compacta of NH- and 9-MeNH-treated mice were diminished to 76 and 66% of values in control mice, respectively. The formation of a toxic metabolite, 2,9-di-N,N′-methylated norharmanium cation (2,9-Me2NH+), was 14 and eight times higher in the brain of mice receiving 9-MeNH than that in NH- and 2-MeNH+-treated mice, respectively. In cultured mesencephalic cells from rat embryo, 2,9-Me2NH+ selectively killed TH-positive neurons only at a lower dose but was toxic to all neurons at higher doses. Thus, the excess formation of 2,9-Me2NH+ would induce nonspecific neurotoxicity. These results indicated that 9-indole nitrogen methylation should be the limiting step in the development of the toxicity. NH, a selective dopaminergic toxin precursor, is sequentially methylated to form 2,9-Me2NH+, which could be an underlying factor in idiopathic Parkinson's disease.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1046/j.1471-4159.1998.70020727.x
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