Endogenously Occurring β‐Carboline Induces Parkinsonism in Nonprimate Animals: A Possible Causative Protoxin in Idiopathic Parkinson's Disease

Abstract

To examine whether simple f3-carbolines induce parkinsonian-like symptoms in vivo via N-methylation, the simple~3-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-MeNHtreated 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-Me 2NH~), 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. Key Words: /~-Carboline-Parkinsonism-Animal model-Dopamine-Nigrostriatal degeneration-Bradykinesia-N-Methylation.

Protective Actions of the Vesicular Monoamine Transporter 2 (VMAT2) in Monoaminergic Neurons

“…BCs have a wide variety of pharmacological effects including the inhibition of plasmalemmal dopamine transport, inhibition of MAO, and, perhaps the most unusual, inverse agonism of GABA A receptors at the benzodiazepine site [222,223]. Like some TIQs, it has been thought that BCs impact addiction and neurodegeneration: in vitro, BCs have been shown to act as plasmalemmal and vesicular uptake inhibitors of serotonin and dopamine, and, in vivo, can reduce striatal serotonin and dopamine concentrations, and lead to bradykinesia [224][225][226]. Conversely, one BC, pinoline, has been postulated to confer protective effects from oxidative stress [227].…”

Thermodynamic Study of Small Hydrophobic Ions at the Water–Lipid Interface

“…In relation with Eq. [2], the total interacting molecule concentration is [P] Since the interacting molecule binds only to the outer halflayer with a composition estimated by about two-thirds parts of the total lipid (29), all the magnitudes implying phospholipid moles have been corrected by the accessibility factor (β = 0.65). Then, the concentration of unoccupied sites at equilibrium will be…”

“…Parkinsonian-like symptoms via N-methylation of simple β-carbolines have been recently described (2). Humans are exposed to norharman in daily life to a larger extent than to carcinogenic heterocyclic amines, being present at relatively high level in cigarette smoke condensates and cooked foods (3).…”

Influence of neurotoxins and oxidative stress on the onset and progression of Parkinson’s disease

“…Kawai et al [67] synthesized a novel TIQ species including a DA moiety which, when injected intraperitoneally into mice, induced parkinsonian symptoms; in synaptosomes, it exhibited a high affinity for the striatal DA transporter. Matsubara et al [80] reported that norharman and two of its methylated derivatives, when systemically applied, produced bradykinesia and reduced locomotion in mice. In particular, 9-mono-N′-methylnorharman (9-MeNH) potently decreased striatal and midbrain DA levels and those of serotonin (5HT) in several brain regions, reduced TH-positive cell numbers in the SNc by a third, and led to the formation of the nonspecifically cytotoxic methylated norharmanium ion, 2,9-Me 2 NH + .…”