Striatal dopaminergic toxicity following intranigral injection in rats of 2-methyl-norharman, a β-carbolinium analog of N-methyl-4-phenylpyridinium ion (MPP+)

Neafsey, Edward J.; Drucker, George E.; Raikoff, Kiril; Collins, Michael A.

doi:10.1016/0304-3940(89)90645-9

Cited by 52 publications

(19 citation statements)

References 17 publications

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“…The intraneuronal toxic action of MPTP-derived MPP+ is generally considered to be energized sequestration by mitochondria, inhibition of oxidation of substrates for mitochondrial NADH dehydrogenases at site I, ATP depletion, and cessation of cellular energy-dependent processes (1 (9,19).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial respiratory inhibition by N-methylated beta-carboline derivatives structurally resembling N-methyl-4-phenylpyridine.

Albores

Neafsey

Drucker

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

111

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Mitochondrial accumulation and respiratory inhibition are critical steps in the actions of N-methyl-4-phenylpyridinium ion (MPP+), the toxic metabolite of the parkinsonism-inducing agent, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. We examined the respiratory characteristics of 2-methylated fi-carbolines (2-MejBCs) and 2-methylated 3,4-dihydro-f3-carbolines (2-MeDHIBCs), which encompass the MPP+ structure. As indoleamine derivatives, they could have endogenous roles in idiopathic parkinsonism. With rat liver mitochondria, the order for inhibition of NAD'-linked 02 consumption (6-min preincubations) was as follows: MPP+ = 2-methylharmine > 2-methylharmol = 2-methylharmaline >> 2-methylharmalol > 2-methylnorharman > 6-OH-2-methyiharmalan >> 2-methylharman. Similar to MPP+, 2-MeDHI3C/2-MePC inhibition was potentiated by tetraphenylboron and reversed by dinitrophenol, consistent with the involvement of cationic forms. However, the participation of neutral forms was indicated by the 2-MeDHfiC/2-MeBC inhibitory time courses, which were unlike MPP+. The neutral forms probably arise via indolic nitrogen deprotonation because the characteristics of a cationic .-carboline that cannot N-deprotonate, 2,9-dimethylnorharman, mirrored MPP+ rather than 2-MeCs. Succinate-supported respiration was also significantly blocked by 2-MeDHI3Cs/2-MefiCs, but results with tetraphenylboron and 2,9-dimethylnorharman indicated that cationic forms were less important than in the inhibition of NAD+-linked respiration. We suggest that the relatively potent inhibition by certain 2-MeDHI3Cs/2-MeIJCs involves neutral forms for passive mitochondrial entry and cationic as well as neutral forms that act at several respiratory sites. Respiratory inhibition could reasonably underlie the reported neurotoxicity of 2-MefiCs.Interest in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a street drug contaminant that selectively destroys nigrostriatal cells, has stimulated investigations of environmental or endogenous toxins that might be associated with idiopathic parkinsonism (1, 2). An oxidation product of MPTP, N-methyl-4-phenylpyridine (MPP+), is believed to be the species that exerts neurotoxicity by inhibiting the mitochondrial respiratory chain at site I (NADH dehydrogenase) (3,4). Intrigued by the structural overlap between MPP+ and indole-derived p-carboline (,8C) compounds that are methylated (quaternized) on the 2-nitrogen (2-Mef3Cs), we and others (5-9) have hypothesized possible neurotoxic roles for 2-MeBCs in Parkinson disease. Endogenous biosynthetic pathways can be envisioned for 2-MepC formation from indoleamines or even tryptophan (10).Although ,BCs and their hydrogenated derivatives (3,4-dihyro-,BCs; DHPCs) have been studied extensively (see Discussion), little is known about the toxic capabilities of their N-methylated analogs. Hoppel et al. (8) noted that the ,BC, 2-methylharmine, was an effective mitochondrial respiratory inhibitor, and we now present results showing that several 2-MeDHfC/2-Mef3C isomers with 7-oxygenat...

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Section: Discussionmentioning

confidence: 99%

Mitochondrial respiratory inhibition by N-methylated beta-carboline derivatives structurally resembling N-methyl-4-phenylpyridine.

Albores

Neafsey

Drucker

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

111

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“…In addition to inhibition of complex I complex II was totally blocked at the same concentration (Janetzky et al, 1995). Thus, respiratory inhibition may underlie the neurotoxicity of [3-carbolines observed in primary cell cultures of C57/Black mouse mesencephalon containing dopaminergic neurons and in vivo (Neafsey et al, 1989;Grote et al, 1995;Sontag et al, 1995). However, Krueger et al (1993) could only detect partial inhibition of complex I and II activities at very high concentrations of the [3-carbolinium compounds, 2,9 dimethylharmaninium and 2,9-dimethylnorharmaninium.…”

Section: 522mentioning

confidence: 94%

“…Three weeks after intranigral injection of the [~-carboline (137 ~tg 2-methyl-norharman iodide) striatal dopamine, DOPAC and HVA concentrations ipsilateral to the injection site are reduced 41-64% compared to vehicle-injected controls (Neafsey et al, 1989). However, the lesion produced by 2-methyl-norharman appeared to be non-specific, affecting dopaminergic and non-dopaminergic cells and fibers.…”

Section: Neurotoxic Effects Owl Monkeys (Aotus Trivirgatus) Chronicallymentioning

confidence: 96%

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Animal models of Parkinson's disease: An empirical comparison with the phenomenology of the disease in man

Gerlach

Riederer

1996

J. Neural Transmission

442

221

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Animal models are an important aid in experimental medical science because they enable one to study the pathogenetic mechanisms and the therapeutic principles of treating the functional disturbances (symptoms) of human diseases. Once the causative mechanism is understood, animal models are also helpful in the development of therapeutic approaches exploiting this understanding. On the basis of experimental and clinical findings. Parkinson's disease (PD) became the first neurological disease to be treated palliatively by neurotransmitter replacement therapy. The pathological hallmark of PD is a specific degeneration of nigral and other pigmented brainstem nuclei, with a characteristic inclusion, the Lewy body, in remaining nerve cells. There is now a lot of evidence that degeneration of the dopaminergic nigral neurones and the resulting striatal dopamine-deficiency syndrome are responsible for its classic motor symptoms akinesia and bradykinesia. PD is one of many human diseases which do not appear to have spontaneously arisen in animals. The characteristic features of the disease can however be more or less faithfully imitated in animals through the administration of various neurotoxic agents and drugs disturbing the dopaminergic neurotransmission. The cause of chronic nigral cell death in PD and the underlying mechanisms remain elusive. The partial elucidation of the processes underlie the selective action of neurotoxic substances such as 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), has however revealed possible molecular mechanisms that give rise to neuronal death. Accordingly, hypotheses concerning the mechanisms of these neurotoxines have been related to the pathogenesis of nigral cell death in PD. The present contribution starts out by describing some of the clinical, pathological and neurochemical phenomena of PD. The currently most important animal models (e.g. the reserpine model, neuroleptic-induced catalepsy, tremor models, experimentally-induced degeneration of nigrostriatal dopaminergic neurons with 6-OHDA, methamphetamine, MPTP, MPP+, tetrahydroisoquinolines, beta-carbolines, and iron) critically reviewed next, and are compared with the characteristic features of the disease in man.

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“…N-Methylated β-carbolinium ions such as 2-methyl-norharman induce large lesions after injection in the substantia nigra of rats (Neafsey et al, 1989) and are also increased in the frontal cortex of parkinsonians (Gearhart et al, 2000). 2-Methylated β-carbolines are comparable to MPP + as inhibitors of mitochondrial respiration (Albores et al, 1990).…”

Section: Discussionmentioning

confidence: 99%

The Harman and Norharman Reduced Dopamine Content and Induced Cytotoxicity in PC12 Cells

Yang¹,

Lim²,

Lee³

2008

Biomolecules and Therapeutics

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-The effects of harman and norharman on dopamine content and L-DOPA-induced cytotoxicity were investigated in PC12 cells. Harman and norharman decreased the intracellular dopamine content for 24 h. The IC 50 values of harman and norharman were 20.4 µM and 95.8 µM, respectively. Tyrosine hydroxylase (TH) activity and TH mRNA levels were also decreased by 20 µM harman and 100 µM norharman. Under the same conditions, the intracellular cyclic AMP levels were decreased by harman and norharman. In addition, harman and norharman at concentrations higher than 80 µM and 150 µM caused cytotoxicity at 24 h in PC12 cells. Non-cytotoxic ranges of 10-30 µM harman and 50-150 µM norharman inhibited L-DOPA (20-50 µM)-induced increases of dopamine content at 24 h. Harman at 20-150 µM and norharman at 100-300 µM also enhanced L-DOPA (20-100 µM)-induced cytotoxicity at 24 h. These results suggest that harman and norharman decrease dopamine content by reducing TH activity and aggravate L-DOPA-induced cytotoxicity in PC12 cells.

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Striatal dopaminergic toxicity following intranigral injection in rats of 2-methyl-norharman, a β-carbolinium analog of N-methyl-4-phenylpyridinium ion (MPP+)

Cited by 52 publications

References 17 publications

Mitochondrial respiratory inhibition by N-methylated beta-carboline derivatives structurally resembling N-methyl-4-phenylpyridine.

Mitochondrial respiratory inhibition by N-methylated beta-carboline derivatives structurally resembling N-methyl-4-phenylpyridine.

Animal models of Parkinson's disease: An empirical comparison with the phenomenology of the disease in man

The Harman and Norharman Reduced Dopamine Content and Induced Cytotoxicity in PC12 Cells

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