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

Abstract

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...

Elevated levels of harman and norharman in cerebrospinal fluid of Parkinsonian patients

“…So especially in the substantia nigra of patients with PD increased 2-N-methylation of [3-carbolines may take place. These 2-methylated [3-carbolines may stimulate or even induce neuronal degeneration due to their toxic effects on mitochondrial respiration in the substantia nigra of Parkinsonian patients, where complex 1 deficiency was reported in tissue homogenates (Albores et al, 1990;Schulz and Flint Beal, 1994). On the basis of these studies detection of significantly increased CSF concentrations of norharman and harman in Parkinsonian patients compared to controls may give another hint for the hypothesis of a possible initiating and/or sustaining effect of [3-carbolines on …”

“…The underlying pathophysiological processes remain unclear up to now. 2-methylated [3-carbolines may inhibit NADH-coenzyme Q reductase (complex 1) of the electron transport chain within mitochondria, thereby leading to a fall in ATP production and thus initiating cell death (Albores et al, 1990). Such a decrease in the activity of complex 1 has consistently been found in the brain, especially in homogenates of the substantia nigra, but also in platelets, muscle and lymphocytes of Parkinsonian patients (Schulz and Flint Beal, 1994).…”

The organic cation transporter-3 is a pivotal modulator of neurodegeneration in the nigrostriatal dopaminergic pathway

“…Thus, this novel piece of information is not only of critical value for our understanding of the mechanism of cell death in the widely used MPTP model of Parkinson's disease, but it may also be extended to other toxic cations. While our current knowledge is incomplete regarding the array of dopaminergic toxic cations that can be released from astrocytes through Oct3, the toxic cationic metabolites of compounds such as tetraisoquinolines and ␤-carbolines may be released through this mechanism on the basis of their structural similarity to MPP ϩ (24,25). For instance, tetraisoquinolines can be metabolized by MAO-B in astrocytes to form isoquinolinium cations (24) and ␤-carbolines can be converted to ␤-carbolinium in astrocytes by myeloperoxidase (26,27).…”

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

“…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). In Parkinson's diseases, the biosynthesis of N-methylated β-carboline derivatives is enhanced probably due to the failure of further catabolisation and detoxification of those N-methylated compounds (Green et al, 1991).…”

“…In contrast, the dopamine metabolites of MAO could produce the cellular damages by the formation of reactive oxygen species (Cohen, 1983). In addition, β-carbolines have been proposed as neuronal toxins because of the structural similarity to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium (MPP + ) (Albores et al, 1990;Fields et al, 1992). However, these inconsistent functions of harman and norharman on dopamine biosynthesis and cytotoxicity could not be fully elucidated.…”