1-Methyl-?-carboline (Harmane), a potent endogenous inhibitor of benzodiazepine receptor binding

Rommelspacher, Hans; Nanz, Christel; Borbe, Harald O.; Fehske, Klaus J.; Müller, Wernér E.G.; Wollert, U.

doi:10.1007/bf00498436

Cited by 117 publications

(33 citation statements)

References 24 publications

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“…For example, tobacco smoke contains high levels of the harmala alkaloids harman and norharman, also known as beta-carbolines, which are monoamine oxidase inhibitors and act as inverse agonists at the GABA A benzodiazepine receptor site (25). Other substances, such as carbon monoxide (26), influence the balance of excitatory and inhibitory neurotransmission and might be expected to directly or indirectly modify GABA A regulation.…”

Section: Discussionmentioning

confidence: 99%

Tobacco smoking interferes with GABA _A receptor neuroadaptations during prolonged alcohol withdrawal

Cosgrove

McKay

Esterlis

et al. 2014

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

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Understanding the effects of tobacco smoking on neuroadaptations in GABA A receptor levels over alcohol withdrawal will provide critical insights for the treatment of comorbid alcohol and nicotine dependence. We conducted parallel studies in human subjects and nonhuman primates to investigate the differential effects of tobacco smoking and nicotine on changes in GABA A receptor availability during acute and prolonged alcohol withdrawal. We report that alcohol withdrawal with or without concurrent tobacco smoking/nicotine consumption resulted in significant and robust elevations in GABA A receptor levels over the first week of withdrawal. Over prolonged withdrawal, GABA A receptors returned to control levels in alcohol-dependent nonsmokers, but alcohol-dependent smokers had significant and sustained elevations in GABA A receptors that were associated with craving for alcohol and cigarettes. In nonhuman primates, GABA A receptor levels normalized by 1 mo of abstinence in both groups-that is, those that consumed alcohol alone or the combination of alcohol and nicotine. These data suggest that constituents in tobacco smoke other than nicotine block the recovery of GABA A receptor systems during sustained alcohol abstinence, contributing to alcohol relapse and the perpetuation of smoking.alcohol dependence | tobacco smoking | neuroimaging | GABA A receptors | translational A lcohol dependence and tobacco smoking are highly comorbid (1). Alcohol-dependent smokers who quit drinking but continue smoking may have a reduced severity of alcohol withdrawal and relapse risk (2) compared with alcohol-dependent smokers who stop smoking and drinking at the same time (3-5). This has led to some complacency in the field about treating the addiction to nicotine in alcohol-dependent smokers, and few treatment settings provide any systematic tobacco treatment (6). However, a large part of the morbidity and mortality from alcohol dependence can be attributed to concurrent tobacco smoking (7), and a large number of alcohol-dependent individuals in treatment express a desire to quit smoking (8). Understanding the involvement of tobacco smoking in the neuroadaptations and behavioral changes that occur during alcohol withdrawal will provide critical insights to direct treatment strategies.Given the multiple molecular targets for alcohol in the brain and numerous constituents of tobacco smoke, it is likely that the neurobiology of this comorbidity is complex. However, the γ-aminobutyric acid (GABA) system may be an important point of convergence of the effects of tobacco smoke and alcohol in the brain. For example, nicotine reinforcement has been critically linked to activation of GABA neurons (9), and alcohol appears to both directly stimulate extrasynaptic GABA A receptors with relatively high affinity (10) and to indirectly stimulate the release of GABA and neurosteroids (11), such as allopregnanolone, that also stimulate extrasynaptic GABA A receptors (12, 13). Alcohol and neurosteroids can act at synaptic GABA A receptors, but the af...

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Section: Discussionmentioning

confidence: 99%

Tobacco smoking interferes with GABA _A receptor neuroadaptations during prolonged alcohol withdrawal

Cosgrove

McKay

Esterlis

et al. 2014

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

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“…71,72) Harmala alkaloids have been used in some hallucinogenic preparations of South American and African tribes. 73) Furthermore, plants containing harmala alkaloids have long been used in traditional medicine to treat asthma, jaundice, lumbago, and other ailments. [19][20][21] Certain b-carboline alkaloids have a wide spectrum of neuropharmacological and psychopharmacological actions on the central nervous system such as tremorogenesis, 74,75) hypothermia, 76) hallucinogenesis, 77,78) monoamine oxidase (MAO) inhibition, 79,80) and convulsive or anticonvulsive actions.…”

Section: Discussionmentioning

confidence: 99%

The .BETA.-Carboline Alkaloid Harmol Induces Cell Death via Autophagy but Not Apoptosis in Human Non-small Cell Lung Cancer A549 Cells

Abe

Yamada

Moriya

et al. 2011

Biological & Pharmaceutical Bulletin

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Lung cancer is a leading cause of death worldwide, and the long-term survival rate of lung cancer patients is one of the lowest among cancers.1,2) Two major types of lung cancer have been identified: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). NSCLC, the most prevalent subtype, is relatively resistant to chemotherapy and radiation therapy. On the other hand, SCLC is initially highly sensitive to chemotherapy and radiation therapy, but shows resistance to treatment in the majority of patients.3) The high mortality in NSCLC is due to the difficulty of early diagnosis and its high potential for local invasion and distant metastasis. Although relatively effective chemotherapeutic agents have been developed, lung cancer still has a low cure rate. Furthermore, the adverse effects of chemotherapeutic compounds often hamper the quality of life of lung cancer patients. Therefore, the discovery of effective novel prophylactic, diagnostic, and therapeutic treatments for NSCLC is urgently needed."Apoptosis" has been used as a synonym for programmed cell death (PCD), and is a well-known form of PCD. Since the 1960s, various morphological forms of PCD have been recognized. Clarke classified cell death into 4 types, including type I PCD (apoptosis) and type II PCD (autophagy). 4)Numerous studies have demonstrated that most chemotherapy agents and certain naturally occurring compounds induce cell death by activating the apoptotic pathway. It is thought that apoptosis induction in tumor cells with either drugs or natural products is effective therapy for cancer and immune system diseases. On the other hand, autophagy is one of the major regulatory mechanisms in the degradation of intracellular proteins and organelles. 5,6) During autophagy, the cytosol and whole organelles become encased in double-membrane vacuoles such as autophagosomes, and subsequently fuse with lysosomes.5) Degradation of the sequestered material generates nucleotides, amino acids, and free fatty acids that are recycled for macromolecular synthesis and ATP generation.7) Although originally characterized as a survival response to nutrient deficiency, autophagy is now recognized as frequently induced in response to a variety of stressors to maintain cellular homeostasis. [8][9][10][11][12] In recent years, the importance of autophagy has been emphasized in various biological fields, including cancer. 9,[13][14][15] Furthermore, cancer cells show less autophagy than normal cells. 16,17) These findings indicate that autophagy induction is an attractive modality of anticancer therapy.b-Carboline alkaloids occur in a number of medicinal plants such as Peganum harmala, Passiflora edulis, Passiflora incarnata, and Banisteriopsis caapi.18,19) These plants have been used in traditional medicine to treat asthma, jaundice, lumbago, and other human ailments.19-21) Recently, it has been reported that certain b-carboline alkaloids and their related compounds have cytotoxic effects on cancer cells. [22][23][24] We also reported previously that harm...

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“…However, that mitochondrial benzodiazepine receptors may mediate inhibition of respiratory control is of interest (32), and simple PCs are relatively potent benzodiazepine receptor ligands (33). Whether respiratory inhibition by 2-methylated analogs is linked to mitochondrial benzodiazepine receptors remains open to inquiry.…”

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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1-Methyl-?-carboline (Harmane), a potent endogenous inhibitor of benzodiazepine receptor binding

Cited by 117 publications

References 24 publications

Tobacco smoking interferes with GABA _A receptor neuroadaptations during prolonged alcohol withdrawal

Tobacco smoking interferes with GABA _A receptor neuroadaptations during prolonged alcohol withdrawal

The .BETA.-Carboline Alkaloid Harmol Induces Cell Death via Autophagy but Not Apoptosis in Human Non-small Cell Lung Cancer A549 Cells

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

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1-Methyl-?-carboline (Harmane), a potent endogenous inhibitor of benzodiazepine receptor binding

Cited by 117 publications

References 24 publications

Tobacco smoking interferes with GABA A receptor neuroadaptations during prolonged alcohol withdrawal

Tobacco smoking interferes with GABA A receptor neuroadaptations during prolonged alcohol withdrawal

The .BETA.-Carboline Alkaloid Harmol Induces Cell Death via Autophagy but Not Apoptosis in Human Non-small Cell Lung Cancer A549 Cells

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

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Tobacco smoking interferes with GABA _A receptor neuroadaptations during prolonged alcohol withdrawal

Tobacco smoking interferes with GABA _A receptor neuroadaptations during prolonged alcohol withdrawal