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

Kühn, Wilfried; Müller, Thomas; Große, H; Rommelspacher, Hans

doi:10.1007/bf01271257

Cited by 83 publications

(49 citation statements)

References 14 publications

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“…Norharman, harman, 2-Me-norharmanium, and 2,9-(Me) 2 -norharmanium were found in the human brain and/or the CSF. A neurotoxic 2,9-dimethylated beta-carbolinium ion (2,9-(Me) 2 -norharmanium) was found in half of the PD, but not at all in non-PD, patients examined (Matsubara et al, 1995;Kuhn et al, 1996). These results suggest that beta-carbolinium compounds as well as isoquinolinium compounds may also be candidate neurotoxins that produce PD.…”

Section: Neurotoxic Substances Producing Pd In Humans and Animalsmentioning

confidence: 74%

Cellular and Molecular Mechanisms of Parkinson’s Disease: Neurotoxins, Causative Genes, and Inflammatory Cytokines

2006

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1. Parkinson's disease (PD) is considered to be an aging-related neurodegeneration of catecholamine (CA) systems [typically A9 dopamine (DA) neurons in the substantia nigra and A6 noradrenaline (NA) neurons in the locus coeruleus]. The main symptom is movement disorder caused by a DA deficiency at the nerve terminals of fibers that project from the substantia nigra to the striatum. Most PD is sporadic (sPD) without any hereditary history. sPD is speculated to be caused by some exogenous or endogenous substances that are neurotoxic toward CA neurons, which toxicity leads to mitochondrial dysfunction and subsequent oxidative stress resulting in the programmed cell death (apoptosis or autophagy) of DA neurons. 2. Recent studies on the causative genes of rare familial PD (fPD) cases, such as alpha-synuclein and parkin, suggest that dysfunction of the ubiquitin-proteasome system (UPS) and the resultant accumulation of misfolded proteins and endoplasmic reticulum stress may cause the death of DA neurons. 3. Activated microglia, which accompany an inflammatory process, are present in the nigro-striatum of the PD brain; and they produce protective or toxic substances, such as cytokines, neurotrophins, and reactive oxygen or nitrogen species. These activated microglia may be neuroprotective at first in the initial stage, and later may become neurotoxic owing to toxic change to promote the progression toward the death of CA neurons.4. All of these accumulating evidences on sPD and fPD points to a hypothesis that multiple primary causes of PD may be ultimately linked to a final common signal-transduction pathway leading to programmed cell death, i.e., apoptosis or autophagy, of the CA neurons.

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Section: Neurotoxic Substances Producing Pd In Humans and Animalsmentioning

confidence: 74%

Cellular and Molecular Mechanisms of Parkinson’s Disease: Neurotoxins, Causative Genes, and Inflammatory Cytokines

2006

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“…Carbolinium ions have been found in the human brain and have been discussed as endogenous causative factors of PD (Matsubara et al 1993). Kuhn et al (1996) suggested that β-carbolines such as harmane and norharmane might be neurotoxins causing PD. Gearhart et al (2002) found β-carboline 2N-methyltransferase activity in the mammalian brain.…”

Section: Discussionmentioning

confidence: 99%

The cyanobacterial alkaloid nostocarboline: an inhibitor of acetylcholinesterase and trypsin

et al. 2008

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Preselected cyanobacterial strains (available from culture collections and our own isolates), belonging primarily to the heterocystous cluster, were screened for inhibitors against butyrylcholinesterase. About one-half of the extracts exhibited inhibitory activity. Nostocarboline, the responsible metabolite in Nostoc 78-12A, was studied in more detail as an acetylcholinesterase (AChE) inhibitor. The compound showed potent activity against this enzyme (IC 50 = 5.3 µM), and the Michaelis-Menten kinetics indicated a non-competitive component in the inhibitory mechanism. In addition, nostocarboline turned out to be a potent inhibitor of trypsin (IC 50 = 2.8 µM), and thus is the first described cyanobacterial serine protease inhibitor of an alkaloid structure. The function of nostocarboline in aquatic ecosystems and its potential as a lead compound for the development of useful therapeutic AChE inhibitors is discussed.

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“…These include several isoquinoline and β-carboline species, which bear a strong structural resemblance to MPTP/MPP + . β-carboline [81] and tetrahydroisoquinoline (TIQ) species [93] have been isolated from the brain (particularly from the nigrostriatal system) [79] and CSF of IP patients, while Kuhn et al [72] reported increased plasma and CSF levels of the β-carbolines harman and norharman in IP patients. Such molecules, which have long been implicated in processes associated with alcohol and opiate addiction [40], exhibit to varying degrees a number of relevant cytotoxic properties, including uptake by dopaminergic neurons, impairment of mitochondrial function and induction of dopaminergic cell degeneration [24,59,82,92].…”

Section: Neuromelanin (Nm)mentioning

confidence: 99%

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

Foley

Riederer

2000

J Neurol

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It is generally accepted that progressive, irreversible and regionally specific neurodegeneration and the presence of Lewy bodies are the essential pathological hallmarks of idiopathic parkinsonism. The causes of these phenomena, however, remain to be elucidated. One of the leading hypotheses is that oxidative stress induced by reactive oxygen species (ROS), such as the hydroxyl radical, damages essential components of the neuron, resulting ultimately in cell death. Observations in the parkinsonian brain at post-mortem support this hypothesis; for example, widespread oxidative protein modification is evident. There are several potential sources of increased oxidative stress in Parkinson's disease, including mitochondrial dysfunction, increased free iron levels and impaired free radical defence mechanisms. Further, it is possible that glial, rather than neuronal, elements are primarily responsible for the initial increase in oxidative stress in the substantia nigra. It is likely that parkinsonism is the result of aberrations at multiple levels of neuronal function. Oxidative stress is no doubt one of the events involved in neurodegeneration, but is unlikely to be the initiating event. It is to be expected that the search for this event will continue for many years.

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

Cited by 83 publications

References 14 publications

Cellular and Molecular Mechanisms of Parkinson’s Disease: Neurotoxins, Causative Genes, and Inflammatory Cytokines

Cellular and Molecular Mechanisms of Parkinson’s Disease: Neurotoxins, Causative Genes, and Inflammatory Cytokines

The cyanobacterial alkaloid nostocarboline: an inhibitor of acetylcholinesterase and trypsin

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

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