The effects of pyridinium salts, structurally related compounds of 1-methyl-4-phenylpyridinium ion (MPP+), on tyrosine hydroxylation in rat striatal tissue slices

Hirata, Yoko; Sugimura, Hideyuki; Takei, Hisashi; Nagatsu, Toshiharu

doi:10.1016/0006-8993(86)90636-0

Cited by 43 publications

(21 citation statements)

References 15 publications

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“…MPP+ iodide (1) was purchased from Research Biochemicals (Wayband, MA, USA). All the other MPP' analogs (2-10) as iodides were synthesized as described in [26]. Their purity was checked by 'H-NMR and HPLC.…”

Section: Andr>mentioning

confidence: 99%

Electronic and Conformational Effects on the Lipophilicity of Isomers and Analogs of the Neurotoxin 1‐Methyl‐4‐phenylpyridinium (MPP⁺)

Altomare¹,

Carrupt²,

Tayar³

et al. 1991

Helvetica Chimica Acta

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A number of isomers and analogs of the neurotoxin 1 -methyl-4-phenylpyridinium (MPP+) were examined for their lipophilic behavior. Their partition coefficients in the l-octanol/H20 system were measured by centrifugal partition chromatography (CPC), which, being much faster and markedly more precise than the classical shakeflask method, proved a very promising alternative for assessing lipophilicity. A smaller-than-expected lipophilicity was shown by the ortho-isomer of MPPC (M2PP+) and is explained in terms of electronic effects and rigidity, as revealed by UV and NMR spectroscopy, and conformational analysis. Implications of lipophilicity in modulating the in oivo dopaminergic neurotoxicity of the examined compounds are also discussed.

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Section: Andr>mentioning

confidence: 99%

Electronic and Conformational Effects on the Lipophilicity of Isomers and Analogs of the Neurotoxin 1‐Methyl‐4‐phenylpyridinium (MPP⁺)

Altomare¹,

Carrupt²,

Tayar³

et al. 1991

Helvetica Chimica Acta

Self Cite

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“…TMIQ (and/or a charged metabolite) fulfils this criterion, since nomifensine reversed TMIQ inhibitions of TH activity also. Under comparable conditions, nomifensine reverses TH inhibition induced by MPTP and MPP + (Hirata and Nagatsu, 1985 b;Hirata et al, 1986). Further MPTP-like activity is shown by the MAO dependence of TMIQ induced TH inhibition, suggesting that conversion to an active TMIQ metabolite is necessary.…”

Section: Discussionmentioning

confidence: 98%

“…(This may also be a central factor favouring adrenaline over phenylethylamine or dopamine as a potential source for an endogenous tetrahydroisoquinoline MPTP analog, since there is no requirement for a non-specific methyltransferase step to follow formation of an aldehyde condensation product.) In addition, 4, 6, 7-hydroxylation of TMIQ appears significant for TH inhibition, since the MAO oxidized metabolite of N-methyltetrahydroisoquinoline (N-methylisoquinolinium), although an active inhibitor (Hirata et al, 1986), is approximately 10-fold weaker than TMIQ, MPTP or MPP +, all of which have micromolar IC50 values. Whether 4, 6, 7-hydroxylation influences affinity for the dopamine reuptake carrier and/or inhibition of DHR (Abell etal., 1984), or TH remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

“…The acute effects of MPTP on TH activity depend critically on it's conversion by monoamine oxidase (MAO) to the charged species 1-methyl-4-phenylpyridinium (MPP +) and concentration of the metabolite by the dopamine reuptake carrier (Javitch et al, 1985;Hirata and Nagatsu, 1985 a, b;Hirata et al, 1986). Inhibition of TH activity produced by MPTP in vitro is accompanied by reduced concentration of the cofactor tetrahydrobiopterin I-(6 R) -(L-erythro-1,2-dihydroxypropyl) -2-amino -4-hydroxy-5,6,7,8 -tetrahydropteridine; BH4] (Hirata and Nagatsu, 1985 b).…”

Section: Introductionmentioning

confidence: 99%

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1,2,3,4-Tetrahydro-2-methyl-4,6,7-isoquinolinetriol inhibits tyrosine hydroxylase activity in rat striatal synaptosomes

Liptrot

Holdup

Phillipson

1994

J. Neural Transmission

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1,2,3,4-tetrahydro-2-methyl-4,6,7-isoquinolinetriol (TMIQ), a tetrahydroisoquinoline derivative of adrenaline, was tested for potency as an analog of the dopamine depleting agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in assays of tyrosine hydroxylase (TH) activity in the striatal synaptosome preparation. TMIQ inhibited TH activity with an IC50 (4 x 10(-6)M) similar to that found for MPTP (IC50 1 x 10(-6)M). TH inhibitions produced by IC50 concentrations of TMIQ were reversed by monoamine oxidase (MAO)-A or MAO-B inhibitors (clorgyline or deprenyl), or the dopamine reuptake blocker nomifensine, or excess cofactor (6R)-5,6,7,8-tetrahydro-L-biopterin. TMIQ did not appear to act at the presynaptic D2 sulpiride sensitive autoreceptor for dopamine synthesis modulation. These in vitro data are consistent with earlier findings that TMIQ acts as a dopamine depleting agent, and with the possibility that TMIQ may have a degree of MPTP-like activity in vivo.

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“…It was proposed that environmental or endogenously generated toxins could account for this, and several candidate toxins were considered (28,44,47,73,77,86,89,104). No potential toxic agent, though, seemed able to generate sustained enthusiasm.…”

Section: Swerdlowmentioning

confidence: 99%

Does Mitochondrial DNA Play a Role in Parkinson's Disease? A Review of Cybrid and Other Supportive Evidence

Swerdlow

2012

Antioxidants & Redox Signaling

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Significance: Mitochondria are currently believed to play an important role in the neurodysfunction and neurodegeneration that underlie Parkinson's disease (PD). Recent Advances: While it increasingly appears that mitochondrial dysfunction in PD can have different causes, it has been proposed that mitochondrial DNA (mtDNA) may account for or drive mitochondrial dysfunction in the majority of the cases. If correct, the responsible mtDNA signatures could represent acquired mutations, inherited mutations, or population-distributed polymorphisms. Critical Issues and Future Directions: This review discusses the case for mtDNA as a key mediator of PD, and especially focuses on data from studies of PD cytoplasmic hybrid (cybrid) cell lines. Antioxid. Redox Signal. 16, 950-964.

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The effects of pyridinium salts, structurally related compounds of 1-methyl-4-phenylpyridinium ion (MPP+), on tyrosine hydroxylation in rat striatal tissue slices

Cited by 43 publications

References 15 publications

Electronic and Conformational Effects on the Lipophilicity of Isomers and Analogs of the Neurotoxin 1‐Methyl‐4‐phenylpyridinium (MPP⁺)

Electronic and Conformational Effects on the Lipophilicity of Isomers and Analogs of the Neurotoxin 1‐Methyl‐4‐phenylpyridinium (MPP⁺)

1,2,3,4-Tetrahydro-2-methyl-4,6,7-isoquinolinetriol inhibits tyrosine hydroxylase activity in rat striatal synaptosomes

Does Mitochondrial DNA Play a Role in Parkinson's Disease? A Review of Cybrid and Other Supportive Evidence

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The effects of pyridinium salts, structurally related compounds of 1-methyl-4-phenylpyridinium ion (MPP+), on tyrosine hydroxylation in rat striatal tissue slices

Cited by 43 publications

References 15 publications

Electronic and Conformational Effects on the Lipophilicity of Isomers and Analogs of the Neurotoxin 1‐Methyl‐4‐phenylpyridinium (MPP+)

Electronic and Conformational Effects on the Lipophilicity of Isomers and Analogs of the Neurotoxin 1‐Methyl‐4‐phenylpyridinium (MPP+)

1,2,3,4-Tetrahydro-2-methyl-4,6,7-isoquinolinetriol inhibits tyrosine hydroxylase activity in rat striatal synaptosomes

Does Mitochondrial DNA Play a Role in Parkinson's Disease? A Review of Cybrid and Other Supportive Evidence

Contact Info

Product

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Electronic and Conformational Effects on the Lipophilicity of Isomers and Analogs of the Neurotoxin 1‐Methyl‐4‐phenylpyridinium (MPP⁺)

Electronic and Conformational Effects on the Lipophilicity of Isomers and Analogs of the Neurotoxin 1‐Methyl‐4‐phenylpyridinium (MPP⁺)