Biomedical subjects

S K Youngster

Publications and source records attributed to S K Youngster.

At least 19 recordsLinked to original sources

PubMed1992

Dopaminergic neurotoxicity of 1-methyl-4-phenylpyridinium analogs in cultured neurons: relationship to the dopamine uptake system and inhibition of mitochondrial respiration.

Several analogs of 1-methyl-4-phenylpyridinium (MPP+) were evaluated for their affinity for the dopamine uptake system and their ability to inhibit NADH dehydrogenase (complex I) of the mitochondrial electron-transport chain. Moreover, these compounds were tested for their ability to cause selective dopaminergic neurotoxicity in cultured mesencephalic neurons. Simultaneous [3H]dopamine and gamma-amino-[14C]butyric acid uptake and immunocytochemical techniques were used as indices of neuronal damage in cultured cells. The compounds that were potent and selective dopaminergic neurotoxins had high affinity for the dopamine transport system, as measured by their ability to cause dopamine release, and were similar to MPP+ in inhibiting mitochondrial respiration. One compound (1-methyl-4-phenylpyrimidinium) had high affinity for the dopamine uptake system but was a weak inhibitor of mitochondrial respiration and, accordingly, was not neurotoxic. The 4'-alkylated analogs of MPP+, which were poor substrates for the dopamine uptake system and extremely potent inhibitors of mitochondrial respiration, caused a nonselective damage of neurons in culture. Analogs that were not substrates for the dopamine carrier and not inhibitors of mitochondrial respiration were not neurotoxic. This study describes the neurotoxicity of a number of analogs of MPP+ and highlights the importance of the dopamine uptake system and the ability to inhibit mitochondrial respiration as critical processes in conferring selectivity and neurotoxicity, respectively, to MPP+ and analogs, for dopaminergic neurons in culture.

1-Methyl-4-phenylpyridinium↗

PubMed1991

Evidence that the inhibition sites of the neurotoxic amine 1-methyl-4-phenylpyridinium (MPP+) and of the respiratory chain inhibitor piericidin A are the same.

1-Methyl-4-phenylpyridinium (MPP+), the neurotoxic bioactivation product of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), interrupts mitochondrial electron transfer at the NADH dehydrogenase-ubiquinone junction, as do the respiratory chain inhibitors rotenone, piericidin A and barbiturates. Proof that these classical respiratory chain inhibitors and MPP+ react at the same site in the complex NADH dehydrogenase molecule has been difficult to obtain because none of these compounds bind covalently to the target. The 4'-alkyl derivatives of MPP+ inhibit NADH oxidation in submitochondrial particles at much lower concentrations than does MPP+ itself, but still dissociate on washing the membrane preparations, with consequent re-activation of the enzyme. The MPP+ analogues with short alkyl chains prevent the binding of 14C-labelled piericidin A to the membrane and thus must act at the same site, but analogues with alkyl chains longer than heptyl do not prevent binding of [14C]piericidin.

1-Methyl-4-phenylpyridinium↗

PubMed1991

Interaction of 1-methyl-4-phenylpyridinium ion (MPP+) and its analogs with the rotenone/piericidin binding site of NADH dehydrogenase.

Nigrostriatal cell death in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease results from the inhibition of mitochondrial respiration by 1-methyl-4-phenylpyridinium (MPP+). MPP+ blocks electron flow from NADH dehydrogenase to coenzyme Q at or near the same site as do rotenone and piericidin and protects against binding of and loss of activity due to these inhibitors. The 4'-analogs of MPP+ showed increasing affinity for the site with increasing length of alkyl chain, with the lowest Ki, for 4'-heptyl-MPP+, being 6 microM. The 4'-analogs compete with rotenone for the binding site in a concentration-dependent manner. They protect the activity of the enzyme from inhibition by piericidin in parallel to preventing its binding, indicating that the analogs and piericidin bind at the same inhibitory site(s). The optimum protection, however, was afforded by 4'-propyl-MPP+. The lesser protection by the more lipophilic MPP+ analogs with longer alkyl chains may involve a different orientation in the hydrophobic cleft, allowing rotenone and piericidin to still bind even when the pyridinium cation is in a position to interrupt electron flow from NADH to coenzyme Q.

1-Methyl-4-phenylpyridinium↗

PubMed1990

A new class of powerful inhibitors of monamine oxidase A.

It is well established that 1-methyl-4-phenylpyridinium (MPP), the neurotoxic bioactivation product of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and most of its analogs are good competitive inhibitors of monoamine oxidase A, with Ki values in the micromolar range, but they inhibit monoamine oxidase B only at much higher concentrations. We report here the finding that alkyl derivatives of MPP+ substituted at the 4' position of the aromatic ring are considerably more effective reversible inhibitors of the A type enzyme, with Ki values in the nanomolar range (0.075-1.6 microM). They inhibit the B type enzyme only at 2 to 3 orders of magnitude higher concentrations (32-374 microM).

1-Methyl-4-phenylpyridinium↗

PubMed1990

4'-alkylated analogs of 1-methyl-4-phenylpyridinium ion are potent inhibitors of mitochondrial respiration.

1-Methyl-4-phenylpyridinium ion, a major brain metabolite of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, is an inhibitor of Complex I of the mitochondrial respiratory chain. We have synthesized several analogs of 1-methyl-4-phenylpyridinium ion containing various alkyl groups in the 4' position of the phenyl ring and have tested them for their abilities to inhibit the oxidation of NADH-linked substrates by intact mouse liver mitochondria. These compounds are considerably more potent inhibitors than MPP+ itself, with potency increasing as the length of the alkyl chain increases. The most potent inhibitor, 1-methyl-4-(4'heptylphenyl)pyridinium ion, was about 200 times as effective as MPP+. These analogs should prove to be useful tools for studying the nature of the process whereby MPP+ and its pyridinium analogs interact with Complex I to inhibit mitochondrial respiration.

1-Methyl-4-phenylpyridinium↗

PubMed1990

Mechanism-based inactivation of monoamine oxidases A and B by tetrahydropyridines and dihydropyridines.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its primary oxidation product, 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP+), are mechanism-based inhibitors of monoamine oxidases A and B. The pseudo-first-order rate constants for inactivation were determined for various analogues of MPTP and MPDP+ and the concentrations in all redox states were measured throughout the reaction. Disproportionation was observed for all the dihydropyridiniums, but non-enzymic oxidation was insignificant. The dihydropyridiniums were poor substrates for monoamine oxidase A and, consequently, inactivated the enzyme only slowly, despite partition coefficients lower than those for the tetrahydropyridines. For monoamine oxidase B, the dihydropyridiniums were more effective inactivators than the tetrahydropyridines. Substitutions in the aromatic ring had no major effect on the inactivation of monoamine oxidase B, but the 2'-ethyl- and 3'-chloro-substituted compounds were very poor mechanism-based inactivators of monoamine oxidase A. It is clear that both oxidation steps can generate the reactive species responsible for inactivation.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1990

In vivo intracerebral microdialysis studies in rats of MPP+ analogues and related charged species.

The in vivo dopaminergic neurotoxic properties of 45 MPTP and MPP+ analogues and related compounds were examined by an intrastriatal microdialysis assay in conscious rats. MPP(+)-like toxicity, as evidenced by the irreversible effects on DA release and enhancement of lactate formation, was observed with a variety of structural types although no compound was more toxic than MPP+. The following global structure-toxicity relationships could be derived: (1) only permanently charged compounds showed neurotoxic effects; (2) with the exception of amino groups, hydrophilic substituents abolished toxicity; (3) activity was enhanced by lipophilic groups although increased steric bulk around the nitrogen atom tended to decrease activity; (4) nonaromatic, quaternary systems (methiodide of MPTP, guanidinium derivatives) were only weakly toxic; and (5) certain bi- and tricyclic systems, including putative metabolites of potential endogenous MPTP-like compounds, were weakly toxic. The lack of toxic effects following perfusions with DA itself confirmed that MPTP dopaminergic neurotoxicity is not likely to be mediated by the MPP(+)-induced release of DA. With some interesting exceptions, these in vivo data correlate reasonably well with in vitro data on the nerve terminal uptake properties and the inhibitory effects on mitochondrial respiration of these compounds.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1989

Structural dependence of the inhibition of mitochondrial respiration and of NADH oxidase by 1-methyl-4-phenylpyridinium (MPP+) analogs and their energized accumulation by mitochondria.

Nineteen structural analogs of 1-methyl-4-phenylpyridinium (MPP+) were studied for their capacity to inhibit the mitochondrial oxidation of NAD+-linked substrates and the aerobic oxidation of NADH in inner membrane preparations from cardiac mitochondria. In the majority of cases, a good correlation was found between the two inhibition effects monitored. A few compounds were effective inhibitors of NADH oxidase but had only marginal effects on mitochondrial respiration. From studies of their accumulation by mitochondria, it appears likely that the latter compounds are not effectively concentrated by intact mitochondria by the electrical gradient and, in part for this reason, cannot reach sufficiently high concentrations at the appropriate binding site of NADH dehydrogenase. In addition, evidence is presented that the penetration of pyridinium analogs to the inhibition site in the NADH dehydrogenase complex may also be rate limiting. The data support the thesis that, for a substituted tetrahydropyridine to be acutely neurotoxic, its pyridinium oxidation product must be actively accumulated in the mitochondria and must inhibit NADH-ubiquinone oxidoreductase in its membrane environment.

1-Methyl-4-phenylpyridinium↗

PubMed1989

Oxidation of analogs of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by monoamine oxidases A and B and the inhibition of monoamine oxidases by the oxidation products.

Twenty analogs of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were tested for their capacity to be oxidized by pure monoamine oxidase-A (MAO-A) prepared from human placenta and pure monoamine oxidase-B (MAO-B) prepared from beef liver. Several of the MPTP analogs were very good substrates for MAO-A, for MAO-B, or for both and had low Km values and high turnover numbers. These values were similar to or even better than those of kynuramine and benzylamine, good substrates for MAO-A and MAO-B, respectively. MPTP had relatively low Km values for oxidation by both MAO-A and MAO-B. In contrast, the turnover number for MPTP oxidation by MAO-B was considerably higher than the value for MAO-A. The corresponding pyridinium species of MPTP and several of the MPTP analogs inhibited MAO-A competitively with Ki values at micromolar concentrations; in contrast the pyridinium species inhibited MAO-B competitively at considerably higher concentrations (i.e., 100 microM or greater Ki values). The data provide information concerning the structural requirements for the oxidation of tetrahydropyridines by MAO-A and MAO-B and the inhibition of these enzymes by pyridiniums.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1989

Structure-activity study of the mechanism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. I. Evaluation of the biological activity of MPTP analogs.

Several analogs of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were synthesized and compared to MPTP for their ability to be oxidized by monoamine oxidase (MAO) and for their ability to cause nigrostriatal dopaminergic neurotoxicity in mice. Most of the compounds were oxidized by mouse brain MAO, either predominantly by the B-form or by both the A- and B-forms. The MAO-catalyzed oxidation of all of the MAO substrates resulted in the formation of dihydropyridinium intermediates which, in turn, except for the dihydropyridinium of 1-methyl-4-benzyl-1,2,3,6-tetrahydropyridine, formed pyridinium species as the final oxidation product. Nine analogs were found to be neurotoxic; all were oxidized by MAO to pyridinium compounds. However, some non-neurotoxic MPTP analogs were also oxidized by MAO. Neither 1-methyl-4-benzyl-1,2,3,6-tetrahydropyridine nor the compounds which were not substrates for MAO were neurotoxic. Also, the neurotoxicity of all of the compounds tested was blocked by inhibiting either MAO-B, MAO-A or both MAO-B and MAO-A together, indicating that MAO activity was necessary for the neurotoxicity of the compounds to be manifested. The capacity of an MPTP analog to be oxidized by MAO to a pyridinium appears to be a necessary, but not sufficient, parameter in determining the neurotoxic potential of the compound.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1989

Structure-activity study of the mechanism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. II. Evaluation of the biological activity of the pyridinium metabolites formed from the monoamine oxidase-catalyzed oxidation of MPTP analogs.

In the accompanying paper, several tetrahydropyridine analogs of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were screened for their abilities to be oxidized by monoamine oxidase (MAO) to pyridiniums and to produce neurotoxicity in mice. We reported that most of the analogs were oxidized by MAO to pyridiniums and some of the analogs were neurotoxic. We concluded that the capacity of a tetrahydropyridine MPTP analog to be oxidized by MAO to a pyridinium was a necessary, but not sufficient, condition for the compound to be a neurotoxin. In the present paper we attempt to explain further the neurotoxicity or lack of neurotoxicity of these analogs by evaluating the abilities of the pyridinium compounds to serve as substrates for the neostriatal dopamine (DA) transport system and as inhibitors of mitochondrial respiration. We now report that all of the neurotoxic MPTP analogs are oxidized to pyridiniums that are good substrates for the neostriatal DA carrier and good inhibitors of mitochondrial respiration. The results are consistent with an important role for both uptake of the pyridiniums by the DA carrier and inhibition by the pyridiniums of mitochondrial respiration in the neurotoxicity induced by MPTP and its analogs.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1988

Role for monoamine oxidase-A (MAO-A) in the bioactivation and nigrostriatal dopaminergic neurotoxicity of the MPTP analog, 2'Me-MPTP.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration leads to the selective destruction of the dopaminergic neurons of the nigrostriatal pathway in experimental animals including monkeys and mice. The neurotoxicity of MPTP is dependent upon its monoamine oxidase-B (MAO-B)-catalyzed conversion to the 1-methyl-4-phenylpyridinium species (MPP+). A methylated analog of MPTP. A methylated analog of MPTP, namely 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'Me-MPTP), is a more potent dopaminergic neurotoxin than MPTP in mice. Although the selective inhibition of MAO-B is sufficient to protect mice against MPTP-induced neurotoxicity, it is reported here that complete inhibition of MAO-B failed to prevent 2'Me-MPTP-induced dopaminergic neurotoxicity. However, the neurotoxicity of 2'Me-MPTP was completely prevented and 2'Me-MPP+ formation was markedly attenuated in mice in which both MAO-A and MAO-B were almost totally inhibited. This information about the role of MAO-A in the bioactivation of 2'Me-MPTP may be of relevance to those who speculate that the MAO-B catalyzed bioactivation of MPTP or a similar compound may be the cause of idiopathic Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1988

Studies with the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and several of its analogs.

The nigrostriatal dopaminergic neurotoxicity of MPTP was prevented in mice in a dose-dependent manner by the monoamine oxidase-B (MAO-B) inhibitor deprenyl. This finding, combined with other observations, points out the important role of MAO-B in the bioactivation of MPTP. In the present study, some comparisons between MPTP and several of its structural analogs will be presented.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1988

Importance of monoamine oxidase A in the bioactivation of neurotoxic analogs of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a potent dopaminergic neurotoxin that causes biochemical, pharmacological, and pathological deficits in experimental animals similar to those seen in human parkinsonian patients. All of the deficits can be prevented by treating mice with selective inhibitors of monoamine oxidase B (MAO-B), including deprenyl, prior to MPTP administration. We now report that the dopaminergic neurotoxicity of two potent MPTP analogs, namely the 2'-methyl and 2'-ethyl derivatives (2'-MeMPTP and 2'-EtMPTP), cannot be prevented by deprenyl pretreatment. However, the neurotoxicity of these two analogs can be prevented by pretreatment with a combination of deprenyl and the selective MAO-A inhibitor clorgyline at doses that are sufficient to almost completely inhibit both MAO-B and MAO-A activities. Moreover, the neurotoxicity of 2'-EtMPTP (but not of 2'-MeMPTP and MPTP) can be significantly attenuated by clorgyline alone. There was a parallel between the capacity of the MAO inhibitors to decrease the brain content of the pyridinium species after administration of the tetrahydropyridines and the capacity of the MAO inhibitors to protect against the neurotoxic action of the tetrahydropyridines. The data support the conclusion that both 2'-MeMPTP and 2'-EtMPTP are bioactivated to pyridinium species to a significant extent by MAO-A. Further, it appears that the formation of the pyridinium species plays an important role in the neurotoxic process.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1987

1-Methyl-4-cyclohexyl-1,2,3,6-tetrahydropyridine (MCTP): an alicyclic MPTP-like neurotoxin.

1-Methyl-4-cyclohexyl-1,2,3,6-tetrahydropyridine (MCTP), an analog of MPTP, was found to be an MPTP-like neurotoxin. MCTP administration caused extensive losses of neostriatal dopamine and its major metabolites in male Swiss-Webster mice. Under similar experimental conditions, MCTP was approximately as potent as MPTP. Like MPTP, MCTP was a good substrate for monoamine oxidase-B (MAO-B) and its neurotoxicity was prevented in mice by AGN-1135, a selective inhibitor of MAO-B. The neurotoxicity of MCTP and of MPTP was also prevented by the dopamine uptake inhibitor mazindol. 1-Methyl-4-cyclohexylpyridinium ion (MCP+), the 4-electron oxidation product of MCTP, caused release of previously accumulated [3H]dopamine from mouse neostriatal synaptosomes. This release was blocked by mazindol, which indicates that MCP+, like 1-methyl-4-phenylpyridinium ion (MPP+), the 4-electron oxidation product of MPTP, is a substrate for the dopamine transport system. Like MPP+, MCP+ was found to inhibit the mitochondrial oxidation of NADH-linked substrates. It appears that conjugation between the tetrahydropyridine ring and a 4-substituent is not a requirement for an MPTP analog to possess neurotoxicity.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1987

MPTP, MPP+ and mitochondrial function.

1-Methyl-4-phenylpyridinium (MPP+), the putative toxic metabolite of the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), inhibited NAD(H)-linked mitochondrial oxidation at the level of Complex I of the electron transport system. MPTP and MPP+ inhibited aerobic glycolysis in mouse striatal slices, as measured by increased lactate production; MPTP-induced effects were prevented by inhibition of monoamine oxidase B activity. Several neurotoxic analogs of MPTP also form pyridinium metabolites via MAO; these MPP+ analogs were all inhibitors of NAD(H)-linked oxidation by isolated mitochondria. 2'-Methyl-MPTP, a more potent neurotoxin in mice than MPTP, was also more potent than MPTP in inducing lactate accumulation in mouse brain striatal slices. Overall, the studies support the hypothesis that compromise of mitochondrial oxidative capacity is an important factor in the mechanisms underlying the toxicity of MPTP and similar compounds.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1987

Evaluation of the biological activity of several analogs of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Several analogs of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were synthesized and screened for their capacity to be oxidized by monoamine oxidase (MAO-A or MAO-B) and their capacity to produce nigrostriatal dopaminergic neurotoxicity in mice. All of the compounds were relatively weak substrates for MAO-A but many of the compounds were found to be good substrates for MAO-B. Only three of the compounds, in addition to MPTP itself, were found to be neurotoxic. These were 1-methyl-4-cyclohexyl-1,2,3,6-tetrahydropyridine, 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine and 1-methyl-4-(3'-methoxyphenyl)-1,2,3,6-tetrahydropyridine. All three of these neurotoxic compounds were found to be substrates for MAO-B; in contrast no compound was found to be neurotoxic that was not oxidized by MAO-B. The capacity of the compounds studied to be oxidized by MAO-B appears to be an important aspect of the neurotoxic process.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1987

Characteristics of 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine-induced neurotoxicity in the mouse.

1-Methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'CH3-MPTP) was shown previously to be a more potent neurotoxicant than 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. The present investigation was conducted to determine possible reasons for the greater potency of 2'CH3-MPTP and to determine if its neurotoxic action might be similar to that of MPTP. 2'CH3-MPTP was a much better substrate for monoamine oxidase than was MPTP (Km values of 66 and 114 microM and Vmax values of 3433 and 1389 nmol/g of tissue per hr for 2'CH3-MPTP and MPTP, respectively) and it is likely that this is an important feature which contributes to its greater potency. In addition, its pyridinium metabolite, 1-methyl-4-(2'-methylphenyl)pyridinium was found to be an excellent substrate for the dopamine carrier with Km and Vmax values (513 nM and 4.1 nmol/g of tissue per min, respectively) similar to those of 1-methyl-4-phenylpyridinium (872 nM and 5.2 nmol/g of tissue per min, respectively). In vivo, 2'CH3-MPTP-induced neurotoxicity, like MPTP-induced neurotoxicity, was attenuated by the pretreatment of mice with a dopamine uptake inhibitor (mazindol or GBR 13069). However, selective doses of the monoamine oxidase (MAO)-B inhibitors, deprenyl or MDL 72145, failed to prevent in vivo neurotoxicity induced by 2'CH3-MPTP although these doses effectively blocked MPTP-induced neurotoxicity. Protection against 2'CH3-MPTP-induced neurotoxicity was observed only at a nonselective dose of MDL 72145 which blocked both MAO-B and MAO-A activities.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗