An antisense oligonucleotide targeted at MAO-B attenuates rat striatal serotonergic neurotoxicity induced by MDMA

Falk, Erin M.; Cook, Valerie J.; Nichols, David E.; Sprague, Jon E.

doi:10.1016/s0091-3057(02)00728-1

Cited by 33 publications

(22 citation statements)

References 20 publications

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“…5). We share the opinion of Falk et al (2002), who state that "increased body temperature can potentiate neurotoxic events, but the underlying basis of MDMA-induced neurotoxicity is unrelated to the production of hyperthermia". …”

Section: Discussionmentioning

confidence: 70%

“…For example, inducing hypothermia can protect against MDMA-mediated neurotoxicity (Malberg et al, 1996), and raising body temperature can potentiate the neurotoxicity. However, although pretreatment with fluoxetine provides protection against MDMA-induced serotonergic neurotoxicity, it did not inhibit MDMA-induced hyperthermia, indicating a temperature-independent mechanism (Falk et al, 2002). An essential role for hyperthermia in MDMA-induced neurotoxicity is further questioned by the finding that inhibiting monoamine oxidase-B with antisense oligonucleotides blocks the neurotoxicity of MDMA with no significant effect on ambient body temperature (Falk et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…However, although pretreatment with fluoxetine provides protection against MDMA-induced serotonergic neurotoxicity, it did not inhibit MDMA-induced hyperthermia, indicating a temperature-independent mechanism (Falk et al, 2002). An essential role for hyperthermia in MDMA-induced neurotoxicity is further questioned by the finding that inhibiting monoamine oxidase-B with antisense oligonucleotides blocks the neurotoxicity of MDMA with no significant effect on ambient body temperature (Falk et al, 2002). Moreover, mazindol also protects against MDMAinduced neurotoxicity without altering MDMA-induced hyperthermia (Shankaran et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

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Serotonergic Neurotoxic Metabolites of Ecstasy Identified in Rat Brain

Jones¹,

Duvauchelle²,

Ikegami³

et al. 2005

J Pharmacol Exp Ther

111

130

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The selective serotonergic neurotoxicity of 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) depends on their systemic metabolism. We have recently shown that inhibition of brain endothelial cell ␥-glutamyl transpeptidase (␥-GT) potentiates the neurotoxicity of both MDMA and MDA, indicating that metabolites that are substrates for this enzyme contribute to the neurotoxicity. Consistent with this view, glutathione (GSH) and N-acetylcysteine conjugates of ␣-methyl dopamine (␣-MeDA) are selective neurotoxicants. However, neurotoxic metabolites of MDMA or MDA have yet to be identified in brain. Using in vivo microdialysis coupled to liquid chromatography-tandem mass spectroscopy and a high-performance liquid chromatography-coulometric electrode array system, we now show that GSH and N-acetylcysteine conjugates of N-methyl-␣-MeDA are present in the striatum of rats administered MDMA by subcutaneous injection. Moreover, inhibition of ␥-GT with acivicin increases the concentration of GSH and N-acetylcysteine conjugates of N-methyl-␣-MeDA in brain dialysate, and there is a direct correlation between the concentrations of metabolites in dialysate and the extent of neurotoxicity, measured by decreases in serotonin (5-HT) and 5-hydroxyindole acetic (5-HIAA) levels. Importantly, the effects of acivicin are independent of MDMA-induced hyperthermia, since acivicin-mediated potentiation of MDMA neurotoxicity occurs in the context of acivicin-mediated decreases in body temperature. Finally, we have synthesized 5-(N-acetylcystein-S-yl)-N-methyl-␣-MeDA and established that it is a relatively potent serotonergic neurotoxicant. Together, the data support the contention that MDMA-mediated serotonergic neurotoxicity is mediated by the systemic formation of GSH and N-acetylcysteine conjugates of N-methyl-␣-MeDA (and ␣-MeDA). The mechanisms by which such metabolites access the brain and produce selective serotonergic neurotoxicity remain to be determined.Although the selectivity of (Ϯ)-3,4-methylenedioxymethamphetamine (MDMA, ecstasy) and (Ϯ)-3,4-methylenedioxyamphetamine (MDA) for the serotonergic system in rats and humans is firmly established, the mechanism(s) involved are not fully understood. In rats, MDMA is cleared mainly by hepatic metabolism by N-demethylation to form MDA. MDMA and MDA are further O-demethylenated to 3,4-dihydroxymethamphetamine (N-methyl-␣-methyldopamine; N-Me-␣-MeDA) and 3,4-dihydroxyamphetamine (␣-methyldopamine; ␣-MeDA), respectively. N-Me-␣-MeDA and ␣-MeDA are highly redox-unstable catechols and are conjugated with sulfate and glucuronic acid. Both catechols can also be rapidly oxidized to their corresponding orthoquinones and form adducts with glutathione (GSH) and other thiol-containing compounds (Lim and Foltz, 1988;Hiramatsu et al., 1990). Alternatively, N-Me-␣-MeDA and ␣-MeDA can be O-methylated to form 4-hydroxy-3-methoxymethamphetamine (3-O-Me-N-Me-␣-MeDA) or 4-hydroxy-3-methoxyamphetamine (3-O-Me-␣-MeDA), respectively.

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Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Serotonergic Neurotoxic Metabolites of Ecstasy Identified in Rat Brain

Jones¹,

Duvauchelle²,

Ikegami³

et al. 2005

J Pharmacol Exp Ther

111

130

View full text Add to dashboard Cite

show abstract

“…Corroborating this hypothesis, previous studies have shown that MDMA-induced chronic 5-HT loss requires the activity of MAO-B and involves oxidative stress (Schmidt, 1987;Sprague and Nichols, 1995;Sprague et al, 1998). More recently, it was demonstrated that MDMA-induced 5-HT depletion observed in wild-type mice did not occur in MAO-Bdeficient mice (Fornai et al, 2001) and that an antisense oligonucleotide targeted at MAO-B attenuates rat striatal serotonergic neurotoxicity induced by MDMA (Falk et al, 2002). Moreover, it was also shown that dopamine uptake into serotonergic nerve endings, followed by MAO-B metabolism and subsequent oxidative stress also contributes to the neurotoxic effects of MDMA (Hrometz et al, 2004;Jones et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Monoamine Oxidase-B Mediates Ecstasy-Induced Neurotoxic Effects to Adolescent Rat Brain Mitochondria

Alves¹,

Summavielle²,

Alves³

et al. 2007

J. Neurosci.

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“…That is, a hyperthermic response occurs at ambient temperatures greater than 24°C, and a hypothermic response occurs at ambient temperatures of 20°C or lower (Gordon et al, 1991;Taffe et al, 2006;Von Huben et al, 2007). Although a hyperthermic response to MDMA is not essential for subsequent serotonergic neurotoxicity (Shankaran et al, 1999;Falk et al, 2002;Darvesh and Gudelsky, 2004;Jones et al, 2005), experimental manipulations such as pharmacological agents (Farfel and Seiden, 1995;Malberg et al, 1996), surgical removal of pituitary and thyroid glands (Sprague et al, 2003), and changes in ambient temperature (Malberg and Seiden, 1998) that attenuate MDMA-induced hyperthermia also attenuate the subsequent neurotoxic effects. A better understanding of MDMA disposition in nonhuman primates at cool, room, and warm ambient temperatures may provide insight into any relationship between ambient temperature, thermoregulation, MDMA metabolism, and subsequent neurotoxicity.…”

mentioning

confidence: 99%

Ambient Temperature Effects on 3,4-Methylenedioxymethamphetamine-Induced Thermodysregulation and Pharmacokinetics in Male Monkeys

Banks¹,

Sprague²,

Kisor³

et al. 2007

Drug Metab Dispos

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ABSTRACT:Changes in ambient temperature are known to alter both the hyperthermic and the serotonergic consequences of 3,4-methylenedioxymethamphetamine (MDMA). Metabolism of MDMA has been suggested to be a requisite for these neurotoxic effects, whereas the hyperthermic response is an important contributing variable. The aim of the present study was to investigate the interaction between ambient temperature, MDMA-induced thermodysregulation, and its metabolic disposition in monkeys. MDMA (1.5 mg/kg i.v.) was administered noncontingently at cool (18°C; n ‫؍‬ 5), room (24°C; n ‫؍‬ 7), and warm (31°C; n ‫؍‬ 7) ambient temperatures. For 240 min following MDMA administration, core temperature was recorded and blood samples were collected for analysis of MDMA and its metabolites 3,4-dihydroxymethamphetamine (HHMA), 3,4-dihydroxyamphetamine, and 3,4-methylenedioxyamphetamine (MDA). A dose of 1.5 mg/kg MDMA induced a hypothermic response at 18°C, a hyperthermic response at 31°C, and did not significantly change core temperature at 24°C. Regardless of ambient temperature, plasma MDMA concentrations reached maximum within 5 min, and HHMA was a major metabolite. Curiously, the approximate elimination half-life (t 1/2 ) of MDMA at 18°C (136 min) and 31°C (144 min) was increased compared with 24°C (90 min) and is most likely because of volume of distribution changes induced by core temperature alterations. At 18°C, there was a significantly higher MDA area under the concentration-time curve (AUC) and a trend for a lower HHMA AUC compared with 24°C and 31°C, suggesting that MDMA disposition was altered. Overall, induction of hypothermia in a cool environment by MDMA may alter its disposition. These results could have implications for MDMA-induced serotonergic consequences.

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An antisense oligonucleotide targeted at MAO-B attenuates rat striatal serotonergic neurotoxicity induced by MDMA

Cited by 33 publications

References 20 publications

Serotonergic Neurotoxic Metabolites of Ecstasy Identified in Rat Brain

Serotonergic Neurotoxic Metabolites of Ecstasy Identified in Rat Brain

Monoamine Oxidase-B Mediates Ecstasy-Induced Neurotoxic Effects to Adolescent Rat Brain Mitochondria

Ambient Temperature Effects on 3,4-Methylenedioxymethamphetamine-Induced Thermodysregulation and Pharmacokinetics in Male Monkeys

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