Carvedilol reverses hyperthermia and attenuates rhabdomyolysis induced by 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) in an animal model*

Sprague, Jon E.; Moze, Petra; Caden, David; Rusyniak, Daniel E.; Holmes, Courtney; Goldstein, David S.; Mills, Edward

doi:10.1097/01.ccm.0000165969.29002.70

Cited by 70 publications

(73 citation statements)

References 32 publications

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“…First, in the hyperthyroid state, UCP1-dependent thermogenesis is blunted as a result of suppression of adrenergic signaling in brown adipocytes (Golozoubova et al, 2004), but isolated SKM mitochondria from hyperthyroid rats show enhanced FFA-induced uncoupling (Brand et al, 1992). In addition, SKM is the primary contributor to thermogenesis and oxygen consumption induced by NE in animals (Rose et al, 1999), and humans (Astrup et al, 1985), and a 35-fold increase in plasma NE precedes MDMA-induced hyperthermia (Sprague et al, 2005). Interestingly, combined antagonism of ␣ 1 -and ␤ 3 -AR, which are expressed in SKM (Martin et al, 1990;Sillence et al, 1993), prevents and reverses hyperthermia induced by MDMA (Sprague et al, 2005).…”

Section: Determinants Of Sympathomimetic-induced Hyperthermia 277mentioning

confidence: 99%

Roles of Norepinephrine, Free Fatty Acids, Thyroid Status, and Skeletal Muscle Uncoupling Protein 3 Expression in Sympathomimetic-Induced Thermogenesis

Sprague

Yang

Sommers

et al. 2006

J Pharmacol Exp Ther

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Thyroid hormone (TH) plays a fundamental role in thermoregulation, yet the molecular mediators of its effects are not fully defined. Recently, skeletal muscle (SKM) uncoupling protein (UCP) 3 was shown to be an important mediator of the thermogenic effects of the widely abused sympathomimetic agents 3,4-methylenedioxymethamphetamine (MDMA; Ecstasy) and methamphetamine. Expression of UCP3 is regulated by TH. Activation of UCP3 is indirectly regulated by norepinephrine (NE) and is dependent upon the availability of free fatty acids (FFAs). We hypothesized that UCP3 may be a molecular link between TH and hyperthermia, requiring increased levels of both NE and FFAs to accomplish the thermogenic effect. Here, we demonstrate that MDMA (40 mg/kg s.c.) significantly increases plasma FFA levels 30 min after treatment. Pharmacologically increasing NE levels through the inhibition of phenylethanolamine N-methyltransferase with Ϯ2,3-dichloro-␣-methylbenzylamine potentiated the hyperthermic effects of a 20 mg/kg dose of MDMA. Using Western blots and regression analysis, we further illustrated that chronic hyperthyroidism in rats potentiates the hyperthermic effects of MDMA and increases levels of SKM UCP3 protein in a linear fashion according to levels of circulating plasma TH. Conversely, chronic hypothyroidism results in a hypothermic response to MDMA that is directly proportionate to decreased UCP3 expression. Acute TH supplementation did not change the skeletal muscle UCP3 expression levels or temperature responses to MDMA. These findings suggest that, although MDMA-induced hyperthermia appears to result from increased NE and FFA levels, susceptibility is ultimately determined by TH regulation of UCP3-dependent thermogenesis.Hyperthermia results from a severe, unregulated rise in core body temperature induced by high ambient temperature, strenuous exercise, endocrinopathy, or drug exposure. To our knowledge, no drug treatment has been established through controlled trials as an efficacious therapy for conditions that involve severe hyperthermia, with the exception of malignant hyperthermia, which is effectively reversed with dantrolene (Blank and Boggs, 1993). The lack of therapeutic options for the management of hyperthermia probably results from an inadequate understanding of the basic molecular mechanisms of thermogenesis.The principal active thyroid hormone (TH) 3,5,3Ј-triiodo-Lthyronine is formed from the precursor 3,5,3Ј,5Ј-tetraiodothyronine (T 4 , thyroxine) by deiodinases present in various tissues (Bianco and Larsen, 2005). Although TH has been established as the primary endocrinologic regulator of body temperature (Silva, 2005) and facultative thermogenesis (FT) (for review see Lowell and Spiegelman, 2000), the mechanisms involved are complex and incompletely characterized. One family of genes regulated by TH (Gong et al., 1997) and believed to play a significant role in FT encodes for the mitochondrial uncoupling proteins (UCPs).UCPs "uncouple" free energy stored in the mitochondrial electrochemical p...

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Section: Determinants Of Sympathomimetic-induced Hyperthermia 277mentioning

confidence: 99%

Roles of Norepinephrine, Free Fatty Acids, Thyroid Status, and Skeletal Muscle Uncoupling Protein 3 Expression in Sympathomimetic-Induced Thermogenesis

Sprague

Yang

Sommers

et al. 2006

J Pharmacol Exp Ther

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“…This treatment protocol allowed us to compare the effectiveness of each drug in terms of the onset of its therapeutic action, strength, and duration. All drugs tested in this study are FDA-approved, currently used to treat chronic diseases in humans, and have previously been shown to decrease MDMA-induced body hyperthermia under standard laboratory conditions (Blessing et al, 2003;Sprague et al, 2005;Hysek et al, 2012;Liechti, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…This protocol is more relevant for human conditions because MDMA is recreationally used in social settings associated with high arousal (eg, rave parties, music festivals). Third, in contrast to most studies, where a treatment drug was administered before or at the same time as MDMA (Yeh, 1997;Sprague et al, 2005;Shioda et al, 2008;Hysek et al, 2012;Taffe, 2012), we injected each of the three test drugs-clozapine, carvedilol, and labetalol-after the MDMA injection, when brain and body temperatures were already significantly increased (438°C). This dosing regimen closely mimics the clinical situation, in which MDMA-intoxicated patients are treated for pathological hyperthermia in hospital emergency rooms.…”

Section: Experimental Protocolmentioning

confidence: 99%

“…We also dissolved labetalol in saline and carvedilol in a 3 : 1 volume ratio of DMSO:PBS. We injected all 'treatment' drugs intraperitoneally at the same dose (5 mg/kg, 1 ml/kg volume); this dose was chosen based on previous studies (Blessing et al, 2003;Sprague et al, 2005).…”

Section: Experimental Protocolmentioning

confidence: 99%

“…We assessed the effects of clozapine, an atypical neuroleptic, and carvedilol and labetalol, mixed alpha-and beta-adrenoceptor blockers. These medications are routinely used to treat chronic health problems in humans, and were chosen because of their preclinical success in attenuating MDMA-induced body hyperthermia (Blessing et al, 2003;Sprague et al, 2005). Clozapine acts on multiple neural receptors and glial cells in the brain, presumably inhibiting MDMA-induced metabolic activation, sympathetic tone, and centrally mediated vasoconstriction (Baldessarini and Frankenburg, 1991;Breier et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

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Clinically Relevant Pharmacological Strategies That Reverse MDMA-Induced Brain Hyperthermia Potentiated by Social Interaction

Kiyatkin

Ren

Wakabayashi

et al. 2015

Neuropsychopharmacol

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MDMA-induced hyperthermia is highly variable, unpredictable, and greatly potentiated by the social and environmental conditions of recreational drug use. Current strategies to treat pathological MDMA-induced hyperthermia in humans are palliative and marginally effective, and there are no specific pharmacological treatments to counteract this potentially life-threatening condition. Here, we tested the efficacy of mixed adrenoceptor blockers carvedilol and labetalol, and the atypical antipsychotic clozapine, in reversing MDMA-induced brain and body hyperthermia. We injected rats with a moderate non-toxic dose of MDMA (9 mg/kg) during social interaction, and we administered potential treatment drugs after the development of robust hyperthermia (42.5°C), thus mimicking the clinical situation of acute MDMA intoxication. Brain temperature was our primary focus, but we also simultaneously recorded temperatures from the deep temporal muscle and skin, allowing us to determine the basic physiological mechanisms of the treatment drug action. Carvedilol was modestly effective in attenuating MDMA-induced hyperthermia by moderately inhibiting skin vasoconstriction, and labetalol was ineffective. In contrast, clozapine induced a marked and immediate reversal of MDMA-induced hyperthermia via inhibition of brain metabolic activation and blockade of skin vasoconstriction. Our findings suggest that clozapine, and related centrally acting drugs, might be highly effective for reversing MDMA-induced brain and body hyperthermia in emergency clinical situations, with possible life-saving results.

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Skeletal Muscle Toxicology

Kenaston¹,

Abramson²,

Pfeiffer³

et al. 2009

General, Applied and Systems Toxicology

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The skeletal musculature is necessary for normal motor functions such as walking or breathing. It accounts for between 35 and 45% of total body weight in humans and is the most energetically demanding tissue in the body. Skeletal muscle is a unique tissue with intricate organizational arrangement, requiring precise regulation of intracellular ions and cooperation by a multitude of cellular proteins. As a result, it also has susceptibilities to a diverse array of toxic insults. Derangements of skeletal muscle function can cause loss of movement, multiorgan involvement and even organismal demise. In addition to direct effects on skeletal muscle, this tissue can also be responsible for damage to distant tissues and organs by release of large intracellular proteins into the vasculature. As a specific topic, skeletal muscle toxicology has been largely absent from the majority of textbooks. However, it represents an important and specific target of a variety of natural and synthetic toxicants. Here we present an overview of skeletal muscle physiology, including tissue architecture, energetic substrate preferences, and function. Laboratory methods and diagnostic observations to be used for investigating skeletal muscle injury in a research and clinical setting are also discussed. Finally, we provide an in‐depth outline of skeletal muscle toxicants arranged according to their proposed mechanism of action.

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Carvedilol reverses hyperthermia and attenuates rhabdomyolysis induced by 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) in an animal model*

Cited by 70 publications

References 32 publications

Roles of Norepinephrine, Free Fatty Acids, Thyroid Status, and Skeletal Muscle Uncoupling Protein 3 Expression in Sympathomimetic-Induced Thermogenesis

Roles of Norepinephrine, Free Fatty Acids, Thyroid Status, and Skeletal Muscle Uncoupling Protein 3 Expression in Sympathomimetic-Induced Thermogenesis

Clinically Relevant Pharmacological Strategies That Reverse MDMA-Induced Brain Hyperthermia Potentiated by Social Interaction

Skeletal Muscle Toxicology

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