Involvement of mitochondrial/lysosomal toxic cross-talk in ecstasy induced liver toxicity under hyperthermic condition

Pourahmad, Jalal; Eskandari, Mohammad Reza; Nosrati, Masoumeh; Kobarfard, Farzad; Khajeamiri, Ali Reza

doi:10.1016/j.ejphar.2010.06.019

Cited by 34 publications

(21 citation statements)

References 33 publications

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“…At 24 hours after the last METH injection, the damage escalated to severe global, cytoplasmic disappearance (Figure 1), suggestive of autophagy (Rautou et al, 2008). Although the mechanisms by which METH causes hepatotoxicity were not evaluated, the findings are consistent with reports that the metabolism of METH by the liver via the 2D6 p450 enzymes (Lin et al, 1997) may promote hepatocellular damage (Pourahmad et al, 2010, Letelier et al, 2011). Furthermore, amphetamines have been shown to cause hepatocellular mitochondrial damage (Moon et al, 2008).…”

Section: Discussionsupporting

confidence: 85%

Peripheral Ammonia as a Mediator of Methamphetamine Neurotoxicity

Halpin

Yamamoto

2012

J. Neurosci.

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Ammonia is metabolized by the liver and has established neurological effects. The current study examined the possibility that ammonia contributes to the neurotoxic effects of methamphetamine (METH). The results show that a binge dosing regimen of METH to the rat increased plasma and brain ammonia concentrations that were paralleled by evidence of hepatotoxicity. The role of peripheral ammonia in the neurotoxic effects of METH was further substantiated by the demonstration that the enhancement of peripheral ammonia excretion blocked the increases in brain and plasma ammonia and attenuated the long term depletions of dopamine and serotonin typically produced by METH. Conversely, the localized perfusion of ammonia in combination with METH, but not METH alone or ammonia alone, into the striatum recapitulated the neuronal damage produced by the systemic administration of METH. Furthermore, this damage produced by the local administration of ammonia and METH was blocked by the GYKI 52466, an AMPA receptor antagonist. These findings highlight the importance of ammonia derived from the periphery as a small molecule mediator of METH neurotoxicity and more broadly emphasize the importance of peripheral organ damage as a possible mechanism that mediates the neuropathology produced by drugs of abuse and other neuroactive molecules.

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Section: Discussionsupporting

confidence: 85%

Peripheral Ammonia as a Mediator of Methamphetamine Neurotoxicity

Halpin

Yamamoto

2012

J. Neurosci.

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“…METH has been shown to reach some of the highest and longest lasting concentrations in liver and accordingly, has the potential to be directly hepatotoxic (Volkow et al 2010). METH is metabolized in the liver by the cytochrome p450 system (Lin et al 1997) that can lead to the formation of oxidative byproducts and result in cellular damage (Moon et al 2008;Pourahmad et al 2010;Letelier et al 2011). Figure 5.…”

Section: Discussionmentioning

confidence: 99%

Methamphetamine causes acute hyperthermia‐dependent liver damage

Halpin

Gunning

Yamamoto

2013

Pharmacology Res & Perspec

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Methamphetamine-induced neurotoxicity has been correlated with damage to the liver but this damage has not been extensively characterized. Moreover, the mechanism by which the drug contributes to liver damage is unknown. This study characterizes the hepatocellular toxicity of methamphetamine and examines if hyperthermia contributes to this liver damage. Livers from methamphetamine-treated rats were examined using electron microscopy and hematoxylin and eosin staining. Methamphetamine increased glycogen stores, mitochondrial aggregation, microvesicular lipid, and hydropic change. These changes were diffuse throughout the hepatic lobule, as evidenced by a lack of hematoxylin and eosin staining. To confirm if these changes were indicative of damage, serum aspartate and alanine aminotransferase were measured. The functional significance of methamphetamine-induced liver damage was also examined by measuring plasma ammonia. To examine the contribution of hyperthermia to this damage, methamphetamine-treated rats were cooled during and after drug treatment by cooling their external environment. Serum aspartate and alanine aminotransferase, as well as plasma ammonia were increased concurrently with these morphologic changes and were prevented when methamphetamine-induced hyperthermia was blocked. These findings support that methamphetamine produces changes in hepatocellular morphology and damage persisting for at least 24 h after drug exposure. At this same time point, methamphetamine treatment significantly increases plasma ammonia concentrations, consistent with impaired ammonia metabolism and functional liver damage. Methamphetamine-induced hyperthermia contributes significantly to the persistent liver damage and increases in peripheral ammonia produced by the drug.

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“…Specifically, MDMA has been shown to oxidatively modify hepatocellular mitochondrial proteins (Moon et al, 2008). The mechanism by which amphetamines contribute to mitochondrial damage in peripheral organs is unknown, though it can be speculated that the drugs produce reactive oxygen species subsequent to the metabolism of the drugs in the liver by the cytochrome p450 system, or secondarily as a result of the hyperthermic or cardiac effects of the drugs (Skibba et al, 1989, Wang et al, 1990, Hong et al, 1991, Cherner et al, 2010, Pourahmad et al, 2010). The significance of drug-mediated peripheral organ damage is highlighted by the dependence of the brain on peripheral organ function and that alterations in peripheral physiology can contribute to neuronal pathology.…”

Section: Emerging Mechanisms Of Neurotoxicitymentioning

confidence: 99%

Neurotoxicity of methamphetamine and 3,4-methylenedioxymethamphetamine

2014

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Amphetamines are a class of psychostimulant drugs that are widely abused for their stimulant, euphoric, empathogenic and hallucinogenic properties. Many of these effects result from acute increases in dopamine and serotonin neurotransmission. Subsequent to these acute effects, methamphetamine and 3,4 methylenedioxymethamphetamine (MDMA) produce persistent damage to dopamine and serotonin nerve terminals. This review summarizes the numerous interdependent mechanisms including excitotoxicity, mitochondrial damage and oxidative stress that have been demonstrated to contribute to this damage. Emerging non-neuronal mechanisms by which the drugs may contribute to monoaminergic terminal damage, as well as the neuropsychiatric consequences of this terminal damage are also presented. Methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) have similar chemical structures and pharmacologic properties compared to other abused substances including cathinone (khat), as well as a relatively new class of novel synthetic amphetamines known as ‘bath salts’ that have gained popularity amongst drug abusers.

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Involvement of mitochondrial/lysosomal toxic cross-talk in ecstasy induced liver toxicity under hyperthermic condition

Cited by 34 publications

References 33 publications

Peripheral Ammonia as a Mediator of Methamphetamine Neurotoxicity

Peripheral Ammonia as a Mediator of Methamphetamine Neurotoxicity

Methamphetamine causes acute hyperthermia‐dependent liver damage

Neurotoxicity of methamphetamine and 3,4-methylenedioxymethamphetamine

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