Neurotoxic Effects of Methamphetamine

Thrash, Bessy; Karuppagounder, Senthilkumar S.; Uthayathas, Subramaniam; Suppiramaniam, Vishnu; Dhanasekaran, Muralikrishnan

doi:10.1007/s11064-009-0042-5

Cited by 47 publications

(26 citation statements)

References 41 publications

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“…Chronic meth abusers detoxified for at least 11 months also displayed motor deficits [5] similar to patients with Parkinson’s disease. High dose meth treatment has also been shown to produce Parkinson’s disease-like lesions in numerous animal models [6]. Thus, preclinical studies complement the aforementioned clinical reports and show reductions in DA function in the striatum of rats following chronic meth administration [3,7], similar to the neuropathology displayed in early Parkinson’s disease [8].…”

Section: Introductionmentioning

confidence: 93%

Methamphetamine-induced vascular changes lead to striatal hypoxia and dopamine reduction

Kousik¹,

Graves²,

Napier³

et al. 2011

NeuroReport

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Methamphetamine (meth) is a potent psychostimulant known to cause neurotoxicity. Clinical reports suggest meth abuse is a risk factor for Parkinson’s disease. We investigated changes in the blood brain barrier and cerebral vasculature as a mechanism underlying this risk in rats treated acutely and trained to self-administer meth. We observed blood brain barrier leakage in rats treated acutely with meth. Hypoperfusion in the striatum was detected with acute and chronic meth treatment and associated with hypoxia. This was correlated with reductions in striatal tyrosine hydroxylase in rats trained to self-administer meth. These findings suggest a new mechanism of meth-induced neurotoxicity involving striatal vasoconstriction resulting in hypoxia and dopamine reductions leading to an increased risk for Parkinson’s disease for meth abusers.

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Section: Introductionmentioning

confidence: 93%

Methamphetamine-induced vascular changes lead to striatal hypoxia and dopamine reduction

Kousik¹,

Graves²,

Napier³

et al. 2011

NeuroReport

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“…( S )-(+)-Amphetamine [ 1b , (+)-AMP], which is a major metabolite of (+)-METH and a drug of abuse, and (+)-methylenedioxymethamphetamine, the stimulant-inducing chemical in the racemic mixture of (±)-methylenedioxymethamphetamine [ 2 , (±)-MDMA, commonly referred to as ecstasy] are two other widely abused and dangerous stimulants. The potency and stimulant effects of these (+)-METH-like compounds are influenced by the drug’s stereochemistry, with the (+)- or ( S )-isomers producing significantly more psychomimetic effects, stereotyped behavior and locomotor activity,8 and increased production of reactive oxygen species in mice 9. Given the medical importance of all three of these structurally related (+)- or ( S )-isomers, it could be medically advantageous to have a single mAb that could be used in the treatment of medical problems resulting from (+)-METH, (+)-AMP, and/or (+)-MDMA.…”

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confidence: 99%

The Synthesis of Haptens and Their Use for the Development of Monoclonal Antibodies for Treating Methamphetamine Abuse

et al. 2009

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In addition to addiction, the repeated use of (+)-methamphetamine [(+)-METH], (+)amphetamine [(+)-AMP], or (±)-methylenedioxymethamphetamine [(±)-MDMA, commonly called ecstasy] canlead to life-threatening medical problems including cardiovascular injury, severe depression, and psychosis. Currently, there are no specific pharmacotherapies to treat these medical problems. In this study, we report the design and synthesis of two haptens, (S)-(+)-3-(9-carboxynonyloxy) methamphetamine [3a, (+)-METHMO10] and (S)-(+)-3-(5-carboxypentyloxy)methamphetamine [3b, (+)-METH MO6], and their use in generating high affinity (low K D value) monoclonal antibodies (mAbs) against (+)-METH, (+)-AMP, and/or (+)-MDMA. Based on results from the determination of mAb K D values and ligand specificity, the mAbs generated from hapten 3a showed the greatest promise for generating active and passive immunotherapies for treating overdose or addiction from (+)-METH-like stimulants.The abuse of (S)-(+)-methamphetamine [1a-(+)-METH] a and other amphetamine-like stimulants continues to be a major health problem worldwide. 1-3 Indeed, a study by RAND Corporation estimates the economic cost of (+)-METH use in the United States in 2005 was $23.4 billion. 4 This comprehensive estimate includes the economic burden of addiction, premature death, drug treatment, and many other aspects of the drugs impact on Americans. The 2008 National Survey on Drug Use and Health estimates that over 12 million individuals, aged 12 and older, had used (+)-METH in their lifetime, that 850,000 million had used (+)-METH during the past year, and that 314,000 individuals had used (+)-METH during the last month, which defines them as current users. 5 At present there are no specific pharmacotherapies for managing adverse (+)-METH-induced effects like acute overdose and chronic addiction. Preclinical studies in rats show that systemic administration of anti-(+)-METH monoclonal antibodies (mAbs) can rapidly remove the drug from its sites of action in critical tissues like the brain and heart suggesting that immunotherapy could provide an important new medical strategy for addressing (+)-METH-induced adverse health effects in humans, while others suggest antibody catalyzed inactivation of METH could be a possible therapeutic approach. 7 (S)-(+)-Amphetamine [1b, (+)-AMP], which is a major metabolite of (+)-METH and a drug of abuse, and (+)-methylenedioxymethamphetamine, the stimulant-inducing chemical in the racemic mixture of (±)-methylenedioxymethamphetamine [2, (±)-MDMA, commonly referred to as ecstasy] are two other widely abused and dangerous stimulants. The potency and stimulant effects of these (+)-METH-like compounds are influenced by the drug's stereochemistry, with the (+)-or (S)-isomers producing significantly more psychomimetic effects, stereotyped behavior and locomotor activity, 8 and increased production of reactive oxygen species in mice. 9 Given the medical importance of all three of these structurally related (+)-or (S)-isomers, it could be medicall...

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“…This can lead to various neurological consequences, including motor slowing, verbal learning impairment, and psychiatric symptoms (4,5). These METH-induced neurological symptoms are in part mediated by a release of dopamine, a down-regulation of the dopamine transporter (6,7), and by an increase in excitotoxic signaling pathways (8,9). Despite the great need for treating these negative medical effects, currently no FDA-approved pharmacological treatments are available for the medical consequences of METH abuse.…”

Section: Introductionmentioning

confidence: 99%

PEGylation of a High-Affinity Anti-(+)Methamphetamine Single Chain Antibody Fragment Extends Functional Half-Life by Reducing Clearance

et al. 2016

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Purpose Methamphetamine (METH) abuse is a worldwide drug problem, yet no FDA-approved pharmacological treatments are available for METH abuse. Therefore, we produced an anti- METH single chain antibody fragment (scFv7F9Cys) as a pharmacological treatment for METH abuse. ScFv’s have a short half-life due to their small size, limiting their clinical use. Thus, we examined the pharmacokinetic effects of conjugating poly(ethylene) glycol (-PEG) to scFv7F9Cys to extend its functional half-life. Methods The affinity of scFv7F9Cys and PEG conjugates to METH was determined in vitro via equilibrium dialysis saturation binding. Pharmacokinetic and parameters of scFv7F9Cys and scFv7F9Cys-PEG20K (30 mg/kg i.v. each) and their ability to bind METH in vivo were determined in male Sprague-Dawley rats receiving a subcutaneous infusion of METH (3.2 mg/kg/day). Results Of three PEGylated conjugates, scFv7F9Cys-PEG20K was determined the most viable therapeutic candidate. PEGylation of scFv7F9Cys did not alter METH binding functionality in vitro, and produced a 27-fold increase in the in vivo half-life of the antibody fragment. Furthermore, total METH serum concentrations increased following scFv7F9Cys or scFv7F9Cys-PEG20K administration, with scFv7F9Cys-PEG20K producing significantly longer changes in METH distribution than scFv7F9Cys. Conclusions PEGylation of scFv7F9Cys significantly increase the functional half-life of scFv7F9Cys, suggesting it may be a long-lasting pharmacological treatment option for METH abuse.

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Neurotoxic Effects of Methamphetamine

Cited by 47 publications

References 41 publications

Methamphetamine-induced vascular changes lead to striatal hypoxia and dopamine reduction

Methamphetamine-induced vascular changes lead to striatal hypoxia and dopamine reduction

The Synthesis of Haptens and Their Use for the Development of Monoclonal Antibodies for Treating Methamphetamine Abuse

PEGylation of a High-Affinity Anti-(+)Methamphetamine Single Chain Antibody Fragment Extends Functional Half-Life by Reducing Clearance

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