Mitochondria: key players in the neurotoxic effects of amphetamines.
Amphetamines are a class of psychotropic drugs with high abuse potential, as a result of their stimulant, euphoric, emphathogenic, entactogenic, and hallucinogenic properties. Although most amphetamines are synthetic drugs, of which methamphetamine, amphetamine, and 3,4-methylenedioxymethamphetamine ("ecstasy") represent well-recognized examples, the use of natural related compounds, namely cathinone and ephedrine, has been part of the history of humankind for thousands of years. Resulting from their amphiphilic nature, these drugs can easily cross the blood-brain barrier and elicit their well-known psychotropic effects. In the field of amphetamines' research, there is a general consensus that mitochondrial-dependent pathways can provide a major understanding concerning pathological processes underlying the neurotoxicity of these drugs. These events include alterations on tricarboxylic acid cycle's enzymes functioning, inhibition of mitochondrial electron transport chain's complexes, perturbations of mitochondrial clearance mechanisms, interference with mitochondrial dynamics, as well as oxidative modifications in mitochondrial macromolecules. Additionally, other studies indicate that amphetamines-induced neuronal toxicity is closely regulated by B cell lymphoma 2 superfamily of proteins with consequent activation of caspase-mediated downstream cell death pathway. Understanding the molecular mechanisms at mitochondrial level involved in amphetamines' neurotoxicity can help in defining target pathways or molecules mediating these effects, as well as in developing putative therapeutic approaches to prevent or treat the acute- or long-lasting neuropsychiatric complications seen in human abusers.
UCIBIO/REQUIMTE (Rede de Química e Tecnologia), Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira 228, 4050-313, Porto, Portugal. daniel.barbosa@ff.up.pt.|Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal. daniel.barbosa@ff.up.pt.|IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua do Campo Alegre 823, 4150-180, Porto, Portugal. daniel.barbosa@ff.up.pt.
Daniel José
DJ
Barbosa
UCIBIO/REQUIMTE (Rede de Química e Tecnologia), Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira 228, 4050-313, Porto, Portugal.|FP-ENAS (Unidade de Investigação UFP em energia, Ambiente e Saúde), CEBIMED (Centro de Estudos em Biomedicina), Faculdade de Ciências da Saúde, Universidade Fernando Pessoa, Rua 9 de Abril 349, 4249-004, Porto, Portugal.
João Paulo
JP
Capela
UCIBIO/REQUIMTE (Rede de Química e Tecnologia), Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira 228, 4050-313, Porto, Portugal.
Rita
R
Feio-Azevedo
UCIBIO/REQUIMTE (Rede de Química e Tecnologia), Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira 228, 4050-313, Porto, Portugal.
Armanda
A
Teixeira-Gomes
UCIBIO/REQUIMTE (Rede de Química e Tecnologia), Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira 228, 4050-313, Porto, Portugal.
Maria de Lourdes
Mde L
Bastos
UCIBIO/REQUIMTE (Rede de Química e Tecnologia), Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira 228, 4050-313, Porto, Portugal. felixdc@ff.up.pt.
Félix
F
Carvalho
D019969:Amphetamine-Related Disorders / Q000150:complications*; D000662:Amphetamines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D004579:Electron Transport / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000187:drug effects*; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000503:physiopathology
D000662:Amphetamines; D000697:Central Nervous System Stimulants
3,4-Methylenedioxymethamphetamine (MDMA; “ecstasy”); Amphetamine (AMPH); Methamphetamine (METH); Mitochondria; Neurotoxicity; Oxidative stress