Reprint of: Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

Abstract

a b s t r a c tParkinson disease (PD) is a chronic and progressive neurological disease associated with a loss of dopaminergic neurons. In most cases the disease is sporadic but genetically inherited cases also exist. One of the major pathological features of PD is the presence of aggregates that localize in neuronal cytoplasm as Lewy bodies, mainly composed of a-synuclein (a-syn) and ubiquitin. The selective degeneration of dopaminergic neurons suggests that dopamine itself may contribute to the neurodegenerative process in PD. Furthermore, mitochondrial dysfunction and oxidative stress constitute key pathogenic events of this disorder. Thus, in this review we give an actual perspective to classical pathways involving these two mechanisms of neurodegeneration, including the role of dopamine in sporadic and familial PD, as well as in the case of abuse of amphetamine-type drugs. Mutations in genes related to familial PD causing autosomal dominant or recessive forms may also have crucial effects on mitochondrial morphology, function, and oxidative stress. Environmental factors, such as MPTP and rotenone, have been reported to induce selective degeneration of the nigrostriatal pathways leading to a-syn-positive inclusions, possibly by inhibiting mitochondrial complex I of the respiratory chain and subsequently increasing oxidative stress. Recently, increased risk for PD was found in amphetamine users. Amphetamine drugs have effects similar to those of other environmental factors for PD, because long-term exposure to these drugs leads to dopamine depletion. Moreover, amphetamine neurotoxicity involves a-syn aggregation, mitochondrial dysfunction, and oxidative stress. Therefore, dopamine and related oxidative stress, as well as mitochondrial dysfunction, seem to be common links between PD and amphetamine neurotoxicity.

Effects of Partial Inhibition of Respiratory Complex I on H2O2 Production by Isolated Brain Mitochondria in Different Respiratory States

“…Under these circumstances, oxidative stress will be the most important factor favoring neurodegeneration by partial complex I inhibition. In fact, oxidative damage has been shown to be associated with the dopaminergic neurodegeneration observed in PD [13,[51][52][53][54].…”

Toxicological aspects of trans fat consumption over two sequential generations of rats: Oxidative damage and preference for amphetamine

“…Chronically, this cascade reaction generates DA quinones, which are closely related to oxidative insults (Perfeito et al, 2013;Carvalho et al, 2012;Sulzer, 2011), especially in mesocorticolimbic and hippocampal brain areas, where DA exerts a critical role.…”

Signaling Mechanisms in the Nitric Oxide Donor- and Amphetamine-Induced Dopamine Release in Mesencephalic Primary Cultured Neurons

“…DA itself is strongly pro-oxidant, forming hydrogen peroxide and free radicals through autoxidation and normal metabolism, hence deregulating DA signaling and contributing to neurotoxicity (Hastings 2009). The autoxidation of the catechol ring of DA produces superoxide and hydrogen peroxide, which may react with transition metal ions producing the highly toxic hydroxyl radical, while the superoxide may also react with NO, forming the highly toxic ONOO- (Perfeito et al 2013). Therefore, the decrease in the NOC-12-induced DA release or Amphpotentiated effect observed after 30 min may be related to these oxidative mechanisms.…”

“…In fact, the neurotoxicity caused by Amph and the neurodegenerative process observed in Parkinson's disease seem to involve similar sources of oxidative stress, characterized by a redox imbalance between free radicals or other ROS and antioxidant defenses, where NO has an important role (Perfeito et al 2013).…”