Subcutaneous Rotenone Exposure Causes Highly Selective Dopaminergic Degeneration and α-Synuclein Aggregation

Mutational analysis of DJ-1 in Drosophila implicates functional inactivation by oxidative damage and aging

“…Dopaminergic neurons are thought to have high basal levels of oxidative stress due to the highly reactive nature of dopamine (9)(10)(11). Exposure to environmental agents that induce further oxidative stress leads to selective dopaminergic neuron degeneration in animal models (6,(12)(13)(14)(15)(16), reflective of increased risk by such agents for Parkinson's disease in humans (5,12,(17)(18)(19)(20)(21)(22).…”

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

“…In particular, amphetamines were previously described to induce neuronal inclusions and affect proteins belonging to the UPS, in the central nervous system [298]; moreover,ultrastructural and molecular changes were similar to those occurring in PD [299]. AmphetamineͲinduced neuronal inclusions present many features similar to those observed in PD, and the maturation of these inclusions can be reproduced by continuous exposure to parkinsonian neurotoxins such as rotenone [84,300]or MPTP [301].In mice, occurrence of neuronal inclusions combined with increased nigral expression of alphaͲsyn within dopaminergic neurons were found upon treatment with amphetamine derivatives [302], similarly to what occurs following administration of the parkinsonian toxin MPTP [303]. Furthermore, treatment of mice with methamphetamine increased markers of oxidative stress in the striatum and increased the levels of oligomeric alphaͲsyn in the SN [304].…”

“…A similar pathogenic mechanism was suggested for rotenone, a common naturally occurring botanical pesticide, which also acts as an inhibitor of the mitochondrial respiratory chain complex I and leads to a failure of the mitochondrial energy supply of the cell. Betarbet and coͲ workers (2000) showed that chronic treatment with rotenone was sufficient to cause typical features of PD, including loss of dopaminergic neurons andappearance ofalphaͲsyn positive inclusions in rodents [31,32]. The involvement of oxidative damage caused by mitochondrial dysfunction after rotenone treatment was also demonstrated in in vitro models, suggesting specific neuronal death by rotenone [33].…”

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

“…In particular, amphetamines were previously described to induce neuronal inclusions and affect proteins belonging to the UPS, in the central nervous system [299]; moreover, ultrastructural and molecular changes were similar to those occurring in PD [300]. Amphetamine-induced neuronal inclusions present many features similar to those observed in PD, and the maturation of these inclusions can be reproduced by continuous exposure to parkinsonian neurotoxins such as rotenone [84,301] or MPTP [302]. In mice, the occurrence of neuronal inclusions combined with increased nigral expression of a-syn within dopaminergic neurons was found upon treatment with amphetamine derivatives [303], similar to what occurs after administration of the parkinsonian toxin MPTP [304].…”

“…A similar pathogenic mechanism was suggested for rotenone, a common naturally occurring botanical pesticide, which also acts as an inhibitor of the mitochondrial respiratory chain complex I and leads to a failure of the mitochondrial energy supply of the cell. Betarbet and co-workers [31,32] showed that chronic treatment with rotenone was sufficient to cause typical features of PD, including loss of dopaminergic neurons and appearance of a-syn-positive inclusions in rodents. The involvement of oxidative damage caused by mitochondrial dysfunction after rotenone treatment was also demonstrated in in vitro models, suggesting specific neuronal death by rotenone [33].…”