Pesticides and impairment of mitochondrial function in relation with the parkinsonian syndrome

Department of Biochemistry and Molecular Biology, School of Medicine, University of Cadiz, 11003-Cadiz, Spain.
Frontiers in Bioscience (Impact Factor: 3.52). 02/2007; 12(3):1079-93. DOI: 10.2741/2128
Source: PubMed


The Parkinsonian syndrome induced by pesticides is associated with the impairment of mitochondrial function. Toxicants that inhibit selectively NADH-dehydrogenase activity, as rotenone or pyridaben, also show a selective inhibition of O2 uptake and respiratory control in rat brain mitochondria in the presence of NAD-dependent substrates. The IC50 of rotenone and pyridaben for complex I inhibition were in the range 1.7-2.2 microM. The determination of NADH-cytochrome c reductase, succinate-cytochrome c reductase and cytochrome oxidase activities in rat brain submitochondrial showed again the selective inhibition of Complex I by rotenone and pyridaben, whereas paraquat produced a non-selective inhibition affecting all the respiratory chain complexes. In rat brain mitochondria, rotenone and pyridaben markedly decreased mtNOS functional activity with NAD-dependent substrates but not when the substrate was succinate. This observation suggest than mtNOS activity is regulated by the activity of complex I. This regulation and the role of mitochondrial NO diffusion as a signal for mitochondrial biogenesis could have a role in the etiopathology of Parkinson's disease.

Full-text preview

Available from:
  • Source
    • "The interlinked roles of NMDA receptors and mitochondria are central to excitotoxic injuries resulting from glutamate exposure and perturbations in the respiratory chain [40], [41], [48]. Mitochondrial complex I is a common target of pesticides, including rotenone, which is a potent mitochondrial complex I inhibitor with an IC50 of ≈2 µM [49], [50]. Moreover, BBR is suggested to directly interfere with mitochondrial complex I [11]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The global incidence of metabolic and age-related diseases, including type 2 diabetes and Alzheimer's disease, is on the rise. In addition to traditional pharmacotherapy, drug candidates from complementary and alternative medicine are actively being pursued for further drug development. Berberine, a nutraceutical traditionally used as an antibiotic, has recently been proposed to act as a multi-target protective agent against type 2 diabetes, dyslipidemias, ischemic brain injury and neurodegenerative diseases, such as Parkinson's and Alzheimer's disease. However, the safety profile of berberine remains controversial, as isolated reports suggest risks with acute toxicity, bradycardia and exacerbation of neurodegeneration. We report that low micromolar berberine causes rapid mitochondria-dependent toxicity in primary neurons characterized by mitochondrial swelling, increased oxidative stress, decreased mitochondrial membrane potential and depletion of ATP content. Berberine does not induce caspase-3 activation and the resulting neurotoxicity remains unaffected by pan-caspase inhibitor treatment. Interestingly, inhibition of NMDA receptors by memantine and MK-801 completely blocked berberine-induced neurotoxicity. Additionally, subtoxic nanomolar concentrations of berberine were sufficient to sensitize neurons to glutamate excitotoxicity and rotenone injury. Our study highlights the need for further safety assessment of berberine, especially due to its tendency to accumulate in the CNS and the risk of potential neurotoxicity as a consequence of increasing bioavailability of berberine.
    Full-text · Article · Sep 2014 · PLoS ONE
    • "Widespread attention has been paid to rotenone as a potential cause of Parkinsonism. Recent studies have shown that long-term exposure to rotenone may cause changes at the cellular level in the form of injury to central dopaminergic neurons, obvious degeneration and apoptosis of substantia nigra dopaminergic neurons and the appearance of Lewy bodies in neurons, tremor, unsteady gait and other Parkinson's disease symptoms[2223]. Currently, the precise mechanisms underlying rotenone-induced apoptosis in dopaminergic neurons are unclear. In the cell injury induced by rotenone, the following processes are known to participate: increased levels of reactive oxygen species; lipid peroxidation; progressive glutathione deficiency; mitochondrial depolarization; release of cytochrome C; and activation of caspase-3[24252627]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In this study, we established cell models for Parkinson's disease using rotenone. An RNA interference vector targeting Parkin-associated endothelin receptor-like receptor (Pael-R) was transfected into the model cells. The results of reverse-transcription polymerase chain reaction and western blot analysis showed that Pael-R expression was decreased after RNA interference compared with the control group (no treatment) and the model group (rotenone treatment), while the rate of apoptosis and survival of dopaminergic cells did not differ significantly between groups, as detected by flow cytometry and an MTT assay. These experimental findings indicate that the Pael-R gene has no role in the changes in rotenone-induced Parkinson's disease model cells.
    No preview · Article · Feb 2014 · Neural Regeneration Research
  • Source
    • "Pyridaben has been studied for its acute toxicity in different species (3, 4). The inhabitation of complex I by pyridaben directs mtNOS to loose it’s NO producing activity and to become an O2- source (4-6). "
    [Show abstract] [Hide abstract]
    ABSTRACT: A B S T R A C T Objective(s): The adverse effects of pyridaben on reproductive system in male animals are not well established. This study was designed to elucidate how pyridaben can effects the histomorphometric, hormonal alternations and reproductive functions of BALB/c mice. Materials and Methods: For this study, 80 adult and apparently healthy male BALB/c mice were divided into three groups Viz, control, test group 1 and test group 2. Test groups 1 and 2 were received the toxin at doses of 53 mg/kg. BW, and 212 mg/kg. BW, respectively. The experiment period for both groups was 10, 25 and 45 days. Results: The levels of FSH, LH and testosterone were significantly (P<0.05) decreased on the dose and time dependant means. The levels of the ROS and NOS were significantly (P<0.05) increased in all test groups. The percent body weight gains significantly (P<0.05) reduced, whereas weights significantly (P<0.05) increased in test groups in a dose and time dependant manner. The histomorphometric and stereologic findings, including diameters of somniferous tubules, thickness of somniferous tubules epithelium, the leydig's cell distribution, TDI, SI, RI revealed that, all these parameters are also significantly (P<0.05) reduces in test groups in a dose and time dependant manner. Conclusion: Pyridaben causes histomorphometric and stereologic changes in testis, as well as hormonal and reproductive functional alternations in BALB/c mice.
    Full-text · Article · Oct 2013 · Iranian Journal of Basic Medical Sciences
Show more