In support of a role for mitochondrial dysfunction in PD, inhibition of complex I of the electron transport chain (ETC) has been determined to be the mechanism of action of 1-Methyl-4-phenylpyridinium (MPP +) ( Nicklas and Heikkila, 1985 Richardson et al., 2007), the active metabolite of 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP) which has been demonstrated to induce parkinsonism ( Langston et al., 1983). Although the mechanism behind this association is unclear, oxidative stress and brain mitochondrial dysfunction, which has been implicated in neurodegenerative diseases, particularly PD (for reviews see Fiskum et al., 2003 Lin and Beal, 2006), has been proposed as a possible mechanism for the association of pesticides with PD.
Several epidemiological studies ( Priyardarshi et al., 2000 Ascherio et al., 2006 Frigerio et al., 2006 Kamel et al., 2007) have shown an association between pesticide exposure and increased risk of developing PD. Although the vast majority of affected patients have no clear causative factors, both genetic and environmental influences have been implicated ( Warner and Schapira, 2003 Kamel and Hoppin, 2004 BenMoyal-Segal and Soreq, 2006 Brown et al., 2006). Parkinson’s disease (PD) is a progressive neurological disorder characterized by abnormal posture, bradykinesia, rigidity, akinesia and resting tremor. Because mitochondrial dysfunction, oxidative damage, and decreased levels of DAT and VMAT2 are found in PD patients, our data suggests that mxc should be investigated as a possible candidate involved in the association of pesticides with increased risk for PD, particularly in highly-exposed populations. Mxc exposure also caused a dose-related decrease in striatal levels of dopamine (16–31%), which were accompanied by decreased levels of the dopamine transporter (DAT 35–48%) and the vesicular monoamine transporter 2 (VMAT2 21–44%). Following treatment, we observed a dose-related increase in protein carbonyl levels in non-synaptic mitochondria, indicating oxidative modification of mitochondrial proteins which may lead to mitochondrial dysfunction. Adult female CD1 mice were dosed with either vehicle (sesame oil) or mxc (16, 32, or 64 mg/kg/day) for 20 consecutive days.
Here, we sought to determine whether mxc-induced mitochondrial dysfunction results in oxidative damage and dysfunction of the dopamine system. Previously, we have found that the organochlorine pesticide methoxychlor (mxc) causes mitochondrial dysfunction and oxidative stress in isolated mitochondria. Although data on specific pesticides associated with PD are often lacking, several lines of evidence point to the potential involvement of the organochlorine class of pesticides. While the molecular mechanism underlying this association is not clear, several studies have demonstrated a role for mitochondrial dysfunction and oxidative damage in PD. Pesticide exposure has been suggested as an increased risk factor in developing Parkinson’s disease (PD).
0 kommentar(er)
