As oxidative stress had been clearly implicated in the pathogenesis of MPTP-induced parkinsonism,14,133 it was natural to focus to some extent, on environmental oxidants and inhibitors of mitochondrial respiration. Tetrahydroisoquinoline (TIQ) and β-carboline (β-C) derivatives, which are structurally related to MPTP and occur naturally in many foods, produce nigrostriatal damage in experimental animals and have been detected in brain and cerebrospinal fluid (CSF) in PD patients.106,134 As with MPTP’s conversion to MPP+, there is metabolic activation of TIQ

and β-C derivatives by conversion to quinolinium and β-carbolinium Inhibitors,research,lifescience,medical species, respectively, which are DAT substrates and appear to be toxic Inhibitors,research,lifescience,medical to mitochondria.106-134 Pesticides have also been suggested as possible causal or contributing factors in some cases of sporadic PD.105 Both paraquat,

and rotcnone arc potent inhibitors of mitochondrial complex I, and both are potentially neurotoxic.135,136 While neuronal toxicity of paraquat is generally lacking Inhibitors,research,lifescience,medical in specificity, rotenone has been shown to produce an excellent model of PD in rodents when administered chronically in low doses.137 Chronic infusions of rotenone produce selective degeneration of nigrostriatal DA neurons and formation of α-synuclein-positive LB-like structures, accompanied by signs of parkinsonism.138,139 Although epidemiological studies have often suggested a linkage between exposure to pesticides and development of PD,140,141 the interpretability

of such findings has generally been limited by uncertainties Inhibitors,research,lifescience,medical concerning the chemical identity, route, intensity, and duration of exposures.106,134 Oxidative stress Signs of oxidative stress are abundant in the substantia nigra of patients with PD.95 Mitochondrial complex I activity is depressed.142 Levels of intrinsic antioxidants, such as glutathione, are reduced,143 while oxidized products Inhibitors,research,lifescience,medical of proteins, lipids, and DNA increase significantly.144-147 Increasing levels of oxidative stress can LBH589 eventually lead to apoptosis through the intrinsic (or “mitochondrial”) PCD pathway due to cytoplasmic release of cytochrome c, which is Endonuclease proapoptotic, from dysfunctional mitochondria.104 Pathogenic factors peculiar to DA neurons Factors peculiar to midbrain DA neurons may enhance the risk of oxidative damage in SNc, though they clearly are not essential to the neurodegenerative process, as it affects most other vulnerable cell groups. Cytosolic DA can increase oxidative stress within nigral neurons by several routes. Spontaneous autooxidation of DA produces reactive DA-quinone species and the superoxide anion (O2·), as well as hydrogen peroxide (H2O2).148 When not sequestered in synaptic vesicles, DA can form complexes with cysteine that, inhibit mitochondrial complex I.