Increased levels of lipid hydroperoxides in the parkinsonian substantia nigra: An HPLC and ESR study

Oxidative stress appears to be directly involved in the pathogenesis of the neurodegeneration of dopaminergic systems in Parkinson disease. In this study, we formed four dopamine modification adducts derived from docosahexaenoic acid (C22:6/ -3) and arachidonic acid (C18:4/-6), which are known as the major polyunsaturated fatty acids in the brain. Upon incubation of dopamine with fatty acid hydroperoxides and an in vivo experiment using rat brain tissue, all four dopamine adducts were detected. Furthermore, hexanoyl dopamine (HED), an arachidonic acid-derived adduct, caused severe cytotoxicity in human dopaminergic neuroblastoma SH-SY5Y cells, whereas the other adducts were only slightly affected. The HED-induced cell death was found to include apoptosis, which also seems to be mediated by reactive oxygen species generation and mitochondrial abnormality. Additionally, the experiments using monoamine transporter inhibitor and mouse embryonic fibroblast NIH-3T3 cells that lack the monoamine transporter indicate that the HED-induced cytotoxicity might specially occur in the neuronal cells. These data suggest that the formation of the docosahexaenoic acid-and arachidonic acid-derived dopamine adducts in vitro and in vivo, and HED, the arachidonic acid-derived dopamine modification adduct, which caused selective cytotoxicity of neuronal cells, may indicate a novel mechanism responsible for the pathogenesis in Parkinson disease.

Section: Discussionmentioning

confidence: 99%

Formation of Dopamine Adducts Derived from Brain Polyunsaturated Fatty Acids

Liu

Yamada

Maruyama³

et al. 2008

“…Decreased levels of the thiolic antioxidant glutathione (GSH) have been reported in the substantia nigra of PD patients (2)(3)(4), as well as iron accumulation (3,5,6) and decreased mitochondrial complex I (7,8) and ␣-ketoglutarate dehydrogenase (9) activities. In addition, biochemical markers of lipid peroxidation (10,11) and nitric oxide (NO) overproduction, i.e. increased nitrite concentration in cerebrospinal fluid (12), NO radicals detected in PD nigra (13), increased 3-nitrotyrosine immunostaining in Lewy bodies (14), and ␣-synuclein nitration (15) have been found in PD brains.…”

mentioning

confidence: 99%

Nitric Oxide Triggers the Toxicity due to Glutathione Depletion in Midbrain Cultures through 12-Lipoxygenase

Canals¹,

Casarejos

Bernardo

et al. 2003

100

Glutathione (GSH) depletion is the earliest biochemical alteration shown to date in brains ofHere we demonstrate that arachidonic acid (AA) metabolism through the 12-lipoxygenase (12-LOX) pathway is also central for this GSH-NO interaction. LOX inhibitors (nordihydroguaiaretic acid and baicalein), but not cyclooxygenase (indomethacin) or epoxygenase (clotrimazole) ones, prevent cell death in the culture, even when added 10 h after NO treatment. Furthermore, the addition of AA to GSH-depleted cultures precipitates a cell death process that is indistinguishable from that initiated by NO in its morphology, time course, and 12-LOX, GC, and PKG dependence. The first AA metabolite through the 12-LOX enzyme, 12-hydroperoxyeicosatetraenoic acid, induces cell death in the culture, and its toxicity is greatly enhanced by GSH depletion. In addition we show that if GSH synthesis inhibition persists for up to 4 days without any additional treatment, it will induce a cell death process that also depends on 12-LOX, GC, and PKG activation. In this study, therefore, we show that the signaling pathway AA/12-LOX/12-HPETE/GC/ PKG may be important in several pathologies in which GSH decrease has been documented, such as Parkinson's disease. The potentiating effect of NO over such a signaling pathway may be of relevance as part of the cascade of events leading to and sustaining nerve cell death.

“…H 2 O 2 can react with ferrous (Fe 2ϩ ) iron to produce hydroxyl radicals (OH⅐), which can damage nearby proteins, nucleic acids, and membrane phospholipids (1). Iron levels are increased in the SN of PD patients along with elevations in various indices of oxidative damage (2)(3)(4).…”

mentioning

confidence: 99%

Glutathione Depletion in PC12 Results in Selective Inhibition of Mitochondrial Complex I Activity

Jha¹,

Jurma²,

Lalli³

et al. 2000

239

173

Oxidative stress appears to play an important role in degeneration of dopaminergic neurons of the substantia nigra (SN) associated with Parkinson's disease (PD). The SN of early PD patients have dramatically decreased levels of the thiol tripeptide glutathione (GSH). GSH plays multiple roles in the nervous system both as an antioxidant and a redox modulator. We have generated dopaminergic PC12 cell lines in which levels of GSH can be inducibly down-regulated via doxycycline induction of antisense messages against both the heavy and light subunits of ␥-glutamyl-cysteine synthetase, the rate-limiting enzyme in glutathione synthesis. Down-regulation of glutamyl-cysteine synthetase results in reduction in mitochondrial GSH levels, increased oxidative stress, and decreased mitochondrial function. Interestingly, decreases in mitochondrial activities in GSH-depleted PC12 cells appears to be because of a selective inhibition of complex I activity as a result of thiol oxidation. These results suggest that the early observed GSH losses in the SN may be directly responsible for the noted decreases in complex I activity and the subsequent mitochondrial dysfunction, which ultimately leads to dopaminergic cell death associated with PD.