Parkinson's Disease Substantia Research Articles

Complex I, iron, and ferritin in Parkinson's disease substantia nigra.

Elevated iron levels, enhanced oxidative damage, and complex I deficiency have been identified in the substantia nigra of Parkinson's disease patients. To understand the interrelationship of these abnormalities, we analyzed iron levels, ferritin levels, and complex I activity in the substantia nigra of patients with Parkinson's disease. Total iron levels were increased significantly, ferritin levels were unchanged, and complex I activities were decreased significantly in the substantia nigra samples. The failure of ferritin levels to increase with elevated iron concentrations suggests that the amount of reactive iron may increase in the substantia nigra of Parkinson's disease patients. There was no correlation between the iron levels and complex I activity or the iron-ferritin ratio and complex I activity in the substantia nigra samples.

Complex I Inhibitors Induce Dose‐Dependent Apoptosis in PC12 Cells: Relevance to Parkinson's Disease

The mode of cell death in Parkinson's disease (PD) substantia nigra is uncertain. However, evidence is accumulating that certain of the biochemical abnormalities present in PD nigra at the time of death may precipitate apoptosis. We have investigated the mode of death induced by complex I inhibition of dopaminergic cell cultures, and our results suggest that both 1-methyl-4-phenylpyridinium and rotenone cause apoptosis at low concentrations and necrosis at high concentrations. This dose-dependent shift in the mode of cell death induced by these mitochondrial toxins may have important implications for the mechanisms of neuronal cell death in PD.

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

Previous studies examining the involvement of oxidative stress in the substantia nigra in Parkinson's disease have measured terminal products of lipid peroxidation or the function of antioxidant defense systems. We report a more specific early marker of lipid peroxidation, lipid hydroperoxides, in a high-performance liquid chromatography (HPLC) and electron spin resonance (ESR) investigation. HPLC-chemiluminescent detection revealed two classes of lipid hydroperoxides in brain tissue extracts--free fatty acid hydroperoxides and cholesterol lipid hydroperoxides. Only cholesterol lipid hydroperoxides were consistently detected in all tissue extracts. Cholesterol lipid hydroperoxides had a 10-fold increase in the Parkinson's disease substantia nigra compared to control subjects. ESR detection of radical degradation products, including those of lipid hydroperoxides, in nigral homogenates incubated with the spin trap N-t-butyl-alpha-phenyl nitrone (PBN) showed a marked variation in ESR signal between tissues. Despite the increased levels of lipid hydroperoxides in parkinsonian substantia nigra, there was no overall difference in ESR signal intensity between nigral tissues from controls and from patients with Parkinson's disease. The increased levels of an early component of the peroxidation chain in substantia nigra in Parkinson's disease support the hypothesis of a continuous toxic process involving oxygen radical activity. However, using previously frozen tissue, ESR evidence for increased radical formation could not be demonstrated.

Neurofilament mRNA is reduced in Parkinson's disease substantia nigra pars compacta neurons.

Lewy bodies are filamentous neuronal inclusions characteristic of Parkinson's disease, and neurofilament triplet proteins are the major components of the filaments in Lewy bodies. Since the neurofilament proteins found in Lewy bodies are abnormally phosphorylated and partially degraded, the formation of Lewy bodies may be due to the defective metabolism of these proteins, and this could lead to impairments in the structure and function of neurofilament rich neuronal processes (i.e., large caliber axons). To gain further insights into the metabolism of neurofilaments in Parkinson's disease, we evaluated neurofilament mRNA levels by semi-quantitative in situ hybridization histochemistry in postmortem tissues from Parkinson's disease and control subjects. Substantia nigra pars compacta neurons were examined with digoxigenin-UTP labeled cRNA probes to the heavy and light neurofilament mRNAs. The relative abundance of these mRNAs was measured by videodensitometric image analysis of chromogenic reaction product. Using this approach, we demonstrated that the levels of both heavy and light neurofilament mRNAs were reduced in Parkinson's disease substantia nigra pars compacta neurons. Additionally, the levels of heavy neurofilament mRNA were lowest in Lewy body containing neurons in the Parkinson's disease cases. These results suggest that the formation of neurofilament-rich Lewy bodies in substantia nigra pars compacta neurons is associated with reduced levels of the heavy and light neurofilament mRNAs in Parkinson's disease. Thus, it is possible that the accumulation of abnormal neurofilament proteins in Lewy bodies and diminished neurofilament mRNAs contribute to the degeneration of substantia nigra pars compacta neurons in Parkinson's disease.

Irreversible Inhibition of Mitochondrial Complex I by 1‐Methyl‐4‐Phenylpyridinium: Evidence for Free Radical Involvement

Incubation of 10 mM 1-methyl-4-phenylpyridinium (MPP+) with sonicated beef heart mitochondria caused an irreversible time-dependent decrease in NADH-ubiquinone-1 (CoQ1) reductase activity (52% inhibition after 1 h). Inclusion of glutathione, ascorbate, or catalase in the incubation mixture protected the NADH-CoQ1 reductase activity. These results suggest that the interaction of MPP+ with complex I induces free radical generation, which in turn leads to the irreversible inhibition of complex I activity. The generation of free radicals by neurotoxin-induced inhibition of complex I has important implications for our interpretation of the increased oxidative stress observed in Parkinson's disease substantia nigra and for our understanding of the cause(s) of dopaminergic cell death in this disorder.

Excitatory amino acidergic pathways and receptors in the basal ganglia

The striatum receives the majority of excitatory amino acidergic input to the basal ganglia from neocortical and allocortical sources. The subthalamic nucleus and the substantia nigra also receive excitatory amino acidergic inputs from neocortex. The subthalamic nucleus, which has prominent projections to the pallidum and nigra, is the only known intrinsic excitatory amino acidergic component of the basal ganglia. Possible excitatory amino acidergic inputs reach the basal ganglia from the intralaminar thalamic nuclei and the pedunculo-pontine nucleus. The striatum is richly endowed with all subtypes of excitatory amino acid receptors and these appear to be inhomogeneously distributed within the striatal complex. The non-striatal nuclei contain lesser levels of excitatory amino acid receptors and the relative proportion of these receptors varies between nuclei. The presence of high densities of excitatory amino acid receptors is a phylogenetically conserved feature of the striatum and its non-mammalian homologues. In Huntington's disease, there is substantial depletion ofα-amino-3-hydroxy-5-methylisoxazole-4-propionic acid, N-methyl-D-aspartate, and kainate receptors within the striatum. In Parkinson's disease substantia nigra, there is significant loss of N-methyl-D-aspartate andα-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors.

Glutathione peroxidase activity in Parkinson's disease brain

Glutathione peroxidase is an enzyme of major importance in the detoxification of peroxides in brain. Using the spectrophotometric procedure of Paglia and Valentine [8] and Beutler [2] we measured the activity of this enzyme in autopsied brain from 12 patients dying with idiopathic Parkinson's disease and 11 neurologically normal adults matched with respect to age and postmortem interval. In the Parkinson's disease patients glutathione peroxidase activity was slightly but significantly reduced in several brain areas including substantia nigra. Although the magnitude of the glutathione peroxidase deficiency in Parkinson's disease substantia nigra was small (19% reduction), coupled with the reported marked deficiency of reduced glutathione [9] it may represent one of the contributing factors leading to nigral dopamine neurone loss.