Substantia nigra in Parkinson’s disease

The number of neurons may decrease in some areas, such as substantia nigra (in Parkinson s disease), nucleus basalis of Meynert, the hippocampus, the adjacent temporal cortex, and olfactory pathways (in Alzheimer s disease). 

Both the histamine neuron innervation and the density of H3 receptors are increased in the substantia nigra of Parkinsonian patients (Anichtchik et al. 2000 2001). The receptors probably are the H3 heteroreceptors on striato-nigral GABA terminals, and their increase may contribute to the depression of GABA release in the substantia nigra in Parkinson s disease (Garcia-Ramirez et al. 2004). 

Anichtchik OV, Rinne JO, Kalimo H, Panula P (2000) An altered histaminergic innervation of the substantia nigra in Parkinson s disease. Exp Neurol 163 20-30 Anichtchik OV, Peitsaro N, Rinne JO, Kalimo H, Panula P (2001) Distribution and modulation of histamine H3 receptors in basal ganglia and frontal cortex of healthy controls and patients with Parkinson s disease. Neurobiol Dis 8 707-16... 

Pearce RK, Owen A, Daniel S, Jenner P, Marsden CD (1997) Alterations in the distribution of glutathione in the substantia nigra in Parkinson s disease. J Neural Transm 104 661-677. 

Biomolecular investigation of human substantia nigra in Parkinson s disease by synchrotron radiation Fourier transform infrared microspectroscopy. Arch. Biochem. Biophys., 459, 241-8. 

Moller, A. (1992) Mean volume of pigmented neurons in the substantia nigra in Parkinson s disease. Acta Neurol. Scarul. 85 (Suppl. 137) 37-39. 

McNaught, K. S., and P. lenner. Proteasomal function is impaired in substantia nigra in Parkinson s disease. Neurosci Lett 297(3), 2001 191. ... 

Accumulation of the amyloid (3-peptide in Alzheimer s disease and the deposition of potentially pro-oxidant iron in certain brain regions, especially the substantia nigra, in Parkinson s disease [21]... 

Morris, C. M. Edwardson, J. A. Iron histochemistry of the substantia nigra in Parkinson s disease. Neurodegeneration 1994,3,277-282. 

The etiology of progressive death of dopaminergic neurons in substantia nigra of Parkinson s disease brains remains unclear. Dopamine deficiency in Parkinson s disease is commonly treated with L-dopa and carbidopa, a periphera dopa decarboxylase inhibitor (Sinemet). Since its introduction, L-dopa has been shown to be effective in treating Parkinson s disease. However, high concentrations of L-dopa produce side effects such as psychosis, on-off effects, abnormal involuntary movements, and akinetic crisis. 

What are the main inflaimnatory cells encountered in the substantia nigra of Parkinson s disease ... 

Hayashita-Kinoh H, Yamada M, Yokota T, Mizuno Y, Mochizuki H. Down-regulation of alpha-synuclein expression can rescue dopaminergic cells from cell death in the substantia nigra of Parkinson s disease rat model. Biochem Biophys Res Commun 2006 341 1088-1095. 

Adult dopamin-containing neurons in the substantia nigra rely on Cavl. 3 channels as pacemaker channels. It appears that the resulting enhanced Ca2+ load renders these channels more susceptible to neurotoxic effects and neurodegeneration as observed in Parkinson s disease. Preclinical evidence suggests that block of these with dihydropyridines causes a switch to a Cavl.3-independent pacemaker and protects these neurons from neurotoxicity. 

The new work has established that a neurodegenerative pathway leading from soluble to insoluble, filamentous a-synuclein is central to Lewy body diseases and multiple system atrophy. The development of experimental models of a-synucleinopathies has opened the way to the identification of the detailed mechanisms by which the formation of inclusions causes disease. These model systems have also made it possible to identify disease modifiers that may well lead to the development of the first mechanism-based therapies for these diseases. At a conceptual level, it will be important to understand whether a-synuclein has a role to play in disorders, such as autosomal-recessive juvenile forms of parkinsonism caused by mutations in the Parkin, DJ-1 and PINK-1 genes, or whether there are entirely separate mechanisms by which the dopaminergic nerve cells of the substantia nigra degenerate in Parkinson s disease and in inherited disorders with parkinsonism. 

The mechanism of the neurological symptoms in Parkinson s disease was discovered from the ability of reserpine to cause akinesia in humans by the depletion of central catecholamine stores. The dopamine levels in patients who died from parkinsonism were found to be extremely low because of deterioration of the dopaminergic neuronal cell bodies and the pathways connecting the substantia nigra with the corpus striatum. 

Functional circuitry between the cortex, basal ganglia, and thalamus. The major neurotransmitters are indicated. In Parkinson s disease, there is degeneration of the pars compacta of the substantia nigra, leading to overactivity in the indirect pathway (red) and increased glutamatergic activity by the subthalamic nucleus. 

Dopamine oxidation. In Parkinson s disease, cell death is localised to the dopamine-producing cells of the substantia nigra. Radicals are produced during the oxidation of DA, but whether the formation of these species is responsible for neuronal cell death or occurs as a consequence of cell turnover has not been established. Haque et al. have observed semiquinones from DA and is meta-... 

The pathological characteristic of Parkinson s disease is the selective degeneration of dopamine neurons in the pars compacta of the substantia nigra. The mechanism for the loss of neurons remains to be elucidated, and recently apoptosis has been proposed as a death process in Parkinson s disease. For example, the level of a product of the oxidative stress, 4-hydroxy-2-nonenal protein adduct, was found to increase in the nigral neurons of parkinsonian brains. Peroxynitrite (see Figure 13.6) has been proposed to be involved in the neuronal cell death in some neurodegenerative diseases, such as amyotrophic lateral sclerosis. 

Good PF, Olanow CW, Perl DP. 1992a. Neuromelanin-containing neurons of the substantia nigra accumulate iron and aluminum in Parkinson s disease A LAMMA study. Brain Res 593 343-346. 

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