Neuronal degeneration

Lewy bodies are typical in neuronal degeneration, which is accompanied by the presence of these eosinophilic intracellular inclusions of 5-25 pm diameter in a proportion of still surviving neurons. Lewy bodies contain neurofilament, tubulin, microtubule-associated proteins 1 and 2, and gelsolin, an actin-modulating protein. 

Clearly a disorder eombining (1) with (a) would mean that little improvement could be expeeted by manipulating the lost NT, since the nerves are no longer there to release it physiologieally. The main hope then would be to try to replenish the neurons with transplants (regeneration may be possible one day) and hope they become appropriately innervated, or modify the action of some other NT which has become exaggerated (or redueed), as a result of the primary NT loss. By contrast it is easier to treat a disorder, whether eharaeterised by neuronal degeneration ((1) above) or not (2), if it is suffieient just to provide NT (b), as appears to be the case in Parkinsonism. 

Hirsch, EC and Hunot, S (2000) Nitric oxide, glial cells and neuronal degeneration in Parkinsonism. Trends Pharmacol. Sci. 21 163-165. 

Although there is no evidence that the neuronal degeneration of AzD results, as in cardiovascular ischaemia, from the excitotoxicity of increased intracellular Ca +, some calcium channel blockers have been tried in AzD. They have had little effect but surprisingly a pyrrolidone derivative nefiracetam, which opens L-type voltage-sensitive calcium channels (VSCCs) reduces both scopolamine- and )S-amyloid-induced impairments of learning and memory in rats (Yamada et al. 1999). This effect can be overcome by VSCC antagonists, but nefiracetam has not been tried in humans. 

Neurotoxieity of METH was shown to oeeur in rats by virtue of the facts that (1) levels of DA and aetivity of the enzyme that is rate limiting for DA synthesis were deereased for a long period after eessation of drug treatment (Rieaurte et al. 1980 Rieaurte et al. 1982 Hotehkiss et al. 1979) (2) the number of reuptake sites for DA were redueed (Rieaurte et al. 1980 Rieaurte et al. 1982) and (3) there was shown to be neuronal degeneration in DA-rieh areas of the brain (Rieaurte et al. 1982 Rieaurte et al, 1984). 

Previous studies have also indicated that fenfluramine produces signs of neuronal degeneration (Harvey and McMaster 1975 Harvey and McMaster 1977 Harvey et al. 1977). Recent immunohistochemical studies also indicated that fenfluramine produced morphological damage to 5-HT terminal fields (Appel and De Souza 1988). Collectively, the neurochemical and histological data support the idea that fenfluramine is neurotoxic to 5-HT. 

Moore, R.Y., and Heller, A. Monoamine levels and neuronal degeneration in rat brain following lateral hypothalamic lesions. J Pharmacol Exp Ther 156 12-22, 1967. 

PD affects approximately one million Americans (1% of people over 60 years of age). The average age of onset is 60 years of age, and PD is fairly uncommon in those under age 40. The etiology of PD is unknown, but genetic predisposition, environmental factors, or combinations of these have been proposed to explain why nerve cells in the substantia nigra deteriorate. About 15% of patients with PD have a first-degree relative with the disease. The pathogenesis of cell death (neuron degeneration) may be due to oxidative stress, mitochondrial... 

Human prion disease models have also been developed in mice [154,155]. Crossing the species barrier into an experimentally accessible animal system, the prions responsible for Creutzfeldt Jakob disease, new variant CJD, Gerstmann-Straussler-Scheinker disease, and fatal familial insomnia produce a reproducible time-dependent neuronal degeneration leading to death. 

Other diseases with disruptions in neurofilament organization include diabetic neuropathy and Charcot-Marie-Tooth disease. For these diseases, the disruption of neuro filaments may be a secondary effect as in the case of trembler axons or a direct effect. For example, some forms of Charcot-Marie-Tooth peripheral neuropathy result from mutations in a neurofilament subunit [22, 43]. In most cases, neuronal degeneration is an eventual consequence, but neuronal function may be impaired prior to substantial loss of neurons. Generally, disruptions of neurofilaments have the most severe consequences in large motor neurons, which is consistent with the fact that the largest neurons have the highest levels of neurofilament expression. 

Hafezparast, M., Klocke, R., Ruhrberg, C. et al. Mutations in dynein link motor neuron degeneration to defects in retrograde transport. Science 300 808-812, 2003. 

Both NMDA and AMPA/kainate receptors contribute to excitotoxic neuronal degeneration of neurons and glia 563 Excitotoxicity leads to increased Ca2+ and Zn2+, which can activate cytotoxic intracellular pathways 564... 

Both NMDA and AMPA/kainate receptors contribute to excitotoxic neuronal degeneration of neurons and glia. 

Alzheimer s disease, Parkinson s disease, Huntington s disease and amyotrophic lateral sclerosis (ALS) are four prominent fatal neurodegenerative disorders that involve the death of specific populations of neurons (see details in respective chapters). Studies of patients and animal and culture models have provided considerable insight in the cellular and molecular mechanisms responsible for synaptic dysfunction and neuronal degeneration in each disorder [18], In Alzheimer s disease, abnormalities in proteolytic processing of the amyloid precursor protein, due to gene... 

Oosthuyse, B., Moons, L., Storkebaum, E. et al. Deletion of the hypoxia-response element in the vascular endothelial growth factor promotor causes motor neuron degeneration. Nat. Genet. 28 131-138, 2001. 

Gurney, M. E., Pu, H., Chiu, A. Y. etal. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 264 1772-1775,1994. 

Wang, J., Xu, G., Gonzales, V. et al. Fibrillar inclusions and motor neuron degeneration in transgenic mice expressing superoxide dismutase 1 with a disrupted copper-binding site. Neurobiol. Dis 10 128-138,2002. 

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