Abstract
Parkinsons disease (PD) is a complex neurodegenerative disorder characterised by dopaminergic cell loss in the substantia nigra. In addition, neurodegeneration occurs at a number of extra-nigral locations and involves a variety of non-dopaminergic neurotransmitter systems. Etiopathogenic mechanisms leading to cell death include oxidative stress and free radical generation, mitochondrial dysfunction, glutamate receptor mediated excitotoxicity, inflammation, oligodendrocytic interaction and neurotrophic factors, ubiquitin-proteosome system involvement, autophagy and apoptosis. Each of these is a potential target for novel pharmacotherapies including bioenergetic agents, inhibitors of excitotoxicity, neurotrophic factors, proteosomal enhancers and anti-apoptotic agents. Evidence has also been gained from cell culture and animal models for the potential disease modifying action of currently available dopaminergic therapies. These drugs have undergone clinical evaluation using studies with novel designs including “delayed start” methodology and studies using neuroimaging as a surrogate marker of dopaminergic cell loss. It is estimated from clinical, pathological and imaging studies that at least 50% of dopaminergic neurons are lost before the development of significant motor symptoms with a pre-motor phase of approximately 6-8 years. A number of pre- and post-synaptic neuroplastic homeostatic mechanisms occur during this period to maintain motor function. However these changes have been implicated in the development of motor complications (wearing “off” and dyskinesias). The evidence for treatments of motor complications in PD is discussed as are potential non-dopaminergic therapeutic targets to delay or improve motor complications.
Keywords: Parkinson's disease, Alpha-synuclein, PINK1, LRRK2, mitochondria, oxidative stress, Lewy body
Current Topics in Medicinal Chemistry
Title: Etiopathogenesis and Treatment of Parkinsons Disease
Volume: 9 Issue: 10
Author(s): David A. Gallagher and Anthony H. V. Schapira
Affiliation:
Keywords: Parkinson's disease, Alpha-synuclein, PINK1, LRRK2, mitochondria, oxidative stress, Lewy body
Abstract: Parkinsons disease (PD) is a complex neurodegenerative disorder characterised by dopaminergic cell loss in the substantia nigra. In addition, neurodegeneration occurs at a number of extra-nigral locations and involves a variety of non-dopaminergic neurotransmitter systems. Etiopathogenic mechanisms leading to cell death include oxidative stress and free radical generation, mitochondrial dysfunction, glutamate receptor mediated excitotoxicity, inflammation, oligodendrocytic interaction and neurotrophic factors, ubiquitin-proteosome system involvement, autophagy and apoptosis. Each of these is a potential target for novel pharmacotherapies including bioenergetic agents, inhibitors of excitotoxicity, neurotrophic factors, proteosomal enhancers and anti-apoptotic agents. Evidence has also been gained from cell culture and animal models for the potential disease modifying action of currently available dopaminergic therapies. These drugs have undergone clinical evaluation using studies with novel designs including “delayed start” methodology and studies using neuroimaging as a surrogate marker of dopaminergic cell loss. It is estimated from clinical, pathological and imaging studies that at least 50% of dopaminergic neurons are lost before the development of significant motor symptoms with a pre-motor phase of approximately 6-8 years. A number of pre- and post-synaptic neuroplastic homeostatic mechanisms occur during this period to maintain motor function. However these changes have been implicated in the development of motor complications (wearing “off” and dyskinesias). The evidence for treatments of motor complications in PD is discussed as are potential non-dopaminergic therapeutic targets to delay or improve motor complications.
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Cite this article as:
Gallagher A. David and Schapira H. V. Anthony, Etiopathogenesis and Treatment of Parkinsons Disease, Current Topics in Medicinal Chemistry 2009; 9 (10) . https://dx.doi.org/10.2174/156802609789378227
DOI https://dx.doi.org/10.2174/156802609789378227 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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