title: L-DOPA: a scapegoat for accelerated neurodegeneration in Parkinson's disease?
abstract: There is consensus that amelioration of the motor symptoms of Parkinson's disease is most effective with L-DOPA (levodopa). However, this necessary therapeutic step is biased by an enduring belief that L-DOPA is toxic to the remaining substantia nigra dopaminergic neurons by itself, or by specific metabolites such as dopamine. The concept of L-DOPA toxicity originated from pre-clinical studies conducted mainly in cell culture, demonstrating that L-DOPA or its derivatives damage dopaminergic neurons due to oxidative stress and other mechanisms. However, the in vitro data remain controversial as some studies showed neuroprotective, rather than toxic action of the drug. The relevance of this debate needs to be considered in the context of the studies conducted on animals and in clinical trials that do not provide convincing evidence for L-DOPA toxicity in vivo. This review presents the current views on the pathophysiology of Parkinson's disease, focusing on mitochondrial dysfunction and oxidative/proteolytic stress, the factors that can be affected by L-DOPA or its metabolites. We then critically discuss the evidence supporting the two opposing views on the effects of L-DOPA in vitro, as well as the animal and human data. We also address the problem of inadequate experimental models used in these studies. L-DOPA remains the symptomatic 'hero' of Parkinson's disease. Whether it contributes to degeneration of nigral dopaminergic neurons, or is a 'scapegoat' for explaining undesirable or unexpected effects of the treatment, remains a hotly debated topic.
authors: Department of Physiology and Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, 85 Park Rd., Auckland 1142, New Zealand. j.lipski@auckland.ac.nz
authors: Janusz
authors: J
authors: Lipski
authors: Robert
authors: R
authors: Nistico
authors: Nicola
authors: N
authors: Berretta
authors: Ezia
authors: E
authors: Guatteo
authors: Giorgio
authors: G
authors: Bernardi
authors: Nicola B
authors: NB
authors: Mercuri
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects* / Q000627:therapeutic use*; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism; D006801:Humans; D007980:Levodopa / Q000009:adverse effects* / Q000378:metabolism / Q000627:therapeutic use*; D008928:Mitochondria / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000473:pathology; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology
chemical_list: D000978:Antiparkinson Agents; D007980:Levodopa; D004298:Dopamine