L-DOPA-induced hyperhomocysteinemia in Parkinson's disease: Elephant in the room

Biochim Biophys Acta. 2016 Sep;1860(9):1989-97. doi: 10.1016/j.bbagen.2016.06.018. Epub 2016 Jun 16.


Background: Dopamine replacement therapy by its precursor, L-3.4-dihydroxyphenylalanine (L-DOPA), has been the treatment of choice for Parkinson's disease. However, the possible contributory effect of L-DOPA therapy on the progression of Parkinson's disease mediated by the L-DOPA-induced toxic metabolites remains elusive.

Scope of review: Prolong use of L-DOPA leads to behavioral impediments and instigate the generation of several toxic metabolites. One such metabolite is homocysteine, the level of which increases in the plasma of Parkinson's disease patients undergoing L-DOPA therapy, as well as in brain of animal models of the disease. In concoction with parkinsonian neurotoxins, Hcy exaggerates dopaminergic neurodegeneration, while its intranigral infusion has been demonstrated to decrease the dopamine level as well as causes dopaminergic neurodegeneration. Therefore, it can be propounded that elevated level of Hcy (hyperhomocysteinemia) is one of the underlying causes of L-DOPA-induced side-effects and aggravates the progressive nature of Parkinson's disease, which has been focused here. We have provided a conjectural discussion on the involvement of Hcy in L-DOPA-induced dyskinesia in Parkinson's disease.

Conclusion: Hyperhomocysteinemia as a result of prolonged L-DOPA therapy is the emerging cause of L-DOPA-induced behavioral abnormalities and progressive nature of Parkinson's disease.

General significance: This review highlights that hyperhomocysteinemia could be a putative contributor of the side-effects of chronic L-DOPA therapy because of its neurotoxic potency.

Keywords: Catechol O-methyl transferase; Dopaminergic neurons; Dyskinesia; Homocysteine; Neurotoxicity; Oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antiparkinson Agents / adverse effects
  • Antiparkinson Agents / therapeutic use
  • Behavior, Animal / drug effects
  • Brain / drug effects
  • Brain / metabolism
  • Dopamine / metabolism
  • Humans
  • Hyperhomocysteinemia / chemically induced*
  • Levodopa / adverse effects*
  • Levodopa / pharmacology*
  • Levodopa / therapeutic use*
  • Parkinson Disease / drug therapy*
  • Parkinson Disease / metabolism


  • Antiparkinson Agents
  • Levodopa
  • Dopamine