Fluctuations in brain levels of levodopa play a key role in the production of dyskinesia (abnormal involuntary movements) and motor fluctuations in Parkinson's disease. This project explores the possibility that chronic treatment with levodopa induces the formation of new blood vessels with a leaky wall within the brain's basal ganglia. Such a process may modify the kinetics of levodopa transport from blood to brain in a way that favours the occurrence of dyskinesia and motor fluctuations.
Final Outcome
Working in a pre-clinical model of PD, Dr. Cenci and coworkers detected large and transient increases in brain levels of levodopa and dopamine during the expression of dyskinesia. In the same model, chronic treatment with levodopa was found to stimulate the growth of small blood vessels (a process termed “angiogenesis”) and to increase the permeability of the blood-brain barrier (BBB) in certain parts of the basal ganglia. Antiparkinsonian treatments inducing motor activation in the absence of dyskinesia did not have any of the above effects. The angiogenic action of levodopa was found to be mediated by one specific type of dopamine receptor (the D1 type) and to depend on the activation of intracellular signaling molecules termed “extracellular signal-regulated kinases 1 and 2 (ERK1/2)”. Pharmacological inhibition of either D1-type receptors or ERK1/2 suppressed both angiogenesis and dyskinesia in parkinsonian models treated with levodopa. Very recently, Dr. Cenci’s group has found that the development of certain forms of dyskinesia in the model can be attenuated by anti-angiogenic substances (the same sort of substances that are used to inhibit vessel growth in cancer). These results support the hypothesis that levodopa-induced angiogenesis (causing localized increases in BBB permeability) contribute to the development of dyskinesias in PD.
Dr. Cenci is now collaborating with Dr. Paul Lockman of Texas Tech University Health Sciences Center, Amarillo, Texas, who has developed accurate methods to study changes in BBB permeability in brain cancer. Additionally, she received supplemental funding from MJFF to test whether blocking new blood vessel generation induced by levodopa can suppress the development of levodopa-induced dyskinesias. She also examined post-mortem brain tissue from PD subjects to see if similar evidence of LDOPA-induced changes in blood vasculature were present.
Results of this work were published in Neuropsychopharmacology, the Journal of Neurochemistry and the Journal of Neuroscience.