Neoangiogenesis and Blood-Brain Barrier in L-DOPA-Induced Dyskinesia

Levodopa is still the most effective treatment for Parkinson's disease, but has a great potential to induce abnormal involuntary movements (dyskinesia).

Working on a pre-clinical model of PD, we have discovered that treatment with levodopa causes remodeling of small blood vessels in the brain's basal ganglia nuclei. In these structures we have found a large proliferation of cells lining the inner wall of blood vessels (endothelium) associated with a reduced expression of proteins that are required to maintain a tight barrier between blood and brain tissue. These changes occurred only in pre-clinical models exhibiting dyskinesia in response to levodopa. Moreover, anti-parkinsonian drugs that have a low potential to induce dyskinesia did not cause any microvascular alteration in the basal ganglia.

Since the brain endothelium regulates the transport of levodopa from blood to brain, we hypothesize that the newly grown capillaries with leaky walls promote a rapid entry of levodopa into the brain, thus favouring the occurrence of dyskinesia and motor fluctuations. This hypothesis will be addressed in the continuation of the project using different approaches. We shall identify the mechanisms of microvessel growth (angiogenesis) in dyskinesia, and we shall try and block this phenomenon using so-called angiostatic substances in a pre-clinical model receiving levodopa treatment.