Neoangiogenesis and blood-brain barrier in L-DOPA-induced dyskinesia

Promising Outcomes of Original Grant:
Working on a pre-clinical model of Parkinson´s disease, we have found that levodopa treatment induces proliferation of endothelial cells and angiogenesis in the basal ganglia. Microvessels affected by endothelial proliferation lack some of the proteins that normally maintain the integrity of the blood-brain barrier (BBB). This angiogenic response is dependent on the activation of a particular type of dopamine receptor (the “D1” class), and correlates with the severity of the motor complications (dyskinesia) induced by levodopa. Treatments that inhibit angiogenesis were found to significantly reduce the development of dyskinesia in the pre-clinical model.

Objectives for Supplemental Investigation: 
In this project extension, we shall continue to study levodopa-induced angiogenesis with two mail goals (i) to determine its functional implications, and (ii) to verify whether it also occurs in the brains of people with Parkinson´s disease. To start with, we shall determine the precise extent of blood-brain barrier leakage in levodopa-treated, dyskinetic and non-dyskinetic rats using tracer molecules of different molecular weights, which will be injected intravenously. We shall also determine the possible relationship of BBB leakage with particular phases (“on” versus “off”) of the levodopa dosing cycles, and with an increased local cerebral blood flow in the affected regions. This part of the project will be carried out in collaboration with Dr. Paul Lockman (Texas Tech University of Health Sciences). In parallel, we shall examine the expression of angiogenesis and BBB markers in post-mortem brain tissue donated by Parkinson´s patients. The patient cases have been selected at the Queen Square Brain Bank (London), where detailed documentation on the medications received by each patient, and on the presence or absence of dyskinesia, is available.

Importance of This Research for the Development of a New PD Therapy:
Our studies on the microvascular modifications induced by levodopa are expected to reveal novel mechanistic targets for Parkinson´s therapy. Our results from the pre-clinical model of levodopa-induced dyskinesia suggest that treatments inhibiting angiogenesis may reduce the development of motor complications in Parkinson´s disease.  Moreover, the brain endothelium and its supporting cells have receptors for a variety of neurotransmitters, which regulate both cell proliferation and local cerebral blood flow. These receptors represent novel therapeutic targets for future investigations.