Biochemical and pharmacokinetic studies in vivo in Parkinson’s disease

Sammanfattning: Parkinson’s disease (PD) is a neurodegenerative disease affecting approximately 25000 people in Sweden. The main cause of the disease is the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) projecting to the striatum. The motor symptoms of PD, due to decreased levels of dopamine, includes bradykinesia, rigidity and tremor.During the 1960ies oral L-dopa treatment was introduced increasing quality of life for PD patients. In recent decades, enzyme inhibitors have been introduced, increasing bioavailability of L-dopa in plasma. After 5-10 years of L-dopa treatment, 50% of PD patients develop disabling dyskinesias. This can be due to rapid changes in L-dopa conentrations with non physiological stimulation of the dopamine receptor.For over 20 years deep brain stimulation (DBS) has grown to be a good neurosurgical procedure for improving quality of life in advanced PD with disabling dyskinesias. With stereotactic technique, electrodes are implanted in the brain and connected to a pacemaker sending electrical impulses. The most common target in PD is the subthalamic nucleus (STN). The knowledge about DBS mechanism(s) and its interaction with L-dopa is unsatisfactory.The aims of this thesis were; to study the effect of the enzyme inhibitor entacapone on the L-dopa concentration over the blood brain barrier (BBB); to study possible interactions between L-dopa and DBS; to study alterations in neurotransmitters during DBS; to visualize microdialysis catheters in anatomical targets and to estimate sampling area of the catheters.In all four papers the microdialysis technique was used. It is a well-established technique for continuous sampling of small water-soluble molecules within the extracellular fluid space in vivo, allowing studies of pharmaceutical drugs and neurotransmitters.We showed that entacapone increases the bioavailability of L-dopa in blood with a subsequent increase of L-dopa peak levels in the cerebrospinal fluid. This in turn may cause a larger burden on the dopaminergic neurons causing an increased degeneration rate and worsening of the dyskinesias; we showed that 18% of L-dopa crosses the BBB and that there is a possible interaction between L-dopa and DBS, L-dopa concentrations increase during concomitant STN DBS, which can clarify why its possible to decrease L-dopa medication after DBS surgery. The research has also shown that STN DBS has an effect on various neurotransmitter systems, mainly L-dopa, dopamine and GABA. We showed that STN DBS may have an effect on the SNc, resulting in putaminal dopamine release.We have shown that with stereotactic technique, it is safe to do microdialysis sampling in specific areas in the human brain. Simulations with the finite element method combined with patient specific preoperative MRI and postoperative CT images gave us exact knowledge about the positions of the catheters and that the studied structures were the intended. The research has given an assumption of the maximum tissue volume that can be sampled around the microdialysis catheters.