Parkinson's disease is a neurodegenerative disorder where a progressive loss of dopamine neurons occurs in the substantia nigra of ventral mesencephalon. The cause of the disease is unknown but for instance, neuroinflammation has shown to be involved.
Treatment is primarily based on l-dopa therapy, but severe side effects such as dyskinesia is developed over time, which demands for development of alternate treatment strategies such as replacing the lost dopamine neurons with new neurons. Therefore grafting therapy was developed. Prior to the initial grafting trials in patients suffering from Parkinson's disease were conducted, it had been documented in animal experiments that transplanted dopamine neurons could innervate the host brain, release dopamine, and form proper synaptic contacts with the host brain. However, clinical trials of grafting in Parkinson's disease was recently thoroughly evaluated and the outcome lead to conclusions about drawbacks concerning cell viability, cell availability, short-distance reinnervation, and side effects such as dyskinesia developed after grafting. Therefore more basic animal experiments are needed before further advancements in the clinics are possible. For example, from animal experiments it has been shown that although many dopamine neurons project to the host brain there is a subpopulation of dopamine neurons that do not target the host striatum. Thus, we need to study what factors may hinder/trigger dopamine neurons to grow. Furthermore, little is still known about the mechanisms how l-dopa is converted to dopamine in the dopamine-depleted brain. The increased neuroinflammatory state of the parkinsonian brain might influence the outcome of grafting therapy. Therefore our research is focused on how to trigger dopamine neurons to form their nerve fibers, how l-dopa is converted to dopamine, and what influences neuroinflammation.
To improve nerve fiber formation from dopamine neurons organotypic tissue cultures are utilized. The results have documented that neurons form their neurites in two temporally separated sequences, where the initially formed nerve fibers are produced in the absence of glial cells while the secondly formed sequence is growing onto migrating astrocytes. Effects of the nerve growth factor GDNF (glial cell line-derived neurotrohpic factor) has shown to affect the glial-associated nerve fiber growth. Our research is today focused on the role of astrocytes for their production of neurotrophic factors and extracellular matrix molecules such as tenascin and proteoglycans.
Using rapid and spatially resolved catecholamine-sensitive sensors it is possible to detect dopamine in vivo in the brain while l-dopa is not detectable. We are studying how chronic treatment with l-dopa influences extracellular dopamine released by potassium in normal and dopamine-depleted striata. Comparisons of dopamine levels are made between animals with and without dyskinesia, developed by chronic l-dopa treatment. The role of serotonergic nerve fibers when l-dopa is converted to dopamine is investigated.
During the experimental dopamine denervating process neuroinflammatory reaction is obvious. Given diet enriched in antioxidants increases an early, transient microglia reaction, which promotes regeneration of the dopamine system. Regeneration is not found in controls, where instead a slowly increasing microglia reaction is found. Factors influencing this early, transient inflammatory event is investigated. Furthermore, it is hypothesized that the noradrenergic innervation of dopamine neurons coming from locus coeruleus protects against neuroinflammation. Interestingly, in Parkinson's disease the loss of noradrenergic neurons in locus coeruleus is greater than the loss of dopamine neurons and thus might take part in the ongoing neuroinflammatory progress in Parkinson's disease. Therefore, the interactions of locus coeruleus and the substantia nigra are investigated.