Repair of the CNS using endogenous and transplanted neural stem cells.

Restoration of the damaged central nervous system is a vast challenge. However, there is a great need for research into this topic, due to the prevalence of central nervous system disorders and the devastating impact they have on people's lives. A number of strategies are being examined to achieve this goal, including cell replacement therapy, enhancement of endogenous plasticity and the recruitment of endogenous neurogenesis. The current chapter reviews this topic within the context of Parkinson's disease, Huntington's disease and stroke. For each disease exogenous cell therapies are discussed including primary (foetal) cell transplants, neural stem cells, induced pluripotent stem cells and marrow stromal cells. This chapter highlights the different mechanistic approaches of cell replacement therapy versus cells that deliver neurotropic factors, or enhance the endogenous production of these factors. Evidence of exogenously transplanted cells functionally integrating into the host brain, replacing cells, and having a behavioural benefit are discussed, along with the ability of some cell sources to stimulate endogenous neuroprotective and restorative events. Alongside exogenous cell therapy, the role of endogenous neurogenesis in each of the three diseases is outlined and methods to enhance this phenomenon are discussed.

Putaminal upregulation of FosB/ΔFosB-like immunoreactivity in Parkinson's disease patients with dyskinesia.

The transcription factor ΔFosB is a mediator of maladaptive neuroplasticity in animal models of Parkinson's disease (PD) and L-DOPA-induced dyskinesia. Using an antibody that recognizes all known isoforms of FosB and ΔFosB, we have examined the expression of these proteins in post-mortem basal ganglia sections from PD patients. The patient cases were classified as being dyskinetic or non-dyskinetic based on their clinical records. Sections from neurologically healthy controls were also included in the study. Compared to both controls and non-dyskinetic cases, the dyskinetic group showed a higher density of FosB/ΔFosB-immunopositive cells in the posterior putamen, which represents the motor region of the striatum in primates. In contrast, the number of FosB/ΔFosB-positive cells did not differ significantly among the groups in the caudate, a region primarily involved with the processing of cognitive and limbic-related information. Only sparse FosB/ΔFosB immunoreactivity was found in the in the pallidum externum and internum, and no significant group differences were detected in these nuclei. The putaminal elevation of FosB/ΔFosB-like immunoreactivity in patients who had been affected by L-DOPA-induced dyskinesia is consistent with results from both rat and non-human primate models of this movement disorder. The present findings support the hypothesis of an involvement of ΔFosB-related transcription factors in the molecular mechanisms of L-DOPA-induced dyskinesia.

Expression pattern of JunD after acute or chronic L-DOPA treatment: comparison with deltaFosB.

In this study, we have used 6-hydroxydopamine-lesioned rats to examine changes in striatal junD and fosB/deltafosB expression induced by acute and chronic treatment with L-DOPA (5 and 15 days). Changes at the protein levels were studied using Western immunoblotting while mRNA changes were compared using in situ hybridization histochemistry. We observed a significant increase in the level of deltaFosB proteins after chronic treatment with L-DOPA, an effect that was not observed for JunD proteins. In addition, the upregulation of deltaFosB was already present after an acute treatment but increased upon chronic treatment. By contrast, junD and deltafosB mRNA were both upregulated significantly above control levels after an acute injection of L-DOPA. In conclusion, this study suggests a differential expression pattern of junD and deltafosB in a rat model of L-DOPA-induced dyskinesia. The upregulation of deltaFosB protein, but not JunD, is likely to reflect an increased stability of the deltaFosB proteins without ongoing enhanced transcription of the encoding genes.

Advances in understanding L-DOPA-induced dyskinesia.

The crucial role of dopamine (DA) in movement control is illustrated by the spectrum of motor disorders caused by either a deficiency or a hyperactivity of dopaminergic transmission in the basal ganglia. The degeneration of nigrostriatal DA neurons in Parkinson's disease causes poverty and slowness of movement. These symptoms are greatly improved by pharmacological DA replacement with L-3,4-dihydroxy-phenylalanine (L-DOPA), which however causes excessive involuntary movements in a majority of patients. L-DOPA-induced dyskinesia (abnormal involuntary movements) provides a topic of investigation at the interface between clinical and basic neuroscience. In this article, we review recent studies in rodent models, which have uncovered two principal alterations at the basis of the movement disorder, namely, an abnormal pre-synaptic handling of exogenous L-DOPA, and a hyper-reactive post-synaptic response to DA. Dysregulated nigrostriatal DA transmission causes secondary alterations in a variety of non-dopaminergic transmitter systems, the manipulation of which modulates dyskinesia through mechanisms that are presently unclear. Further research on L-DOPA-induced dyskinesia will contribute to a deeper understanding of the functional interplay between neurotransmitters and neuromodulators in the motor circuits of the basal ganglia.