Kinesthetic motor imagery and actual execution of movements share a common neural circuitry. Functional magnetic resonance imaging was used in 12 right-handed volunteers to study brain activity during motor imagery and execution of simple and complex unimanual finger movements of the dominant and the nondominant hand. In the simple task, a flexible object was rhythmically compressed between thumb, index and middle finger. The complex task was a sequential finger-to-thumb opposition movement. Premotor, posterior parietal and cerebellar regions were significantly more active during motor imagery of complex movements than during mental rehearsal of the simple task. In 10 of the subjects, we also used transcranial magnetic brain stimulation to examine corticospinal excitability during the same motor imagery tasks. Motor-evoked potentials increased significantly over values obtained in a reference condition (visual imagery) during imagery of the complex, but not of the simple movement. Imagery of finger movements of either hand activated left dorsal and ventral premotor areas and the supplementary motor cortex regardless of task complexity. The effector-independent activation of left premotor areas was particularly evident in the simple motor imagery task and suggests a left hemispherical dominance for kinesthetic movement representations in right-handed subjects.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by a selective loss of dopaminergic neurons in the substantia nigra (SN). It has been suggested that microglial inflammation augments the progression of PD. Neuromelanin (NM), a complex polymer pigment found in catecholaminergic neurons, has sparked interest because of the suggestion that NM is involved in cell death in Parkinson's disease, possibly via microglia activation. To further investigate the possible role of NM in the pathogenesis of PD, we conducted in vivo experiments to find out whether microglial cells become activated after injection of human neuromelanin (NM) into (1) the cerebral cortex or (2) the substantia nigra to monitor in this PD-relevant model both microglial activation and possible neurodegeneration. In this study, adult male Wistar rats received an intracerebral injection of either NM, bacterial lipopolysaccharide (LPS, positive control), phosphate-buffered saline (PBS, negative control) or colloidal gold suspension (negative particular control). After different survival times (1, 8 or 12 weeks), brain slices from the cerebral cortex or substantia nigra (SN, 1 week) were stained with Iba-1 and/or GFAP antibody to monitor microglial and astrocytic reaction, and with tyrosine hydroxylase (TH) to monitor dopaminergic cell survival (SN group only). The injection of LPS induced a strong inflammatory response in the cortex as well in the substantia nigra. Similar results could be obtained after NM injection, while the injection of PBS or gold suspension showed only moderate or no glial activation. However, the inflammatory response declined during the time course. In the SN group, there was, apart from strong microglia activation, a significant dopaminergic cell loss after 1 week of survival time. Our findings clearly indicate that extracellular NM could be one of the key molecules leading to microglial activation and neuronal cell death in the substantia nigra. This may be highly relevant to the elucidation of therapeutic strategies in PD.

The first two authors contributed equally to this work u-Synucleln (a-Syn) accounts, as a major component ofLewy bodies (LB), for the filamentous deposits in many cases of neurodegenerative diseases. Yet, little is known about the molecular mechanisms of neuronal loss in these diseases. The correlation between a-Syn oligomerization/aggregation and pathologies raises the key question of which molecular form of a-Syn (i.e. monomeric u-Syn, protofibrils or mature fibrils) represents the damage-inducing culprit in the scenario of synucieinopathies. We show that human a-Syn protofibrils (PFs) are potent activators of parallel proinflammatory signalling pathways (p38 and ERIO!2 MAP kinases and NF-KB) in microglial cells in vitro. Furthermore, stereotactic injection of a-Syn PFs into the substantia nigra of adult rats leads to a profound activation of microglia and adjacent neuronal cell loss, which can be attenuated by the MAP kinase inhibitor semapimod. We propose that the neurodegenerative process of a-synucieinopathies involves microglial activation through a-Syn released or extruded from cells with pathogenic a-Syn metabolism. Compounds that inhibit the MAPKlNF-KB pathways might be a promising pharmacological strategy for the treatment of the inflammatory component of synucieinopathies inciuding PD.Emerging evidence suggests that multiple factors, both genetic and acquired, contribute to the neurodegeneration of the dopaminergic cells of the substantia nigra observed in Parkinson's disease (PD) (1). A major breakthrough in the understanding ofthe etiopathogenesis ofPD has been a consequence of the finding of autosomal inherited monogenic PD due to defects in different loci, some of them

Objectives: In multiple sclerosis, an autoimmune inflammatory disease, oligodendroglia are primarily affected and play an important role in the onset and process of the degeneration of neuronal axons. High-dose therapy with glucocorticoids like 6α-methylprednisolone (MP) as well as the application of immunomodulatory agents like glatiramer acetate (GA) are commonly used in the treatment of MS. The purpose of our study was to examine, in an adequate cell culture model, the effect of MP and GA on oligodendroglial activation induced by pro-inflammatory stimuli. Methods: In the present study, we measured the mRNA (real-time RT-PCR) and protein (Western blot) expression of inducible nitric oxide synthase (iNOS) and the release of nitric oxide (NO; Griess reagent) of rat oligodendroglial progenitor cell line OLN-93 after pro-inflammatory stimulation, and searched for influences of MP and GA on these parameters. OLN-93 cells were treated either with a combination of TNF-α and IFN-γ alone, or additionally with MP or GA. Cell viability and cell protein contents were determined in parallel. Results: Our results show that TNF-α and IFN-γ increased iNOS mRNA and protein expression and the NO production in OLN-93 cells. The elevated production of NO and iNOS protein was reduced in the presence of MP, whereas under treatment with GA, the cytokine-induced overproduction of NO did not change significantly. Conclusions: The presented data suggest an active role of oligodendroglial cells in inflammatory processes like multiple sclerosis and indicate different properties of MP and GA regarding immunosuppression.