Recently, we confirmed the presence of enhanced neural reconstruction in Parkinson's disease and in an animal model of Parkinson's disease based on increased polysialic acid-like immunoreactivity. Changes in neurogenesis often appear parallel to changes in angiogenesis. Moreover, both these processes share similar modulating factors, like vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 (Flt-1) and VEGFR-2 (Flk-1). Using immunohistochemistry, we identified in this study upregulation of VEGF in the substantia nigra but not in the striatum of patients with Parkinson's disease by enzyme-linked immunosorbent assay. Such overexpression may participate in vascular remodeling and neurogenesis in the substantia nigra of Parkinson's disease.

The endotoxin lipopolysaccharide (LPS), a component of the Gram-negative bacterial cell wall, selectively induces degeneration of substantia nigral (SN) dopaminergic neurons via activation of microglial cells in rats and mice. Caspase-11 plays a crucial role in LPS-induced septic shock in mice. We examined the mechanism of LPS neurotoxicity on SN dopaminergic neurons in C57BL/6 mice and caspase-11 knockout mice. Mice were stereotaxically injected with LPS into the SN on one side and vehicle into the SN of the other side. Immunohistochemistry, Western blotting analysis, enzyme-linked immunosorbent assay, and reverse transcriptase-PCR were performed to evaluate damage of SN dopaminergic neurons and activation of microglial cells. Intranigral injection of LPS at 1 or 3 g/l/site decreased tyrosine hydroxylase-positive neurons and increased microglial cells in the SN compared with the contralateral side injected with vehicle at days 7 and 14 post-injection in C57BL/6 mice. Intranigral injection of LPS at 3 g/l/site induced the expression of caspase-11 mRNA in the ventral midbrain at 6, 8, and 12 h postinjection, and the expression of caspase-11-positive cells in the SN at 8 and 12 h post-injection. Moreover, LPS at 3 g/l/site increased interleukin-1␤ content in the ventral midbrain at 12 and 24 h post-injection. LPS failed to elicit these responses in caspase-11 knockout mice. Our results indicate that the neurotoxic effects of LPS on nigral dopaminergic neurons are mediated by microglial activation, interleukin-1␤, and caspase-11 expression in mice.Parkinson's disease (PD) 1 is histologically characterized by degeneration of dopaminergic neurons in the substantia nigra (SN). High concentrations of microglial cells are present in the SN, and activation of these cells has been observed in the SN of PD patients (1, 2). Recent studies postulated that activation of microglia and neuroinflammatory processes may contribute to the pathogenesis of PD (3, 4). Lipopolysaccharide (LPS), a component of the Gram-negative bacterial cell wall, is a potent inducer of inflammation and activator of microglia (5). Long term stimulation of innate immunity by LPS exacerbates motor neurodegeneration in a mouse model of amyotrophic lateral sclerosis, suggesting that the endotoxin LPS could be involved in neurodegenerative diseases caused by chronic peripheral bacterial infections especially in the presence of genetic or environmental risk factors (6).Dopaminergic neurons are far more sensitive to LPS-induced neurotoxicity than ␥-aminobutyric acidergic or serotonergic neurons, and intranigral injection of LPS induces selective and long lasting dopaminergic neurodegeneration via microglial activation in the SN (5). In PD patients, microglial activation, and selective and irreversible dopaminergic neurodegeneration in the SN are seen (1, 2); therefore intranigral injection of LPS is a suitable model for PD (5). With regard to the signal transduction by LPS, caspase-11 is considered to play a major role because resistance to LPS-induced sept...

Long-term dopamine replacement therapy in Parkinson's disease leads to the development of disabling involuntary movements named dyskinesias that are related to adaptive changes in striatal signaling pathways. The chronic transcription factor ⌬FosB, which is overexpressed in striatal neurons after chronic dopaminergic drug exposure, is suspected to mediate these adaptive changes. Here, we sought to demonstrate the ability of ⌬FosB to lead directly to the abnormal motor responses associated with chronic dopaminergic therapy. Using rAAV (recombinant adenoassociated virus) viral vectors, high levels of ⌬FosB expression were induced in the striatum of dopaminedenervated rats naive of chronic drug administration. Transgenic ⌬FosB overexpression reproduced the entire spectrum of altered motor behaviors in response to acute levodopa tests, including different types of abnormal involuntary movements and hypersensitivity of rotational responses that are typically associated with chronic levodopa treatment. JunD, the usual protein partner of ⌬FosB binding to AP-1 (activator protein-1) sites of genes, remained unchanged in rats with high ⌬FosB expression induced by viral vectors. These findings demonstrate that the increase of striatal ⌬FosB in the evolution of chronically treated Parkinson's disease may be a trigger for the development of abnormal responsiveness to dopamine and the emergence of involuntary movements.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder affecting ∼1 % of people over the age of 65. Neuropathological hallmarks of PD are prominent loss of dopaminergic (DA) neurons in the substantia nigra and formation of intraneuronal protein inclusions termed Lewy bodies, composed mainly of α-synuclein (αSyn). Missense mutations in αSyn gene giving rise to production of degradation-resistant mutant proteins or multiplication of wild-type αSyn gene allele can cause rare inherited forms of PD. Therefore, the existence of abnormally high amount of αSyn protein is considered responsible for the DA neuronal death in PD. Normally, αSyn protein localizes to presynaptic terminals of neuronal cells, regulating the neurotransmitter release through the modulation of assembly of soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex. On the other hand, of note, pathological examinations on the recipient patients of fetal nigral transplants provided a prion-like cell-to-cell transmission hypothesis for abnormal αSyn. The extracellular αSyn fibrils can internalize to the cells and enhance intracellular formation of protein inclusions, thereby reducing cell viability. These findings suggest that effective removal of abnormal species of αSyn in the extracellular space as well as intracellular compartments can be of therapeutic relevance. In this review, we will focus on αSyn-triggered neuronal cell death and provide possible disease-modifying therapies targeting abnormally accumulating αSyn.

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A wireless power transfer system for electric vehicles is required to have high efficiency, a large air gap, and good tolerance for misalignment in the lateral direction and to be compact and lightweight. A new 3 kW transformer has been developed to satisfy these criteria using a novel H-shaped core and split primary capacitors. The design procedure based on the coupling factor k, the winding's Q, and the core loss is described. An efficiency of 90% was achieved across a 200 mm air gap.

Neurons rely heavily on mitochondria for their function and survival. Mitochondrial dysfunction contributes to the pathogenesis of neurodegenerative diseases such as Parkinson's disease. PGC-1α is a master regulator of mitochondrial biogenesis and function. Here we identify necdin as a potent PGC-1α stabilizer that promotes mitochondrial biogenesis via PGC-1α in mammalian neurons. Expression of genes encoding mitochondria-specific proteins decreases significantly in necdin-null cortical neurons, where mitochondrial function and expression of the PGC-1α protein are reduced. Necdin strongly stabilizes PGC-1α by inhibiting its ubiquitin-dependent degradation. Forced expression of necdin enhances mitochondrial function in primary cortical neurons and human SH-SY5Y neuroblastoma cells to prevent mitochondrial respiratory chain inhibitor-induced degeneration. Moreover, overexpression of necdin in the substantia nigra in vivo of adult mice protects dopaminergic neurons against degeneration in experimental Parkinson's disease. These data reveal that necdin promotes mitochondrial biogenesis through stabilization of endogenous PGC-1α to exert neuroprotection against mitochondrial insults.

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