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Investigations that revealed increased levels of iron in postmortem brains from patients with Parkinson's disease (PD) as compared to those from individuals not suffering from neurological disorders are reported. The chemical natures in which iron predominates in the brain and the relevance of neuromelanin for neuronal iron binding are discussed. Major findings have been that iron levels increase with the severity of neuropathological changes in PD, presumably due to increased transport through the blood-brain barrier in late stages of parkinsonism. Glial iron is mainly stored as ferric iron in ferritin, while neuronal iron is predominantly bound to neuromelanin. Iron overload may induce progressive degeneration of nigrostriatal neurons by facilitating the formation of reactive biological intermediates, including reactive oxygen species, and the formation of cytotoxic protein aggregates. There are indications that iron-mediated neuronal death in PD proceeds retrogradely. These results are also discussed with respect to their relevance for disease progression in relation to cytotoxic alpha-synuclein protofibril formation.

Impaired theory of mind on second order tests is specific to schizophrenia when compared to mild learning disability and affective disorder control groups. Subjects with schizophrenia and pre-morbid mild learning disability show greater impairment than subjects with schizophrenia and a pre-morbid IQ within the normal range.

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IL-6 gene expression is controlled by a promoter region containing multiple regulatory elements such as NF-B, NF-IL6, CRE, GRE, and TRE. In this study, we demonstrated that TRE, found within the IL-6 promoter, is embedded in a functional antioxidant response element (ARE) matching an entire ARE consensus sequence. Further, point mutations of the ARE consensus sequence in the IL-6 promoter construct selectively eliminate ARE but not TRE activity. Nrf2 is a redox-sensitive transcription factor which provides cytoprotection against electrophilic and oxidative stress and is the most potent activator of ARE-dependent transcription. Using Nrf2 knock-out mice we demonstrate that Nrf2 is a potent activator of IL-6 gene transcription in vivo. Moreover, we show evidence that Nrf2 is the transcription factor that activates IL6 expression in a cholestatic hepatitis mouse model. Our findings suggest a possible role of IL-6 in oxidative stress defense and also give indication about an important function for Nrf2 in the regulation of hematopoietic and inflammatory processes.Because of its diverse biological function and simultaneous description in different studies, IL-6 was initially assigned several names. It was identified as a T-cell-derived B-cell differentiation factor, as it induced activated B-cells into antibody-producing cells: interferon-␤2 (26 kDa protein), a hybridoma/plasmacytoma growth factor and a hepatocytestimulating factor. The name IL-6 was proposed when the cDNA nucleotide sequences for these proteins had been determined, and the molecules were found to be identical (1). In addition, IL-6 plays a key role in inflammation, being the main inducer of fibrinogen, serum amyloid A protein, the acute phase response and is one of the most important mediators of fever. In muscle and fatty tissues, IL-6 stimulates energy mobilization.The IL-6 promoter is rapidly activated by cytokines, including IL-1 and TNF-␣, as well as by phorbol esters and cyclic AMP. The promoter-region of the IL-6 gene contains multiple regulatory elements such as nuclear factor-B (NF-B), nuclear factor-IL6 (NF-IL6) (also referred to as C/EBP␤), cAMP response element (CRE), TPA (12-O-tetradecanoylphorbol-13-acetate) responsive element (TRE; also referred to as the AP-1 binding site), and the glucocorticoid response element (GRE) (2).Structurally related to TRE is the antioxidant responsive element (ARE, 2 also referred to as the electrophile responsive element (EpRE)) (3, 4). Some TREs are found to be embedded within an ARE, such as in the promoter region of human NAD(P)H:quinine oxidoreductase-1 (NQO1), rat and mouse glutathione S-transferase (GST) Ya subunit, and rat GST-P (5). ARE is commonly found in the promoter region of genes encoding phase II detoxification as well as antioxidant enzymes such as NQO1, thioredoxin, thioredoxin reductase, glutathione peroxidase, and hemeoxygenase-1 (6). Analyses of ARE-nuclear protein complexes have identified numerous nuclear transcription factors including c-Jun, Jun-B, Jun-D, c-Fos, Fra1, Nrf1, Nrf2, ...

One hallmark of Alzheimer's disease is the accumulation of amyloid ␤-peptide (AP), which can initiate a cascade of oxidative events that may result in neuronal death. Because nuclear factor erythroid 2-related factor 2 (Nrf2) is the major regulator for a battery of genes encoding detoxifying and antioxidative enzymes via binding to the antioxidant response element (ARE), it is of great interest to find nontoxic activators of Nrf2 rendering neuronal cells more resistant to AP toxicity. Using ARE-luciferase assay and Western blot, we provide evidence that the kavalactones methysticin, kavain, and yangonin activate Nrf2 time-and dose-dependently in neural PC-12 and astroglial C6 cells and thereby upregulate cytoprotective genes. Viability and cytotoxicity assays demonstrate that Nrf2 activation is able to protect neural cells from amyloid ␤-(1-42) induced neurotoxicity. Down-regulation of Nrf2 by small hairpin RNA as well as extracellular signal-regulated kinase 1/2 inhibition abolishes cytoprotection. We further give evidence that kavalactone-mediated Nrf2 activation is not dependent on oxidative stress production. Our results demonstrate that kavalactones attenuate amyloid ␤-peptide toxicity by inducing protective gene expression mediated by Nrf2 activation in vitro. These findings indicate that the use of purified kavalactones might be considered as an adjunct therapeutic strategy to combat neural demise in Alzheimer disease and other oxidative stress-related diseases.

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been shown to induce parkinsonism in man and non-human primates. Monoamine-oxidase B (MAO-B) has been reported to be implicated in both MPTP-induced parkinsonism and Parkinson's disease, since selegiline (L-deprenyl), an irreversible MAO-B inhibitor, prevents MPTP-induced neurotoxicity in numerous species including mice, goldfish and drosophyla. However, one disadvantage of this substance relates to its metabolism to (-)-methamphetamine and (-)-amphetamine. Rasagiline (R-(+)-N-propyl-1-aminoindane) is a novel irrevesible MAO-B-inhibitor, which is not metabolized to metamphetamine and/or amphetamine. The present study compared the effects of high doses of selegiline and rasagiline (10 mg/kg body weight s.c.) on MPTP-induced dopaminergic neurotoxicity in a non-human primate (Callithrix jacchus) model of PD. Groups of four monkeys were assigned to the following six experimental groups: Group I: Saline, Group II: Selegiline/Saline, Group III: Rasagiline/Saline, Group IV: MPTP/Saline, Group V: Rasagiline/MPTP, Group VI: Selegiline/MPTP. Daily treatment with MAO-B-inhibitors (either rasagiline or selegiline, 10 mg/kg body weight s.c.) was initiated four days prior to MPTP-exposure (MPTP-HCl, 2 mg/kg body weight subcutaneously, separated by an interval of 24 hours for a total of four days) and was continued until the end of the experiment, i.e. 7 days after the cessation of the MPTP-injections, when animals were sacrificed. MPTP-treatment caused distinct behavioural, histological, and biochemical alterations: 1. significant reduction of motor activity assessed by clinical rating and by computerized locomotor activity measurements; 2. substantial loss (approx. 40%) of dopaminergic (tyrosine-hydroxylase-positive) cells in the substantia nigra, pars compacta; and 3. putaminal dopamine depletion of 98% and its metabolites DOPAC (88%) and HVA (96%). Treatment with either rasagiline or selegiline markedly attenuated the neurotoxic effects of MPTP at the behavioural, histological, and at the biochemical levels. There were no significant differences between rasagiline/MPTP and selegiline/MPTP-treated animals in respect to signs of motor impairment, the number of dopaminergic cells in the substantia nigra, and striatal dopamine levels. As expected, both inhibitors decreased the metabolism of dopamine, leading to reduced levels of HVA and DOPAC (by >95% and 45% respectively). In conclusion, rasagiline and selegiline at the dosages employed equally protect against MPTP-toxicity in the common marmoset, suggesting that selegiline-derived metabolites are not important for the neuroprotective effects of high dose selegiline in the non-human MPTP-primate model in the experimental design employed. However, unexpectedly, high dose treatment with both MAO-inhibitors caused a decrease of the cell sizes of nigral tyrosine hydroxylase positive neurons. It remains to be determined, if this histological observation represents potential adverse effects of high dose treatment...

Histochemical GUS-staining and fluorometric analyses revealed strong tissue specific activities of the cell wall invertase promoters Nin88 from Nicotiana tabacum and AtcwINV2 from Arabidopsis thaliana that are restricted tightly to anthers and pollen, respectively. Both in A. thaliana and N. tabacum repression of invertase activity by anther specific RNA-interference turned out to be an efficient method to circumvent carbohydrate supply of the symplastically isolated pollen with subsequent strong decrease of pollen germination ability and seed setting. In the case of tobacco, comparable results were also obtained by expressing a proteinaceous invertase inhibitor, whereas this approach was less efficient in Arabidopis. The present study revealed that anther specific interference with invertase-activity in order to generate male sterile plants can be applied to members of the two different plant families Solanaceae (N. tabacum) and Brassicaceae (A. thalaina) and the strategy seems to be a general tool for practical application in hybrid breeding or as biological safety precautions. To elucidate the compatibility of the isolated promoters beyond plant families, we transferred the regulatory sequences into the respectively heterologous systems, i.e. the Nin88 promoter into Arabidopsis and the AtcwINV2 promoter into tobacco. The specificities of both promoters are maintained in the heterologous backgrounds, but their activities are strongly reduced as GUS-stainings of flowers and pollen revealed and fluorometrical quantification confirmed.