The underlying mechanisms of various types of hereditary dystonia, a common movement disorder, are still unknown. Recent findings in a genetic model of a type of paroxysmal dystonia, the dt sz mutant hamster, pointed to striatal dysfunctions. In the present study, immunhistochemical experiments demonstrated a marked decrease in the number and density of parvalbuminimmunoreactive GABAergic interneurons in all striatal subregions of mutant hamsters. To examine the functional relevance of the reduction of these inhibitory interneurons, the effects of the GABA A receptor agonist muscimol on severity of dystonia were examined after microinjections into the striatum and after systemic administrations. Muscimol improved the dystonic syndrome after striatal injections to a similar extent as after systemic treatment, supporting the importance of the deficiency of striatal GABAergic interneurons for the occurrence of the motor disturbances. The disinhibition of striatal GABAergic projection neurons, as suggested by recent extracellular single-unit recordings in dt sz hamsters, should lead to an abnormal neuronal activity in the basal ganglia output nuclei. Indeed, a significantly decreased basal discharge rate of entopeduncular neurons was found in dt sz hamsters. We conclude that a deficit of striatal GABAergic interneurons leads by disinhibition of striatal GABAergic projection neurons to a reduced activity in the entopeduncular nucleus, i.e., to a decreased basal ganglia output. This finding is in line with the current hypothesis about the pathophysiology of hyperkinesias. The results indicate that striatal interneurons deserve attention in basic and clinical research of those movement disorders.
A study was conducted to test the effects of Jerusalem artichoke inulin (JA) or chicory inulin (CH) in snack bars on composition of faecal microbiota, concentration of faecal SCFA, bowel habit and gastrointestinal symptoms. Forty-five volunteers participated in a double-blind, randomized, placebo-controlled, parallel-group study. At the end of a 7 d run-in period, subjects were randomly assigned to three groups of fifteen subjects each, consuming either snack bars with CH or JA, or snack bars without fructans (placebo); for 7 d (adaptation period), they ingested one snack bar per day (7·7 g fructan/d) and continued for 14 d with two snack bars per day. The composition of the microbiota was monitored weekly. The consumption of CH or JA increased counts of bifidobacteria (þ 1·2 log 10 in 21 d) and reduced Bacteroides/Prevotella in number and the Clostridium histolyticum/C. lituseburense group in frequency at the end of intervention (P,0·05). No changes in concentration of faecal SCFA were observed. Consumption of snack bars resulted in a slight increase in stool frequency. Stool consistency was slightly affected in subjects consuming two snack bars containing CH or JA per day (P, 0·05). Consumption of CH or JA resulted in mild and sometimes moderate flatulence in a few subjects compared to placebo (P, 0·05). No structural differences were detected between CH and JA before and after processing. In conclusion, adaptation on increased doses of CH or JA in bakery products stimulates the growth of bifidobacteria and may contribute to the suppression of potential pathogenic bacteria.Bakery products: Inulin: Man: Faecal microflora: Processed foodsIn modern Western societies the lifestyle is characterized by a highly caloric diet, rich in fat, refined carbohydrates and animal protein, combined with low physical activity, resulting in an overall energy imbalance. Facing the fact that such inappropriate dietary habits are contributing to health risks, including obesity, diabetes, CVD, arterial hypertension and cancer, optimal nutrition that focuses on optimizing the quality of daily diet by 'innovative foods' that favour the maintenance of health may help to decrease current and future health care costs.Within the current discussion on functional foods, scientific research on the physiological effects of fructans is of importance for consumers when food manufacturers and retailers introduce new products with possible 'health benefits'. In the bakery industry, inulin or fructo-oligosaccharides from chicory (Cichorium intubus) roots or Jerusalem artichoke (Helianthus tuberosus) tubers are often used as fat replacers to improve the acceptability of low-fat products by the consumer.Interest in these fructans for human nutrition also stems from their prebiotic properties. Prebiotics are defined as non-digestible food ingredients that beneficially affect the host by selectively stimulating the growth and/or activity of one or a limited number of potentially health-promoting bacteria in the colon such as bifidobacteria or lactobac...
RNA interference (RNAi)-based strategies that mediate the specific knockdown of target genes by administration of small interfering RNAs (siRNAs) could be applied for treatment of presently incurable neurodegenerative diseases such as Parkinson’s disease. However, inefficient delivery of siRNA into neurons hampers in vivo application of RNAi. We have previously established the 4–12 kDa branched polyethylenimine (PEI) F25-LMW with superior transfection efficacy for delivery of siRNA in vivo. Here, we present that siRNA complexed with this PEI extensively distributes across the CNS down to the lumbar spinal cord after a single intracerebroventricular infusion. siRNA against α-synuclein (SNCA), a pre-synaptic protein that aggregates in Parkinson’s disease, was complexed with PEI F25-LMW and injected into the lateral ventricle of mice overexpressing human wild-type SNCA (Thy1-aSyn mice). Five days after the single injection of 0.75 μg PEI/siRNA, SNCA mRNA expression in the striatum was reduced by 65%, accompanied by reduction of SNCA protein by ∼50%. Mice did not show signs of toxicity or adverse effects. Moreover, ependymocytes and brain parenchyma were completely preserved and free of immune cell invasion, astrogliosis, or microglial activation. Our results support the efficacy and safety of PEI nanoparticle-mediated delivery of siRNA to the brain for therapeutic intervention.
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