Pharmacological treatment of fragile X syndrome with GABAergic drugs in a knockout mouse model

Molecular and electrophysiological studies have provided evidence for a general downregulation of the GABAergic system in the Fmr1 knockout mouse. GABA(A) receptors are the main inhibitory receptors in the brain and the GABA(A) receptor was proposed as a novel target for treatment of the fragile X syndrome, the most frequent form of intellectual disability. This study examined the functionality of the GABA(A) receptor in rotarod and elevated plus maze tests with fragile X mice treated with GABA(A) receptor agonists, the benzodiazepine diazepam and the neuroactive steroid alphaxalone. In addition, the effect of GABA(A) receptor activation on the audiogenic seizure activity was determined. We proved that the GABA(A) receptor is still sensitive to GABAergic drugs as the sedative effect of diazepam resulted in a decreased latency time on the rotarod and alphaxalone had a clear anxiolytic effect in the elevated plus maze, decreasing the frequency of entries, the total time spent and the path length in the closed arms. We also observed that treatment with ganaxolone could rescue audiogenic seizures in Fmr1 knockout mice. These findings support the hypothesis that the GABA(A) receptor is a potential therapeutic target for fragile X syndrome.     

Glucocerebrosidase gene mutations: a risk factor for Lewy body disorders

BACKGROUND: Mutations in the glucocerebrosidase (GBA) gene have been reported to modify risk for Parkinson disease (PD) and dementia with Lewy bodies (DLB). However, these findings have not been consistently replicated, and most studies have had substantial methodological shortcomings. OBJECTIVE: To better assess the role of GBA variants in altering risk for Lewy body disorders. DESIGN: Case-control study. SETTING: Four movement disorder clinics in the Seattle, Washington, area. PARTICIPANTS: Seven hundred twenty-one patients with PD, 554 healthy control subjects, and 57 patients with DLB. MAIN OUTCOME MEASURES: Disease status and presence or absence of the 2 most common GBA mutations (N370S and L444P). RESULTS: We observed a significantly higher heterozygote frequency for the 2 mutations in patients with PD (2.9%; P <.001) and those with DLB (3.5%; P = .045) compared with control subjects (0.4%). CONCLUSION: Our findings suggest that GBA mutations exert a large effect on susceptibility for Lewy body disorders at the individual level but are associated with a modest (approximately 3%) population-attributable risk in individuals of European ancestry.     

Intrarectal administration of oxygenated perfluorodecalin promotes healing of murine colitis by targeting inflammatory hypoxia

Intestinal inflammation is associated with enhanced mucosal hypoxia, which contributes to the ongoing inflammatory process and hampers appropriate mucosal healing. We questioned whether local treatment with an oxygen (O(2))-carrying and -releasing molecule (oxygenated perfluorodecalin, O(2)-PFD) could positively influence the course of experimental colitis. The impact of intrarectal (IR) treatment with O(2)-PFD was tested using the murine dextran sodium sulfate (DSS)-induced model of distal colitis, both in preventive and therapeutic settings. Colonic mucosal hypoxia was visualized by pimonidazole staining. Colonic permeability was evaluated with FITC-dextran. In the preventive study, mice treated with O(2)-PFD were protected against DSS colitis compared with saline-treated mice, as demonstrated by reduced shortening of colon length, reduced colonic tumor necrosis factor-alpha levels and a lower histological inflammation score (P<0.05 for all parameters). In the therapeutic study, administration of O(2)-PFD resulted in accelerated recovery of colitis compared with saline-treated littermates, and this was reflected by a better weight evolution, lower myeloperoxidase activity and a lower histological inflammation score (P<0.05 for all parameters). It was found that O(2)-PFD established its therapeutic effects through (1) intrinsic anti-inflammatory effects of the PFD molecule and (2) O(2)-induced preservation and healing of the intestinal epithelial surface. Further in vitro and in vivo studies showed that the barrier-protective activity of O(2)-PFD was obtained through prevention of colonocyte apoptosis and stimulation of colonocyte proliferation during inflammatory hypoxia. These data show that IR treatment with O(2)-PFD promotes colitis healing by the combined actions of direct anti-inflammatory effects and O(2)-induced restitution of the epithelial barrier. As such, O(2)-PFD enemas could be an attractive treatment option for patients with distal inflammatory bowel disease.