Disturbance of rapid eye movement (REM) sleep appears early in both patients with Huntington’s disease (HD) and mouse models of HD. Selective serotonin reuptake inhibitors are widely prescribed for patients with HD, and are also known to suppress REM sleep in healthy subjects. To test whether selective serotonin reuptake inhibitors can correct abnormal REM sleep and sleep-dependent brain oscillations in HD mice, we treated wild-type and symptomatic R6/2 mice acutely with vehicle and paroxetine (5, 10, and 20 mg/kg). In addition, we treated a group of R6/2 mice chronically with vehicle or paroxetine (20 mg/kg/day) for 8 weeks, with treatment starting before the onset of overt motor symptoms. During and after treatment, we recorded electroencephalogram/electromyogram from the mice. We found that both acute and chronic paroxetine treatment normalized REM sleep in R6/2 mice. However, only chronic paroxetine treatment prevented the emergence of abnormal low-gamma (25–45 Hz) electroencephalogram oscillations in R6/2 mice, an effect that persisted for at least 2 weeks after treatment stopped. Chronic paroxetine treatment also normalized REM sleep theta rhythm in R6/2 mice, but, interestingly, this effect was restricted to the treatment period. By contrast, acute paroxetine treatment slowed REM sleep theta rhythm in WT mice but had no effect on abnormal theta or low-gamma oscillations in R6/2 mice. Our data show that paroxetine treatment, when initiated before the onset of symptoms, corrects both REM sleep disturbances and abnormal brain oscillations, suggesting a possible mechanistic link between early disruption of REM sleep and the subsequent abnormal brain activity in HD mice.Electronic supplementary materialThe online version of this article (doi:10.1007/s13311-017-0546-7) contains supplementary material, which is available to authorized users.

Kidney donation results in reductions in kidney function and lasting perturbations in phosphate homeostasis, which may lead to adverse cardiovascular sequelae. However, the acute effects of kidney donation on bone mineral parameters including regulators of calcium and phosphate metabolism are unknown. We conducted a prospective observational controlled study to determine the acute effects of kidney donation on mineral metabolism and skeletal health. Biochemical endpoints were determined before and after donation on days 1, 2 and 3, 6 weeks and 12 months in donors and at baseline, 6 weeks and 12 months in controls. Baseline characteristic of donors (n = 34) and controls (n = 34) were similar: age (53±10 vs 50±14 years, p = 0.33), BMI (26.3±2.89 vs 25.9±3.65, p = 0.59), systolic BP (128±13 vs 130±6 mmHg, p = 0.59), diastolic BP (80±9 vs 81±9 mmHg, p = 0.68) and baseline GFR (84.4±20.2 vs 83.6±25.2 ml/min/1.73m 2 , p = 0.89). eGFR reduced from 84.4±20.2 to 52.3±17.5 ml/min/1.73m 2 (p<0.001) by day 1 with incomplete recovery by 12 months (67.7±22.6; p = 0.002). Phosphate increased by day 1 (1.1(0.9-1.2) to 1.3(1.1-1.4) mmol/L, p <0.001) but declined to 0.8(0.8-1.0) mmol/L (p<0.001) before normalizing by 6 weeks. Calcium declined on day 1 (p = 0.003) but recovered at 6 weeks or 12 months. PTH and FGF-23 remained unchanged, but α-Klotho reduced by day 1 (p = 0.001) and remained low at 6 weeks (p = 0.02) and 1 year (p = 0.04). In this study, we conclude that kidney donation results in acute disturbances in mineral metabolism characterised by a reduced phosphate and circulating α-Klotho concentration without acute changes in the phosphaturic hormones FGF23 and PTH.

BPM31510 is a metabolic modulating agent composed of a parenteral nanodispersion of ubidecarenone which is currently in clinical studies for glioblastoma. Glioblastoma is a highly metabolic and aggressive malignancy with limited treatment options and dismal median survival. Temozolomide (TMZ) as a first line treatment option, however, 90% of recurrent gliomas acquire TMZ chemoresistance. Recently, acquisition to TMZ resistance has been correlated to alterations in mitochondrial metabolism. Thus, in the present study we sought to investigate whether BPM31510 could elicit anti-cancer activity in TMZ naïve and TMZ-chemoresistant glioma models. In vitro, in a 2D model BPM31510 treatment demonstrated anti-cancer activity in a panel of glioma cell lines (rat C6 and human U251-MG and U87-MG), and this effect was translatable in spheroidal 3D cultures. Importantly, in an aggressive rat C6 orthotopic glioma model, treatment with BPM31510 (50mg/kg/day, b.i.d) starting between 4 and 8 days post-implantation resulted in a 32% cure rate compared to 0% in controls (P &lt; 0.001, Fisher's exact test), demonstrating an improved survival (P &lt; 0.01, log rank survival), despite producing a minimal change in median survival (13 vs. 12 days). A marked increase in caspase3 staining was observed in tumors from BPM31510 treated animals compared to controls assessed at a similar time point post-tumor implantation, suggesting a strong apoptotic effect of this agent in vivo. Next, BPM31510 was examined in a cellular model of acquired TMZ resistance (TMZ-R) generated by exposing parental (chemosensitive naïve) U251-MG and U87-MG cells to increasing concentrations of TMZ for 9-12 months. Similar to parental cells, BPM31510 displayed anti-cancer activity in both TMZ-R cell models, as decreased cell viability and an increase in the percentage of apoptotic cells was observed upon BPM31510 treatment. Consistent with prior studies, compared to parental cells, TMZ-R cells demonstrated metabolic rewiring characterized by increases in mitochondrial function parameters and decreased extracellular acidification rate, indicative of glycolytic flux. Regardless of chemosensitivity, BPM31510 decreased mitochondrial substrate oxidation (e.g., succinate, glycerol-3-phosphate) at doses which induce cell death. Concomitantly, increases in the reactive oxygen species production were observed with BPM 31510 treatment in both parental and TMZ-R cell lines. Together, these data define a link between regulation of mitochondrial function and the anti-cancer activity of BPM31510 in both TMZ chemo-sensitive and resistant glioblastoma models, demonstrating a distinct approach in targeting mitochondrial metabolism for the treatment of this clinically intractable disease. Citation Format: Tulin Dadali, Shreya Kulkarni, Ryan Ng, Pallavi Awate, Saie Mogre, Anne R. Diers, Taichang Jang, Milton Merchant, Jiaxin Sun, Stephane Gesta, Khampaseuth Thapa, Seema Nagpal, Lawrence Recht, Niven R. Narain, Rangaprasad Sarangarajan. BPM 31510, a clinical stage metabolic modulator, demonstrates therapeutic efficacy in glioblastoma models of temozolomide chemo-sensitive and resistance by targeting mitochondrial function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 873.

The original article has been corrected to make the spelling of electroencephalogram consistent throughout this article and to fix spacing between words in the legend to Figure 6.The online version of the original article can be found at http://dx