Effects of Intranasal Dantrolene Nanoparticles on Brain Concentration and Behavior in PS19 Tau Transgenic Mice.

Background: Repurposing dantrolene to treat Alzheimer's disease has been shown to be effective in amyloid transgenic mouse models but has not been examined in a model of tauopathy. Objective: The effects of a nanoparticle intranasal formulation, the Eagle Research Formulation of Ryanodex (ERFR), in young adult and aged wild type and PS19 tau transgenic mice was investigated. Methods: The bioavailability of intranasal ERFR was measured in 2 and 9-11-month-old C57BL/6J mice. Blood and brain samples were collected 20 minutes after a single ERFR dose, and the plasma and brain concentrations were analyzed. Baseline behavior was assessed in untreated PS19 tau transgenic mice at 6 and 9 months of age. PS19 mice were treated with intranasal ERFR, with or without acrolein (to potentiate cognitive dysfunction), for 3 months, beginning at 2 months of age. Animal behavior was examined, including cognition (cued and contextual fear conditioning, y-maze), motor function (rotarod), and olfaction (buried food test). Results: The dantrolene concentration in the blood and brain decreased with age, with the decrease greater in the blood resulting in a higher brain to blood concentration ratio. The behavioral assays showed no significant changes in cognition, olfaction, or motor function in the PS19 mice compared to controls after chronic treatment with intranasal ERFR, even with acrolein. Conclusions: Our studies suggest the intranasal administration of ERFR has higher concentrations in the brain than the blood in aged mice and has no serious systemic side effects with chronic use in PS19 mice.

Effects of intranasal dantrolene nanoparticles on brain concentration and behavior in PS19 tau transgenic mice.

Background: Repurposing dantrolene as a potential disease-modifying treatment for Alzheimer's disease has been shown to be effective in amyloid transgenic mouse models but has not been examined in a model of tauopathy. Objective: The effects of a nanoparticle intranasal formulation, the Eagle Research Formulation of Ryanodex (ERFR), in young adult and aged wild type and PS19 tau transgenic mice was investigated. Methods: The bioavailability of intranasal ERFR was measured in 2 months and 9-12 month old C57BL/6J male mice. Mice received a single intranasal dose of ERFR and, after 20 min, blood and brain samples were collected. Dantrolene concentrations in the plasma and brain were analyzed by High Performance Liquid Chromatography. Animal behavior was examined in PS19 tau transgenic mice, with/without acrolein treatment to exacerbate cognitive deficits. Behavioral tests included cognition (cued and contextual fear conditioning, y-maze), motor function (rotarod), and olfaction (buried food test). Results: Dantrolene concentration in the blood and brain decreased with age, though the decrease was greater in the blood resulting in a higher brain to blood concentration ratio. The behavioral assays showed no significant changes in cognition, olfaction or motor function in the PS19 mice compared to controls after chronic ERFR treatment even with acrolein treatment. Conclusion: Our studies suggest that while we did not find PS19 mice to be a reliable Alzheimer animal model to test the therapeutic efficacy of dantrolene, the results suggest a potential for ERFR to be an effective chronic therapy for Alzheimer's disease and that further studies are indicated.

Risk factors for ureteral occlusion during transvaginal uterosacral ligament suspension.

INTRODUCTION AND HYPOTHESIS: To determine any risk factors associated with ureteral occlusion during transvaginal uterosacral ligament suspension (USLS). METHODS: A retrospective query to identify patients that underwent transvaginal USLS at a teaching hospital from 2008 to 2013 was performed. Patients in which ureteral occlusion was identified by cystoscopy were identified (cases), and compared with those without occlusion (controls). Medical records were reviewed for data abstraction. Variables compared between cases and controls included demographics, medical history/examination, concomitant procedures, number of suspension sutures placed, estimated blood loss and length of hospital stay. Univariate analyses were performed to identify potential risk factors for ureteral occlusion, followed by multivariate regression analysis to estimate odds ratios for identified predictors. RESULTS: A total of 144 USLS procedures were performed. Thirteen cases of ureteral occlusion were identified (9%). Baseline prolapse stage, body mass index, parity, previous hysterectomy or pelvic surgery of the groups were similar (all P > 0.05). Univariate analysis identified age (P = 0.04), concomitant anterior colporrhaphy (P = 0.01), and use of a suture-capturing device for suture placement (P = 0.04) as significant factors. On multivariate logistic regression analysis, concomitant anterior colporrhaphy increased ureteral occlusion risk (OR 10.5, 95%CI 2.37-74.99, P = 0.001), while use of a suture-capturing device decreased it (OR 0.1, 95%CI 0-0.41, P = 0.01). The mean number of suspension sutures placed per side was similar in the two groups (2.6 [range 2-4] for cases and 2.4 [range 1-4] for controls, P = 0.15). CONCLUSIONS: During transvaginal USLS, performance of a concomitant anterior colporrhaphy increased the risk of ureteral occlusion, while the use of a suture-capturing device for suspension suture placement was associated with decreased risk.