Potential role of orexin and sleep modulation in the pathogenesis of Alzheimer's disease.

Age-related aggregation of amyloid-ß (Aß) is an upstream pathological event in Alzheimer's disease (AD) pathogenesis, and it disrupts the sleep-wake cycle. The amount of sleep declines with aging and to a greater extent in AD. Poor sleep quality and insufficient amounts of sleep have been noted in humans with preclinical evidence of AD. However, how the amount and quality of sleep affects Aß aggregation is not yet well understood. Orexins (hypocretins) initiate and maintain wakefulness, and loss of orexin-producing neurons causes narcolepsy. We tried to determine whether orexin release or secondary changes in sleep via orexin modulation affect Aß pathology. Amyloid precursor protein (APP)/Presenilin 1 (PS1) transgenic mice, in which the orexin gene is knocked out, showed a marked decrease in the amount of Aß pathology in the brain with an increase in sleep time. Focal overexpression of orexin in the hippocampus in APP/PS1 mice did not alter the total amount of sleep/wakefulness and the amount of Aß pathology. In contrast, sleep deprivation or increasing wakefulness by rescue of orexinergic neurons in APP/PS1 mice lacking orexin increased the amount of Aß pathology in the brain. Collectively, modulation of orexin and its effects on sleep appear to modulate Aß pathology in the brain.

Enhanced transdermal delivery of granisetron by using iontophoresis.

The purpose of the present study was to explore the passive and electrically assisted transdermal transport of Granisetron hydrochloride (GRA) in solution and gel formulation through iontophoresis and also the feasibility of delivering therapeutic amounts of drug for the treatment of chemotherapy-induced nausea and vomiting. In this study, iontophoretic permeation of GRA through guinea pig skin using silver-silver chloride electrode was performed and the effects of different variables on this phenomenon were evaluated. Preliminary in-vitro studies using aqueous GRA formulations investigating the effect of drug concentration (5, 10, 15 and 20 mg mL(-1)) on passive permeation, current density (0.2, 0.4 and 0.5 mA cm(-2)), mode of current application, penetration enhancers and effect of application duration were performed. As expected, GRA delivery was found to be increased with the elevation in drug concentration and current density. Anodal continuous current delivery was more effective in the permeation of GRA than the pulsed current method. Penetration enhancers were ineffective to show synergistic effect in conjunction with iontophoresis. It was evident that reservoir in the skin was not formed during the iontophoretic delivery. The results confirm that GRA is an excellent candidate for iontophoresis. The present study demonstrated the feasibility of GRA transdermal transport through the Lutrol F-127 gel by iontophoresis. Further in-vivo studies will be required to support in-vitro conclusions and develop in-vitro, in-vivo correlations.