Sephin1 Reduces Prion Infection in Prion-Infected Cells and Animal Model.

Prion diseases are fatal infectious neurodegenerative disorders in human and animals caused by misfolding of the cellular prion protein (PrPC) into the infectious isoform PrPSc. These diseases have the potential to transmit within or between species, and no cure is available to date. Targeting the unfolded protein response (UPR) as an anti-prion therapeutic approach has been widely reported for prion diseases. Here, we describe the anti-prion effect of the chemical compound Sephin1 which has been shown to protect in mouse models of protein misfolding diseases including amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) by selectively inhibiting the stress-induced regulatory subunit of protein phosphatase 1, thus prolonging eIF2α phosphorylation. We show here that Sephin1 dose and time dependently reduced PrPSc in different neuronal cell lines which were persistently infected with various prion strains. In addition, prion seeding activity was reduced in Sephin1-treated cells. Importantly, we found that Sephin1 significantly overcame the endoplasmic reticulum (ER) stress induced in treated cells, as measured by lower expression of stress-induced aberrant prion protein. In a mouse model of prion infection, intraperitoneal treatment with Sephin1 significantly prolonged survival of prion-infected mice. When combining Sephin1 with the neuroprotective drug metformin, the survival of prion-infected mice was also prolonged. These results suggest that Sephin1 could be a potential anti-prion drug selectively targeting one component of the UPR pathway.

Systems pharmacology identifies drug targets for Stargardt disease-associated retinal degeneration.

A systems pharmacological approach that capitalizes on the characterization of intracellular signaling networks can transform our understanding of human diseases and lead to therapy development. Here, we applied this strategy to identify pharmacological targets for the treatment of Stargardt disease, a severe juvenile form of macular degeneration. Diverse GPCRs have previously been implicated in neuronal cell survival, and crosstalk between GPCR signaling pathways represents an unexplored avenue for pharmacological intervention. We focused on this receptor family for potential therapeutic interventions in macular disease. Complete transcriptomes of mouse and human samples were analyzed to assess the expression of GPCRs in the retina. Focusing on adrenergic (AR) and serotonin (5-HT) receptors, we found that adrenoceptor α 2C (Adra2c) and serotonin receptor 2a (Htr2a) were the most highly expressed. Using a mouse model of Stargardt disease, we found that pharmacological interventions that targeted both GPCR signaling pathways and adenylate cyclases (ACs) improved photoreceptor cell survival, preserved photoreceptor function, and attenuated the accumulation of pathological fluorescent deposits in the retina. These findings demonstrate a strategy for the identification of new drug candidates and FDA-approved drugs for the treatment of monogenic and complex diseases.

Effects of guanabenz on sodium and water homeostasis.

Sodium retention may partially offset the therapeutic action of some antihypertensive agents. To assess the effects of guanabenz on sodium balance, six men with mild to moderate hypertension were placed on diets with constant sodium intake (120 mEq/day) for approximately 4 weeks. After achieving sodium balance, the subjects received guanabenz (16-24 mg daily) for approximately 2 weeks. Mean supine blood pressure decreased from 144/93 to 133/86 mmHg during guanabenz treatment (p less than 0.001). Guanabenz therapy was associated with a decrease in body weight (mean +/- SE) from 85.4 +/- 7.0 to 84.4 +/- 6.8 kg (p less than 0.01). Sodium balance, glomerular filtration rate, plasma renin activity, mean maximal urine osmolality, fluid intake, urine volume, and serum sodium concentration were unchanged during guanabenz therapy. Three additional balance studies were performed during a period of greater sodium intake (180 mEq/day). Although higher doses of guanabenz were required to achieve blood pressure control, sodium balance still was not affected by the drug. Thus, an effective therapeutic dose of guanabenz administered for 2 weeks had no clinically significant effects on sodium or water homeostasis in patients with mild to moderate hypertension.

Natriuretic and water diuretic effects of guanabenz, a central alpha-2 agonist.

I should like to preface my concluding remarks by noting that our observations are still of a preliminary nature. Guanabenz, an acute central adrenergic inhibitor produces in human subjects (previously volume expanded with saline) changes similar to those previously described in animals, namely a rise or no change in GFR, an enhancement of water diuresis, and a significant natriuresis. Within one week of the acute study and during chronic administration of guanabenz, all of these changes were reversed: GFR, the magnitude of the water diuresis and the enhanced sodium excretion had returned to the baseline pre-guanabenz levels, indicating that certain adaptive, restorative mechanism were operative. One may conclude, however, that the potential natriuretic properties of guanabenz (even during chronic administration), counter-balance the sodium retaining side effects commonly seen with other centrally acting and vasodilating antihypertensive drugs. This property, therefore, makes this agent a scientifically interesting and potentially useful therapeutic drug in the treatment of high blood pressure.