Safety, tolerability, and pharmacokinetics of allopregnanolone as a regenerative therapeutic for Alzheimer's disease: A single and multiple ascending dose phase 1b/2a clinical trial.

Introduction: Allopregnanolone is an endogenous neurosteroid with the potential to be a novel regenerative therapeutic for Alzheimer's disease (AD). Foundations of mechanistic understanding and well-established preclinical safety efficacy make it a viable candidate.

Methods: A randomized, double-blinded, placebo-controlled, single and multiple ascending dose trial was conducted.

Allopregnanolone preclinical acute pharmacokinetic and pharmacodynamic studies to predict tolerability and efficacy for Alzheimer's disease.

To develop allopregnanolone as a therapeutic for Alzheimer's disease, we investigated multiple formulations and routes of administration in translationally relevant animal models of both sexes. Subcutaneous, topical (transdermal and intranasal), intramuscular, and intravenous allopregnanolone were bolus-administered. Pharmacokinetic analyses of intravenous allopregnanolone in rabbit and mouse indicated that peak plasma and brain levels (3-fold brain/plasma ratios) at 5min were sufficient to activate neuroregenerative responses at sub-sedative doses.

Development of a unified clinical trial database for Alzheimer's disease.

Introduction: Data obtained in completed Alzheimer's disease (AD) clinical trials can inform decision making for future trials. Recognizing the importance of sharing these data, the Coalition Against Major Diseases created an Online Data Repository for AD (CODR-AD) with the aim of supporting accelerated drug development. The aim of this study was to build an open access, standardized database from control arm data collected across many clinical trials.

Frontiers in therapeutic development of allopregnanolone for Alzheimer's disease and other neurological disorders.

Allopregnanolone (Allo), a neurosteroid, has emerged as a promising promoter of endogenous regeneration in brain. In a mouse model of Alzheimer's disease, Allo induced neurogenesis, oligodendrogenesis, white matter generation and cholesterol homeostasis while simultaneously reducing β-amyloid and neuroinflammatory burden. Allo activates signaling pathways and gene expression required for regeneration of neural stem cells and their differentiation into neurons.

Medial prefrontal cortex lesions in mice do not impair effort-based decision making.

The function of the medial prefrontal cortex has previously been determined in the rat to play an important role in effort-based decision making and this, along with functions of other areas, has been assumed largely, to hold true in all rodents. In this study, we attempted to replicate this result in mice and to develop a model for effort-based decision making that could be useful for the study of neurological conditions. Mice were trained on a cost-benefit T-maze paradigm, whereby they chose between a low reward with little effort needed to obtain it or a higher reward, which required increased effort.

Transforming growth factor-beta signaling alters substrate permeability and tight junction protein expression at the blood-brain barrier during inflammatory pain.

Our laboratory has shown that peripheral inflammatory pain induced by lambda-carrageenan (CIP) can increase blood-brain barrier (BBB) permeability and alter tight junction (TJ) protein expression leading to changes in BBB functional integrity. However, the intracellular signaling mechanisms involved in this pathophysiologic response have not been elucidated. Transforming growth factor (TGF)-beta signaling pathways are known to regulate vascular integrity and permeability.