Neural cell death mechanisms induced by beta-amyloid and plausible therapeutic targets

Abstract

intravenously (IV; 0.01-1.5 mg/kg).Results: Formulations of Allo were developed through solubility tests and dose range-finding and efficacy studies bridging to SC 10 mg/kg. The SC control formulation (10 mg/kg in PBS/5% EtOH) did not induce detectable sedation indicating that global neuroactivation of GABAergic pathways is not required for neurogenesis. In vitro, intracellular calcium rise occurs rapidly, within one-minute after Allo exposure, indicating that sustained activation of GABA A receptors may not be required. Once/week dosing regimen maximized neurogenesis while concomitantly reducing Alzheimer’s pathology. Results of current analyses indicate promising therapeutic efficacy of soluble IVAllo to promote neuroregenerative capacity. Bridging studies were conducted to simulate SC with IV. IV Allo activates CREB and neuronal differentiation factors including NeuroD to promote neurogenesis within 24h and new cells integrate into pre-existing hippocampal neural networks within weeks following Allo exposure. Our preclinical data indicate that the regenerative effect of ALLO occurs at sub-sedative doses given in a regimen consistent with the time course for regeneration i.e. maximum exposure of once per week not daily as is typical for most therapeutics. Thirty minutes after IV (Allo 1.5 mg/kg) administration in the mouse, the plasma Allo concentration was 51 ng/ml (160 nmol/l) and 192 ng/g in brain cortex, comparable with our previously tested SC formulation (Allo 10 mg/kg) that reached 34 ng/ml (107 nmol/l) in plasma and 159 ng/g in brain cortex within 30 min thereby bridging IVand SC formulation and Allo exposure. PK/PD of Allo in mice and prior human exposure data were used to determine an IV dosing regimen and predicted human exposure in support of planned clinical trials in Alzheimer’s patients. Conclusions: Allo formulations via IVand SC routes of administration induce the regenerative capacity of the brain.