Neurophyxia (Netherlands)

Brain acidosis is prevalent in stroke and other neurological diseases. Acidosis can have paradoxical injurious and protective effects. The purpose of this study is to determine whether a proton receptor exists in neurons to counteract acidosis-induced injury. We analyzed the expression of proton-sensitive GPCRs (G protein-coupled receptors) in the brain, examined acidosis-induced signaling in vitro, and studied neuronal injury using in vitro and in vivo mouse models. GPR68, a proton-sensitive GPCR, was present in both mouse and human brain, and elicited neuroprotection in acidotic and ischemic conditions. GPR68 exhibited wide expression in brain neurons and mediated acidosis-induced PKC (protein kinase C) activation. PKC inhibition exacerbated pH 6-induced neuronal injury in a GPR68-dependent manner. Consistent with its neuroprotective function, GPR68 overexpression alleviated middle cerebral artery occlusion-induced brain injury. These data expand our knowledge on neuronal acid signaling to include a neuroprotective metabotropic dimension and offer GPR68 as a novel therapeutic target to alleviate neuronal injuries in ischemia and multiple other neurological diseases.

Background 2-iminobiotin (2-IB) is an investigational neuroprotective agent in development for the reduction of brain cell injury after cerebral hypoxia-ischemia.Objective The present first-in-human study evaluated the safety, tolerability, pharmacokinetics (PK) and -dynamics (PD) of 2-IB in healthy male subjects, intravenously infused with or without Captisol® as a solubilizing agent.Methods This randomized, double-blind, placebo-controlled, dose-escalation study was executed in 2 groups of 9 healthy male subjects. A single dose of 2-IB 0.6 mg/kg or placebo was infused over periods between 15 min and 4 h, and repeated doses escalating from 0.6 mg/kg to 12 mg/kg, or placebo were infused every 4 h for 6 administrations in total.Results Single and multiple doses of 2-IB up to 6 doses of 6 mg/kg with and without Captisol® were safe and well-tolerated in healthy male subjects. 2-IB proved to be a high-clearance drug with a volume of distribution slightly exceeding total body water volume, and with linear PK that appeared not to be affected by the presence of Captisol®.Conclusion Sulfobutyletherbeta-cyclodextrin (SBECD) in Captisol® had a low-clearance profile with a small volume of distribution, with time-independent PK. Preliminary PD characterization of repeated iv dosing of 2-IB in an acute peripheral hypoxic ischemia model in healthy subjects did not reveal any notable effects of 2-IB, noting that this model was not selected to guide efficacy in the currently pursued indication of cerebral hypoxia-ischemia.