Lipopolysaccharide influences the plasma and brain pharmacokinetics of subcutaneously-administered HsTX1[R14A], a KV1.3-blocking peptide

Abstract

K_V1.3 is a voltage-gated potassium channel that is upregulated in neuroinflammatory conditions, such as Alzheimer's disease and Parkinson's disease. HsTX1[R14A] is a potent and selective peptide blocker of K_V1.3 with the potential to block microglial K_V1.3, but its brain uptake is expected to be limited owing to the restrictive nature of the blood-brain barrier. To assess its peripheral and brain exposure, a LC-MS/MS assay was developed to quantify HsTX1[R14A] concentrations in mouse plasma and brain homogenate that was reliable and reproducible in the range of 6.7-66.7 nM (r² = 0.9765) and 15-150 pmol/g (r² = 0.9984), respectively. To assess if neuroinflammation affected HsTX1[R14A] disposition, C57BL/6 mice were administered HsTX1[R14A] subcutaneously (2 mg/kg) 24 h after an intraperitoneal dose of Escherichia coli lipopolysaccharide (LPS), which is commonly used to induce neuroinflammation; brain and plasma concentrations of HsTX1[R14A] were then quantified over 120 min. LPS treatment significantly retarded the decline in HsTX1[R14A] plasma concentrations, presumably as a result of reducing renal clearance, and led to substantial brain uptake of HsTX1[R14A], presumably through disruption of brain inter-endothelial tight junctions. This study suggests that HsTX1[R14A] may reach microglia in sufficient concentrations to block K_V1.3 in neuroinflammatory conditions, and therefore has the potential to reduce neurodegenerative diseases.

Keywords: Blood-brain barrier (BBB); Central nervous system (CNS); Liquid chromatography-mass spectrometry (LC-MS); Peptide delivery; Pharmacokinetics.