ABSTRACT
Targeting toxic amyloid beta (Aß) oligomers is currently a very attractive drug development strategy for treatment of Alzheimer´s disease. Using mirror-image phage display against Aß1-42, we have previously identified the fully D-enantiomeric peptide D3, which is able to eliminate Aß oligomers and has proven therapeutic potential in transgenic Alzheimer´s disease animal models. However, there is little information on the pharmacokinetic behaviour of D-enantiomeric peptides in general. Therefore, we conducted experiments with the tritium labelled D-peptide D3 (3H-D3) in mice with different administration routes to study its distribution in liver, kidney, brain, plasma and gastrointestinal tract, as well as its bioavailability by i.p. and p.o. administration. In addition, we investigated the metabolic stability in liver microsomes, mouse plasma, brain, liver and kidney homogenates, and estimated the plasma protein binding. Based on its high stability and long biological half-life, our pharmacokinetic results support the therapeutic potential of D-peptides in general, with D3 being a new promising drug candidate for Alzheimer´s disease treatment.
Subject(s)
Alzheimer Disease/drug therapy , Oligopeptides/therapeutic use , Animals , Area Under Curve , Blood Proteins/chemistry , Blood Proteins/metabolism , Chromatography, Thin Layer , Disease Models, Animal , Drug Evaluation, Preclinical , Half-Life , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Microsomes, Liver/metabolism , Oligopeptides/chemistry , Oligopeptides/pharmacokinetics , Protein Binding , ROC Curve , Stereoisomerism , Tritium/chemistryABSTRACT
Hepatic encephalopathy (HE) in chronic liver disease is characterized by neuropsychiatric and motor disturbances and associated with a net increase of inhibitory neurotransmission. Though many studies, mostly carried out in animal models, have linked dysfunctions of single neurotransmitter systems with the pathogenesis of HE, reports concerning neurotransmitter receptor alterations are controversial. Little is known about the situation in humans. We carried out a multireceptor assessment of HE-associated changes in neurotransmitter receptor densities and affinities in human post-mortem brain samples. Dissociation constants and densities of different binding sites for glutamate, GABA, acetylcholine, norepinephrine, serotonin, dopamine and adenosine were determined by in vitro binding assays and quantitative receptor autoradiography in the motor cortex and putamen of HE and control brains. HE cases do not build a homogeneous group, but differ concerning direction and intensity of binding site density divergences from control values. The acetylcholine M2 binding site dissociation constant was significantly higher in HE brains. Nicotinic acetylcholine and adenosine type 1 and 2A densities were significantly down-regulated in the putamen of HE brains. Our data suggest that neurotransmitter alterations are probably not the primary key factor responsible for the neuropsychiatric and motor disturbances associated with HE.