Carrier Mediated Blood‐brain Barrier Transport of Choline and Certain Choline Analogs

Abstract

Abstract— Blood‐brain barrier (BBB) transport of choline and certain choline analogs was studied in adult and suckling rats, and additionally compared in the paleocortex and neocortex of adult rats. Saturable uptake was characterized by a single kinetic system in all cases examined, and in adult rat forebrains we determined a Km= 442 ± 60 μM and Vmax= 10.0 ± 0.6 nmol min‐1 g‐1. In 14–15‐day‐old suckling forebrains a similar Km (= 404 ± 88 μM) but higher Vmax (= 12.5 ± 1.5 nmol min‐1 g‐1) was determined. When choline uptake was compared in two regions of the forebrain, similar Michaelis‐Menten constants were determined but a higher uptake velocity was found in the neocortex (i.e. neocortex Km= 310 ± 103 μM and Vmax= 12.6 ± 2.8 nmol min‐1g‐1; paleocortex Km= 217 ± 76 μM and Vmax= 7.2 ± 1.5 nmol min‐1 g‐1). Administration of radiolabelled choline at low (5 μM) and high (100 μM) concentrations, followed by microwave fixation 60 s later and chloroform‐methanol‐water separations of the homogenized brain did not suggest a relationship between concentration and the appearance of label in lipid or aqueous fractions as observed in another in‐vitro study elaborating two‐component kinetics of choline uptake. It was observed that 60s after carotid injection 12–14% of the radiolabel in the ipsilateral cortex was found in the chloroform‐soluble fraction. Hemicholinium‐3 (Ki= 111 μM), dimethylaminoethanol (Ki= 42 μM), tetraethyl ammonium chloride, tetramethyl ammonium chloride, 2‐hydroxyethyl triethylammonium iodide, carnitine, normal rat serum, and to a lesser extent lithium and spermidine all inhibited choline uptake in the BBB. Unsubstituted ammonium chloride and imipramine did not inhibit choline uptake. No difference was observed in blood‐brain barrier choline uptake of unanesthetised, carotid artery‐catheterized animals, and comparable sodium pentobarbital‐anesthetized controls.

Ventricular Choline Transport

“…3) was markedly reduced by 200 M quinine, 5 mM NMN, 1 mM choline, and 200 M tetrapentylammonium as established previously for rOCT2 (22). 2 Choline uptake via hOCT2 exhibited a similar inhibition profile, with 1 mM TEA replacing choline as an inhibitor (Fig. 3).…”

“…6A). This uptake was largely potential-sensitive as demonstrated by the reduction in the tissue/medium ratio from 14 to 5 when the 2 concentration of potassium in the transport buffer was raised to 102.5 mM (Fig. 6A).…”

The Inhibitory Effect of Rivastigmine and Galantamine on Choline Transport in Brain Capillary Endothelial Cells

“…Despite these restrictions, it has been shown that the charged quaternary ammonium molecule, choline, is transported across the BBB via a saturable carrier-mediated mechanism (Cornford et al, 1978). The plasma choline concentration in healthy adults is approximately 10 μM (Cohen et al, 1995), which is less than the calculated K m for the BBB choline transporter (Sawada et al, 1999;Allen and Smith, 2001;Kang et al, 2005).…”

“…Choline is an essential nutrient that plays an important role as a precursor for the synthesis of the neurotransmitter acetylcholine (Cornford et al, 1978). Abnormal choline transport and metabolism have been implicated in a number of neurodegenerative disorders such as Alzheimer's and Parkinson's disease.…”

Processus de transport à travers la barrière hémato-encéphalique

“…TRANSPORT D'AUTRES PETITES MO-LÉCULES Un système de transport pour la choline a également été décrit (Diamond, 1971;Cornford et al, 1978), ainsi que 2 systèmes de transport pour les précurseurs des acides nucléiques, l'un transportant l'adénine et l'autre certains nucléosides puriques et pyrimidiques (Cornford & Oldendorf, 1975 (Wu & Phillis, 1982;Stefanovich, 1983;Kalaria & Harik, 1986). Un système de transport a également été décrit pour les hormones thyroïdiennes (Pardridge & Mietus, 1980) et plusieurs systèmes de transport pour les vitamines : pyridoxine, acide pantothéni-que, biotine (Spector, 1978;Spector et al, 1986Spector et al, , 1987, thiamine monophosphate (Patrini et al, 1988 (Pardridge et al, 1985) et par des études sur de jeunes lapins (Duffy et al, 1986) (Pardridge, 1986) : celui du facteur insuline-like (Frank et aL, 1986), celui de la transferrine , celui d'albumine cationisée (Kumagai et al, 1986), celui de la leucineencéphaline (Zlokovic et aL, 1987).…”