Effect of aging on the kinetics of blood-brain barrier uptake of tryptophan in rats.

Abstract

The purpose of this investigation was to examine the effect of aging on the blood-brain barrier (BBB) transport of tryptophan. A well established in-situ brain perfusion technique was used to examine brain uptake of 14C-tryptophan in 2-, 12- and 24-month old Sprague-Dawley rats; perfusate tryptophan concentrations ranged from 0.00175 to 2 mM. Uptake data were modeled using non-linear regression analysis. Permeability-surface area product (PA) for tryptophan was significantly lower in 12- and 24-month old rats, as compared to the 2-month old animals. A transport model consisting of both saturable (Michaelis-Menten type) and non-saturable components best described brain uptake of tryptophan in all 3 age groups. However, age-dependent differences in BBB transport parameters of tryptophan were observed. For the saturable component, both Vmax and Km were significantly lower in the 12- and 24-month old rats, as compared to the youngest group of rats. These results suggest that transporter mobility, number and affinity for tryptophan are altered in older rats. Values for Kd, the rate constant for non-saturable brain tryptophan transport, were also significantly lower in animals of the two older age groups. Interestingly, PA values for thiourea, a compound believed to be transporter across BBB by diffusion, were also lower in these two age groups. Aging decreases the ability of the BBB to transport the neutral amino acid tryptophan.