Abstract
Purpose. The purpose of this investigation was to examine the effect of aging on the blood-brain barrier (BBB) transport of tryptophan.
Methods. 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.
Results. 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 transported across BBB by diffusion, were also lower in these two age groups.
Conclusions. Aging decreases the ability of the BBB to transport the neutral amino acid tryptophan.
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REFERENCES
D. Cohen and C. Eisdorfer. Depression. In The Practice of Geriatrics, edited by E. Calkins, P. J. Davis and A. B. Ford, pp 185–205, W.B. Saunders Company, Philadelphia, 1986.
A. D. Mooradian. Effect of aging on the BBB. Neurobiol. Aging 9: 31–39, 1988.
J. M. Ordy and K. R. Brizzee. Neurobiology and aging in nonhuman primates. In Neurobiology of Aging, edited by J. M. Ordy and K. R. Brizzee, Parts II, IV & VIII, pp 104, 260–261 and 575–593, New York Plenum, 1975.
L. D. Lytle and A. Altar. Diet, central nervous system and aging. Fed. Proc. 38: 2017–2022, 1979.
K. R. Brizzee. Quantitative histological studies on aging changes in cerebral cortex of Rhesus monkey and Albino rat with notes on effects of prolonged low-dose ionizing irradiation in the rat. Prog. Brain Res. 40: 141–160, 1973.
Q. R. Smith, S. Momma, M. Aoyagi, and S. I. Rapoport. Kinetics of neutral amino acid transport across the BBB. J. Neurochem. 49: 1651–1658, 1987.
G. S. Sarna, M. D. Tricklebank, B. D. Kantamaneni, A. Hunt, A. Patel, and G. Cuzon. Effect of age on variables influencing the supply of tryptophan to the brain. J. Neurochem. 39: 1283–1290, 1982.
A. D. Mooradian. Blood-brain barrier transport of choline is reduced in the aged rat. Brain Res. 440: 328–333, 1988.
Y. Takasato, S. I. Rapoport, and Q. R. Smith. An in situ brain perfusion technique to study Cerebrovascular transport in the rat. Am. J. Physiol. 247: H484–493, 1984.
Y. Takada, D. T. Visstica, N. H. Greig, D. Purdon, S. I. Rapoport, and Q. R. Smith. Rapid high-affinity transport of a chemotherapeutic amino acid across the BBB. Cancer Res. 52: 2191–96, 1992.
G. L. Atkins and I. A. Nimmo. Current trends in the estimation of Michaelis-Menten parameters. Anal. Biochem. 104: 1–9, 1980.
Y. Takasato, S. Momma, and Q. R. Smith. Kinetic analysis of cerebrovascular isoleucine transport from saline and plasma. J. Neurochem 45: 1013–1020, 1985.
SCI Software Statistical Consultants Inc., PCNONLIN User's Guide, edited by Statistical Consultants Inc., Lexington, KY, 1989.
SPSS User's Guide, edited by SPSS Inc., McGraw-Hill, New York, 1983.
S. Bolton. Transformation and outliers. In Pharmaceutical Statistics—Practical and Clinical Applications, edited by J. Swarbrick, pp 294–299, Marcel Dekker Inc., New York and Basel, 1984.
S. I. Rapoport, K. Ohno and K. D. Pettigrew. Blood-brain barrier permeability in senescent rats. J. Gerontol. 34: 162–169, 1979.
S. I. Rapoport, K. Ohno, and K. D. Pettigrew. Drug entry into brain. Brain Res. 172: 354–359, 1979.
S. Momma, M. Aoyagi, S. I. Rapoport, and Q. R. Smith. Phenylalanine transport across the BBB as studied with the in situ brain perfusion technique. J. Neurochem. 48: 1291–1300, 1987.
W. M. Pardridge. Brain metabolism: a perspective from the BBB. Physiol. Rev. 63: 1481–1535, 1983.
J. L. Meek, L. Bertilsson, D. L. Cheney, G. Zsilla, and E. Costa. Aging-induced changes in acetylcholine and serotonin content of discrete brain nuclei. J. Gerontol. 32: 129–132, 1977.
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Tang, JP., Melethil, S. Effect of Aging on the Kinetics of Blood–Brain Barrier Uptake of Tryptophan in Rats. Pharm Res 12, 1085–1091 (1995). https://doi.org/10.1023/A:1016283003747
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DOI: https://doi.org/10.1023/A:1016283003747