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Age Dependency of Blood-Brain Barrier Penetration by cis- and trans-Permethrin in the Rat

Tanzir B Mortuza1, Gaylen L Edwards1, Catherine A White1

  • 1Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy (T.B.M., C.A.W., B.S.C., J.V.B.), Interdisciplinary Toxicology Program (G.L.E., C.A.W., B.S.C., J.V.B.), and Department of Physiology and Pharmacology, College of Veterinary Medicine (G.L.E.), University of Georgia, Athens, Georgia.

Drug Metabolism and Disposition: the Biological Fate of Chemicals
|December 8, 2018
PubMed

Insights

The immature blood-brain barrier (BBB) allows greater permethrin (PER) insecticide entry in young rats than in adults. This increased permeability may explain why young rodents are more susceptible to PER neurotoxicity.

Area of Science:

  • Neuroscience
  • Toxicology
  • Developmental Biology

Background:

  • Permethrin (PER) is a widely used insecticide, classified as a type I pyrethroid.
  • The blood-brain barrier (BBB) regulates xenobiotic entry into the brain.
  • Pyrethroid neurotoxicity can be influenced by BBB permeability.

Purpose of the Study:

  • To evaluate the efficiency of the blood-brain barrier (BBB) in restricting brain uptake of cis-permethrin (CIS) and trans-permethrin (TRANS) isomers.
  • To determine if BBB function changes during rat maturation.
  • To investigate the relationship between age-dependent BBB permeability and susceptibility to permethrin.

Main Methods:

  • Quantified brain uptake of 14C-labeled CIS and TRANS in Sprague-Dawley rats at postnatal days 14, 21, and 90.
  • Utilized carotid artery perfusion with varying pyrethroid concentrations (1, 10, 50 µM) in albumin solution.
  • Measured brain deposition of each isomer over perfusion durations of 2 or 4 minutes.

Main Results:

  • Brain deposition of both CIS and TRANS isomers was inversely related to age, with significantly higher levels in 14-day-old rats compared to adults (>5-fold).
  • Pyrethroid uptake by the brain was linear across a 50-fold concentration range, indicating passive, nonsaturable BBB permeation.
  • Uptake levels for CIS and TRANS were similar at toxicologically relevant concentrations.

Conclusions:

  • The blood-brain barrier (BBB) is less efficient in immature rats, allowing greater brain penetration of permethrin isomers.
  • Dissimilar BBB permeability does not account for the higher acute neurotoxicity of cis-permethrin.
  • Increased permeability of the immature BBB to permethrin may contribute to the heightened susceptibility of preweanling rodents to insecticide neurotoxicity.

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