Article

Blood–Brain Barrier Permeability and Brain Uptake Mechanism of Kainic Acid and Dihydrokainic Acid

Neurochemical Research, Springer Nature, ISSN 1573-6903

Volume 40, 3, 2015

DOI:10.1007/s11064-014-1499-4, Dimensions: pub.1018093517, PMID: 25488153,

Authors

Gynther, Mikko (1) (2)

* Corresponding author

Affiliations

Organisations

  1. (1) University of Eastern Finland, grid.9668.1
  2. (2) University of Copenhagen, grid.5254.6, KU

Countries

Finland

Denmark

Continents

Europe

Description

The glutamatergic neurotransmitter system is involved in important neurophysiological processes and thus constitutes a promising target for the treatment of neurological diseases. The two ionotropic glutamate receptor agonists kainic acid (KA) and dihydrokainic acid (DHK) have been used as research tools in various in vivo central nervous system disease models in rodents, as well as being templates in the design of novel ligands affecting the glutamatergic system. Both molecules are highly polar but yet capable of crossing the blood-brain barrier (BBB). We used an in situ rat brain perfusion technique to determine the brain uptake mechanism and permeability across the BBB. To determine KA and DHK concentrations in the rat brain, simple and rapid sample preparation and liquid chromatography mass spectrometer methods were developed. According to our results the BBB permeability of KA and DHK is low, 0.25 × 10(-6) and 0.28 × 10(-6) cm/s for KA and DHK, respectively. In addition, the brain uptake is mediated by passive diffusion, and not by active transport. Furthermore, the non-specific plasma and brain protein binding of KA and DHK was determined to be low, which means that the unbound drug volume of distribution in brain is also low. Therefore, even though the total KA and DHK concentrations in the brain are low after systemic dosing, the concentrations in the vicinity of the glutamate receptors are sufficient for their activation and thus the observed efficacy.

Research Categories

Main Subject Area

Fields of Research

Links & Metrics

NORA University Profiles

University of Copenhagen

Danish Open Access Indicator

2015: Unused

Research area: Medicine

Danish Bibliometrics Indicator

2015: Level 1

Research area: Medicine

Dimensions Citation Indicators

Times Cited: 10

Field Citation Ratio (FCR): 2.41

Relative Citation ratio (RCR): 0.48