Premium
Changes in dipole membrane potential at the mouse blood–brain barrier enhance the transport of 99m Technetium Sestamibi more than inhibiting Abcb1, Abcc1, or Abcg2
Author(s) -
Cattelotte Julie,
Tournier Nicolas,
RizzoPadoin Nathalie,
Schinkel Alfred H.,
Scherrmann JeanMichel,
Cisternino Salvatore
Publication year - 2009
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2008.05832.x
Subject(s) - organic cation transport proteins , chemistry , blood–brain barrier , atp binding cassette transporter , p glycoprotein , biophysics , phloretin , membrane potential , abcg2 , transporter , biochemistry , medicine , biology , central nervous system , antibiotics , multiple drug resistance , gene
Cationic 99m Tc‐agents like 99m Tc‐hexakis‐2‐methoxyisobutyl isonitrile ( 99m Tc‐MIBI) cannot be used for brain imaging because they do not enter the brain as readily as some uncharged 99m Tc‐compounds. The mechanism by which cationic 99m Tc‐agents are transported across the blood–brain barrier (BBB) remains unclear. We explored 99m Tc‐MIBI transport by in situ mouse brain perfusion to determine the influence of BBB features like the ATP‐binding cassette transporters (Abcb1/P‐glycoprotein (P‐gp), Abcc1/Mrp1, and Abcg2/Bcrp), organic cation transporters (Slc22a1‐3/Oct1‐3), the transmembrane potential and the dipole membrane potential. P‐gp reduced 99m Tc‐MIBI transport across the BBB of P‐gp‐deficient mice 2.2‐fold, as confirmed by PSC833 and GF120918 inhibition. Paradoxically verapamil decreased its transport ‘0.6‐fold’. Reducing the BBB dipole membrane potential with tetraphenylborate or phloretin increased 99m Tc‐MIBI transport about 12‐ and 20‐fold, respectively. Guanidine, diphenhydramine, and carnitine significantly decreased 99m Tc‐MIBI transport, but tetraethylammonium did not. 99m Tc‐MIBI transport at the BBB is restricted by P‐gp but not by Mrp1 or Bcrp. Some organic cations reduced the influx of 99m Tc‐MIBI into the brain independently of Oct1, 2 and 3, but this could be due to their effect on another cation transporter. The membrane dipole potential of the luminal BBB membrane appeared to be the main factor restricting 99m Tc‐MIBI permeability.