TY - JOUR
T1 - Blood-brain barrier opening to large molecules does not imply blood-brain barrier opening to small ions
AU - Kang, E. J.
AU - Major, S.
AU - Jorks, D.
AU - Reiffurth, C.
AU - Offenhauser, N.
AU - Friedman, A.
AU - Dreier, J. P.
N1 - Funding Information:
This work was supported by the German Science Foundation (Deutsche Forschungsgemeinschaft , DFG 323/6-1 , J.P.D), Bundesministerium für Bildung und Forschung (Era-Net Neuron SDSVD (A.F., J.P.D.), BMBF CSB 01 EO 0801 (J.P.D.), BCCN 01GQ1001C (J.P.D.)), the German Israeli Foundation ( GIF No. 124/2008 , A.F, J.P.D). Alon Friedman was a recipient of a Mercator professorship from the DFG.
PY - 2013/4/1
Y1 - 2013/4/1
N2 - Neuroimaging of exogenous tracer extravasation has become the technique of choice in preclinical and clinical studies of blood-brain barrier permeability. Such tracers have a larger molecular weight than small ions, neurotransmitters and many drugs. Therefore, it is assumed that tracer extravasation indicates both permeability to these and the cancelation of the electrical polarization across the barrier. Electrophysiological anomalies following intracarotideal administration of dehydrocholate, a bile salt causing extravasation of the albumin-binding tracer Evans blue, seemingly supported this. By contrast, electron microscopic studies suggested a different hierarchical pattern of blood-brain barrier dysfunction, a milder degree of impairment being characterized by increased function of the transcellular pathway and a severe degree by opening of the tight junctions. This would imply that the extravasation of macromolecules can occur before disruption of the electrical barrier. However, functional evidence for this has been lacking. Here, we further investigated the electrophysiological anomalies following intracarotideal application of dehydrocholate in rats and found that it caused focal cerebral ischemia by middle cerebral artery thrombosis, the electrophysiological recordings being characteristic of long-lasting spreading depolarization. These observations indicated that intracarotideal dehydrocholate is not a suitable model to study the isolated dysfunction of the blood-brain barrier. Second, we studied the topical application of dehydrocholate to the brain and the application of mannitol into the carotid artery. In both models, we found significant extravasation of Evans blue but no changes in either extracellular potassium or the CO2-dependent intracortical direct current deflection. The latter is assumed to depend on the proton gradient across the barrier in rats which we confirmed in additional experiments in vivo and in vitro. The stability of the extracellular potassium concentration and the CO2-dependent direct current deflection are two functional tests which indicate the integrity of the electrical barrier. Hence, our results provide functional evidence that the blood-brain barrier opening to large molecules does not necessarily imply the opening to small ions consistent with the hierarchy of damage in the previous electron microscopic studies.
AB - Neuroimaging of exogenous tracer extravasation has become the technique of choice in preclinical and clinical studies of blood-brain barrier permeability. Such tracers have a larger molecular weight than small ions, neurotransmitters and many drugs. Therefore, it is assumed that tracer extravasation indicates both permeability to these and the cancelation of the electrical polarization across the barrier. Electrophysiological anomalies following intracarotideal administration of dehydrocholate, a bile salt causing extravasation of the albumin-binding tracer Evans blue, seemingly supported this. By contrast, electron microscopic studies suggested a different hierarchical pattern of blood-brain barrier dysfunction, a milder degree of impairment being characterized by increased function of the transcellular pathway and a severe degree by opening of the tight junctions. This would imply that the extravasation of macromolecules can occur before disruption of the electrical barrier. However, functional evidence for this has been lacking. Here, we further investigated the electrophysiological anomalies following intracarotideal application of dehydrocholate in rats and found that it caused focal cerebral ischemia by middle cerebral artery thrombosis, the electrophysiological recordings being characteristic of long-lasting spreading depolarization. These observations indicated that intracarotideal dehydrocholate is not a suitable model to study the isolated dysfunction of the blood-brain barrier. Second, we studied the topical application of dehydrocholate to the brain and the application of mannitol into the carotid artery. In both models, we found significant extravasation of Evans blue but no changes in either extracellular potassium or the CO2-dependent intracortical direct current deflection. The latter is assumed to depend on the proton gradient across the barrier in rats which we confirmed in additional experiments in vivo and in vitro. The stability of the extracellular potassium concentration and the CO2-dependent direct current deflection are two functional tests which indicate the integrity of the electrical barrier. Hence, our results provide functional evidence that the blood-brain barrier opening to large molecules does not necessarily imply the opening to small ions consistent with the hierarchy of damage in the previous electron microscopic studies.
KW - Blood-brain barrier
KW - Hypercapnia
KW - Paracellular pathway
KW - Spreading depolarization
KW - Stroke
KW - Transcellular pathway
UR - http://www.scopus.com/inward/record.url?scp=84873570552&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2012.12.007
DO - 10.1016/j.nbd.2012.12.007
M3 - Article
AN - SCOPUS:84873570552
SN - 0969-9961
VL - 52
SP - 204
EP - 218
JO - Neurobiology of Disease
JF - Neurobiology of Disease
ER -