Differential regulation of transport proteins in the periinfarct region following reversible middle cerebral artery occlusion in rats.
Members of various transport protein families including ATP-binding cassette transporters and solute carriers were shown to be expressed in brain capillaries, choroid plexus, astrocytes or neurons, controlling drug and metabolite distribution to and from the brain. However, data are currently very limited on how the expression of these transport systems is affected by damage to the brain such as stroke. Therefore we studied the expression of four selected transporters, P-glycoprotein (Mdr1a/b; Abcb1a/b), Mrp5 (Abcc5), Bcrp (Abcg2), and Oatp2 (Slc21a5) in a rat model for stroke. Transporter expression was analyzed by real-time polymerase chain reaction in the periinfarcted region and protein localization and cellular phenotyping were done by immunohistochemistry and confocal immunofluorescence microscopy. After stroke, P-glycoprotein staining was detected in endothelial cells of disintegrated capillaries and by day 14 in newly generated blood vessels. There was no significant difference, however, in the Mdr1a mRNA amount in the periinfarcted region compared with the contralateral site. For Bcrp, a significant mRNA up-regulation was observed from days 3-14. This up-regulation was followed by the protein as confirmed by quantitative immunohistochemistry. Oatp2, located in the vascular endothelium, was also up-regulated at day 14. For Mrp5, an up-regulation was observed in neurons in the periinfarcted region (day 14). In conclusion, after stroke the transport proteins were up-regulated with a maximum at day 14, a time point that coincides with behavioral recuperation. The study further suggests Bcrp as a pronounced marker for the regenerative process and a possible functional role of Mrp5 in surviving neurons.
Dazert
P
P
Department of Pharmacology, Research Center of Pharmacology and Experimental Therapeutics, Ernst-Moritz-Arndt University, Greifswald, Germany.
Suofu
Y
Y
Grube
M
M
Popa-Wagner
A
A
Kroemer
H K
HK
Jedlitschky
G
G
Kessler
C
C
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000503:physiopathology; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D002196:Capillaries / Q000378:metabolism / Q000503:physiopathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002544:Cerebral Infarction / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000502:physiology; D012038:Regeneration / Q000502:physiology; D013997:Time Factors; D015854:Up-Regulation / Q000502:physiology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D015415:Biomarkers; D002352:Carrier Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; D012333:RNA, Messenger; C492375:Abcc5 protein, rat; C489249:Abcg2 protein, rat; C503597:Slco1a4 protein, rat