title: Stroke upregulates TNFalpha transport across the blood-brain barrier.
abstract: To determine how cytokine transport systems at the blood-brain barrier (BBB) participate in stroke progression and recovery, we generated a mouse model of transient middle cerebral artery occlusion (tMCAO). After 1 h of occlusion followed by nearly complete reperfusion, the neurological deficits lasted more than a week as shown by several behavioral tests. Despite the prominent infarct area indicated by reduced cerebral perfusion and confirmed by vital staining, the volume of distribution of (131)I-albumin in various brain regions was not significantly altered over time (12 h to 14 days). In sharp contrast, the blood-to-brain permeation of 125I-TNFalpha was significantly increased 5 days after tMCAO. Furthermore, excess unlabeled TNFalpha abolished this enhanced 125I-TNFalpha uptake. Thus, not only did the known saturable transport system for TNFalpha persist, but it functioned at a higher capacity in tMCAO mice. Upregulation of TNFR1 and TNFR2 partially explains the increased transport, as mRNA for both receptors showed the most pronounced increase (15-fold and 30-fold, respectively) in the ischemic hemisphere 5-7 days after tMCAO. However, even in the hemisphere contralateral to the ischemia induced by stroke, there was increased TNFalpha transport. The bilateral increase in 125I-TNFalpha entry from blood to brain suggests that TNFalpha trafficking in cerebral endothelial cells is influenced by global mediators in addition to the transporting receptors. Given the known multiple modulatory effects of TNFalpha after stroke, the results indicate that the TNFalpha transport system at the BBB facilitates neuroplasticity and plays an important role in stroke recovery.
authors.affiliation: Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808, USA. weihong.pan@pbrc.edu
authors.forename: Weihong
authors.initials: W
authors.lastname: Pan
authors.forename: Yuemin
authors.initials: Y
authors.lastname: Ding
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Yu
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Ohtaki
authors.forename: Tomoya
authors.initials: T
authors.lastname: Nakamachi
authors.forename: Abba J
authors.initials: AJ
authors.lastname: Kastin
mesh_terms: D042931:Aldehyde Oxidase; D000818:Animals; D029681:Arabidopsis Proteins; D001692:Biological Transport / Q000502:physiology; D001812:Blood-Brain Barrier / Q000503:physiopathology*; D002544:Cerebral Infarction / Q000209:etiology / Q000473:pathology; D004195:Disease Models, Animal; D015870:Gene Expression / Q000502:physiology; D007456:Iodine Isotopes / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000502:physiology; D009460:Neurologic Examination / Q000379:methods; D011597:Psychomotor Performance / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D020521:Stroke / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D013778:Tetrazolium Salts; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D029681:Arabidopsis Proteins; D007456:Iodine Isotopes; D012333:RNA, Messenger; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D013778:Tetrazolium Salts; D014409:Tumor Necrosis Factor-alpha; C009591:triphenyltetrazolium; C467964:AAO1 protein, Arabidopsis; D042931:Aldehyde Oxidase