title: Platelet activating factor induces transient blood-brain barrier opening to facilitate edaravone penetration into the brain.
abstract: The blood-brain barrier (BBB) greatly limits the efficacy of many neuroprotective drugs' delivery to the brain, so improving drug penetration through the BBB has been an important focus of research. Here we report that platelet activating factor (PAF) transiently opened BBB and facilitated neuroprotectant edaravone penetration into the brain. Intravenous infusion with PAF induced a transient BBB opening in rats, reflected by increased Evans blue leakage and mild edema formation, which ceased within 6 h. Furthermore, rat regional cerebral blood flow (rCBF) declined acutely during PAF infusion, but recovered slowly. More importantly, this transient BBB opening significantly increased the penetration of edaravone into the brain, evidenced by increased edaravone concentrations in tissue interstitial fluid collected by microdialysis and analyzed by Ultra-performance liquid chromatograph combined with a hybrid quadrupole time-of-flight mass spectrometer (UPLC-MS/MS). Similarly, incubation of rat brain microvessel endothelial cells monolayer with 1 μM PAF for 1 h significantly increased monolayer permeability to (125)I-albumin, which recovered 1 h after PAF elimination. However, PAF incubation with rat brain microvessel endothelial cells for 1 h did not cause detectable cytotoxicity, and did not regulate intercellular adhesion molecule-1, matrix-metalloproteinase-9 and P-glycoprotein expression. In conclusion, PAF could induce transient and reversible BBB opening through abrupt rCBF decline, which significantly improved edaravone penetration into the brain. Platelet activating factor (PAF) transiently induces BBB dysfunction and increases BBB permeability, which may be due to vessel contraction and a temporary decline of regional cerebral blood flow (rCBF) triggered by PAF. More importantly, the PAF induced transient BBB opening facilitates neuroprotectant edaravone penetration into brain. The results of this study may provide a new approach to improve drug delivery into the brain.
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing, China.
authors.forename: Weirong
authors.initials: W
authors.lastname: Fang
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.forename: Lan
authors.initials: L
authors.lastname: Sha
authors.forename: Peng
authors.initials: P
authors.lastname: Lv
authors.forename: Erxin
authors.initials: E
authors.lastname: Shang
authors.forename: Dan
authors.initials: D
authors.lastname: Han
authors.forename: Jie
authors.initials: J
authors.lastname: Wei
authors.forename: Xiaohan
authors.initials: X
authors.lastname: Geng
authors.forename: Qichuan
authors.initials: Q
authors.lastname: Yang
authors.forename: Yunman
authors.initials: Y
authors.lastname: Li
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000096:biosynthesis; D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects*; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001929:Brain Edema / Q000139:chemically induced; D002196:Capillaries / Q000378:metabolism; D002555:Cerebrospinal Fluid / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004396:Coloring Agents; D019040:E-Selectin / Q000096:biosynthesis; D000077553:Edaravone; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005070:Evans Blue; D005434:Flow Cytometry; D007262:Infusions, Intravenous; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D017551:Microdialysis; D018696:Neuroprotective Agents / Q000378:metabolism*; D010972:Platelet Activating Factor / Q000494:pharmacology*; D019275:Radiopharmaceuticals / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012711:Serum Albumin, Radio-Iodinated / Q000378:metabolism; D013778:Tetrazolium Salts; D013844:Thiazoles
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D004396:Coloring Agents; D019040:E-Selectin; D018696:Neuroprotective Agents; D010972:Platelet Activating Factor; D019275:Radiopharmaceuticals; D012711:Serum Albumin, Radio-Iodinated; D013778:Tetrazolium Salts; D013844:Thiazoles; D005070:Evans Blue; D020780:Matrix Metalloproteinase 9; C022616:thiazolyl blue; D000077553:Edaravone; D000983:Antipyrine
keywords: blood-brain barrier; edaravone; microdialysis; platelet activating factor