title: Minoxidil sulfate induced the increase in blood-brain tumor barrier permeability through ROS/RhoA/PI3K/PKB signaling pathway.
abstract: Adenosine 5'-triphosphate-sensitive potassium channel (KATP channel) activator, minoxidil sulfate (MS), can selectively increase the permeability of the blood-tumor barrier (BTB); however, the mechanism by which this occurs is still under investigation. Using a rat brain glioma (C6) model, we first examined the expression levels of occludin and claudin-5 at different time points after intracarotid infusion of MS (30 μg/kg/min) by western blotting. Compared to MS treatment for 0 min group, the protein expression levels of occludin and claudin-5 in brain tumor tissue of rats showed no changes within 1 h and began to decrease significantly after 2 h of MS infusion. Based on these findings, we then used an in vitro BTB model and selective inhibitors of diverse signaling pathways to investigate whether reactive oxygen species (ROS)/RhoA/PI3K/PKB pathway play a key role in the process of the increase of BTB permeability induced by MS. The inhibitor of ROS or RhoA or PI3K or PKB significantly attenuated the expression of tight junction (TJ) protein and the increase of the BTB permeability after 2 h of MS treatment. In addition, the significant increases in RhoA activity and PKB phosphorylation after MS administration were observed, which were partly inhibited by N-2-mercaptopropionyl glycine (MPG) or C3 exoenzyme or LY294002 pretreatment. The present study indicates that the activation of signaling cascades involving ROS/RhoA/PI3K/PKB in BTB was required for the increase of BTB permeability induced by MS. Taken together, all of these results suggested that MS might increase BTB permeability in a time-dependent manner by down-regulating TJ protein expression and this effect could be related to ROS/RhoA/PI3K/PKB signal pathway.
authors: Department of Physiology, Life Science and Biology Pharmacopedia Institution, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning Province, PR China. Electronic address: yanting-gu@163.com.
authors: Yan-ting
authors: YT
authors: Gu
authors: Department of Neurobiology, College Basic of Medicine, China Medical University, Shenyang 110001, Liaoning Province, PR China. Electronic address: xueyixue888@yahoo.com.cn.
authors: Yi-xue
authors: YX
authors: Xue
authors: Department of Orthopaedics, The First Affiliated Hospital, China Medical University, Shenyang 110001, Liaoning Province, PR China.
authors: Yan-feng
authors: YF
authors: Wang
authors: Department of Phytochemistry, Chinese Materia Medica Institution, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning Province, PR China.
authors: Jin-hui
authors: JH
authors: Wang
authors: Department of Physiology, Life Science and Biology Pharmacopedia Institution, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning Province, PR China.
authors: Xia
authors: X
authors: Chen
authors: Department of Physiology, Life Science and Biology Pharmacopedia Institution, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning Province, PR China.
authors: Qian-ru
authors: QR
authors: ShangGuan
authors: Department of Physiology, Life Science and Biology Pharmacopedia Institution, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning Province, PR China.
authors: Yan
authors: Y
authors: Lian
authors: Department of Physiology, Life Science and Biology Pharmacopedia Institution, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning Province, PR China.
authors: Lei
authors: L
authors: Zhong
authors: Department of Physiology, Life Science and Biology Pharmacopedia Institution, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning Province, PR China.
authors: Ying-nan
authors: YN
authors: Meng
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000503:physiopathology; D001932:Brain Neoplasms / Q000473:pathology*; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D057167:Claudins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D017097:Electric Impedance; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005910:Glioma / Q000473:pathology*; D006735:Horseradish Peroxidase / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D008297:Male; D008914:Minoxidil / Q000031:analogs & derivatives* / Q000494:pharmacology; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D057167:Claudins; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; C039516:minoxidil sulfate ester; D008914:Minoxidil; D006735:Horseradish Peroxidase; D019869:Phosphatidylinositol 3-Kinases; D020742:rhoA GTP-Binding Protein
keywords: ATP-sensitive potassium channel; Blood–tumor barrier; Glioma; Reactive oxygen species; Tight junction protein