Intraventricular administration of urokinase as a novel therapeutic approach for communicating hydrocephalus.
Fibrosis of the subarachnoid space (SAS) after infection, inflammation, or hemorrhage can impair cerebrospinal fluid absorption and circulation, causing diffuse ventricular dilatation. In the present study, we tested the hypothesis that urokinase (also known as urokinase-type plasminogen activator [uPA]), a fibrinolytic agent, attenuates fibrosis and ventriculomegaly in a rat model of kaolin-induced communicating hydrocephalus and thus may have potential as a therapy for these conditions. Thirty microliters of sterile 25% kaolin suspension was injected into the basal cisterns of adult Sprague-Dawley rats to induce hydrocephalus, and 2 intraventricular injections of either uPA or vehicle (saline) were administered immediately and 3 days thereafter. Ventricular volumes were measured by magnetic resonance imaging (MRI) on days 3, 14, and 28 after kaolin injection. Fibrosis and reactive astrogliosis were evaluated on day 28 by immunofluorescence and Western blotting. Neurocognitive features were tested using the Morris water maze from days 23 to 28. MRI analysis demonstrated that kaolin administration successfully induced hydrocephalus in rats and that uPA treatment significantly attenuated ventricular enlargement. In addition, uPA inhibited the deposition of laminin and fibronectin, extracellular matrix molecules, in the SAS, attenuated gliosis, and improved learning and memory in kaolin-treated rats. Therefore, we concluded that uPA prevents the development of kaolin-induced communicating hydrocephalus by preventing the development of subarachnoid fibrosis and by eliciting improvements in neurocognition. The results of this study indicate that uPA may be a novel clinical therapy for communicating hydrocephalus.
Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, People's Republic of China.
Zhou
Z
Feng
Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, People's Republic of China.
Qiang
Q
Tan
Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, People's Republic of China.
Jun
J
Tang
Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, People's Republic of China.
Lin
L
Li
Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, People's Republic of China.
Yihao
Y
Tao
Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, People's Republic of China.
Yujie
Y
Chen
Department of Neurosurgery, Sichuan Provincial Corps Hospital, Chinese People's Armed Police Forces, Leshan, People's Republic of China.
Yunfeng
Y
Yang
Department of Neurology, Southwest Hospital, Third Military Medical University, Chongqing, People's Republic of China.
Chunxia
C
Luo
Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, People's Republic of China.
Hua
H
Feng
Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, People's Republic of China.
Gang
G
Zhu
Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, People's Republic of China. Electronic address: qianweichen88@yeah.net.
Qianwei
Q
Chen
Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, People's Republic of China. Electronic address: zhichen@tmmu.edu.cn.
Zhi
Z
Chen
D000818:Animals; D015153:Blotting, Western; D003071:Cognition; D005355:Fibrosis; D005911:Gliosis / Q000378:metabolism / Q000473:pathology; D006849:Hydrocephalus / Q000188:drug therapy*; D007276:Injections, Intraventricular; D007616:Kaolin; D008279:Magnetic Resonance Imaging; D008297:Male; D008954:Models, Biological; D017207:Rats, Sprague-Dawley; D013346:Subarachnoid Space / Q000473:pathology; D014568:Urokinase-Type Plasminogen Activator / Q000008:administration & dosage* / Q000627:therapeutic use*
D007616:Kaolin; D014568:Urokinase-Type Plasminogen Activator