Intraventricular pre-treatment with rAAV-VEGF induces intracranial hypertension and aggravates ischemic injury at the early stage of transient focal cerebral ischemia in rats.
OBJECTIVE
To examine the effects of intraventricular pre-treatment with recombinant adeno-associated virus vectors encoding VEGF (rAAV-VEGF) on early stroke in a rat model of transient middle cerebral artery occlusion (tMCAO).


METHODS
rAAV-VEGF, rAAV-null or physiologic saline was delivered into the lateral ventricle of 93 Wistar rats, respectively. Eight weeks later, the rats were subjected to tMCAO for 2 hours. During the early stage following ischemic reperfusion, intracranial pressure (ICP) and brain water content were measured to make a correlation analysis, T2-weighted MRI was performed to observe cerebral edema volume, and TTC-derived cerebral infarct volume and modified neurological severity scores (NSS) were determined to evaluate the therapeutic efficacy of rAAV-VEGF in tMCAO.


RESULTS
Twenty-four hours following tMCAO, the rAAV-VEGF group, with VEGF overexpression in the rats brain, showed a significantly increase in ICP, brain water content and cerebral edema volume compared with two control groups (p<0.05). The ICP significantly correlated with the brain water content in the infarct hemisphere in all three groups during 24 hours following tMCAO (r=0.93, p<0.05). Forty-eight hours following tMCAO, a 1.3-fold larger infarct volume and 1.3-fold higher NSS were observed in the rAAV-VEGF group than both control groups (p<0.05).


CONCLUSIONS
Our results indicate that intraventricular rAAV-VEGF pre-treatment can result in deleterious intracranial hypertension and augment secondary ischemic insults at the early stage of tMCAO, and pre-ischemic VEGF gene transfer via intraventricular approach may not be a favorable therapeutic strategy for tMCAO which should be adopted with caution or avoided in experimental stroke.
Li
Zhaojian
Z
Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
Wang
Renzhi
R
Li
Shifang
S
Wei
Junji
J
Zhang
Ziheng
Z
Li
Guilin
G
Dou
Wanchen
W
Wei
Yukui
Y
Feng
Ming
M
D000818:Animals; D001834:Body Water / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D001929:Brain Edema / Q000473:pathology; D002544:Cerebral Infarction / Q000473:pathology; D000229:Dependovirus / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D007276:Injections, Intraventricular; D019586:Intracranial Hypertension / Q000503:physiopathology; D007427:Intracranial Pressure / Q000502:physiology; D002546:Ischemic Attack, Transient / Q000209:etiology / Q000503:physiopathology / Q000628:therapy*; D008279:Magnetic Resonance Imaging; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000150:complications; D016896:Treatment Outcome; D042442:Vascular Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D042442:Vascular Endothelial Growth Factors