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.
Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
Zhaojian
Z
Li
Renzhi
R
Wang
Shifang
S
Li
Junji
J
Wei
Ziheng
Z
Zhang
Guilin
G
Li
Wanchen
W
Dou
Yukui
Y
Wei
Ming
M
Feng
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