Viral vector mediated Hsp72 overexpression protects against global cerebral ischemia and when given after experimental stroke
INTRODUCTION: We and others have previously shown that the stress protein HSP72 protected against focal cerebral ischemia and excitotoxin exposure when overexpression occurred prior to the insult, provided the extent of transgene expression was sufficiently high, and the insult not too severe. Whether HSP72 overexpression is protective after focal ischemia or in other brain ischemia models is unknown. We studied whether HSP72 protected when delivered after a stroke, and also if it protected CA1 cells against global cerebral ischemia by using amplicon based viral vectors that permit high levels of transgene expression. METHODS: Bipromoter, defective herpes simplex vectors expressing HSP72 and β-galactosidase as a reporter (or β-galactosidase only as a control) were delivered to the striata of 21 rats 20min after 1h MCA occlusion. 48h after reperfusion, the number of remaining reporter gene positive neurons were counted and expressed as ratio of the number of surviving cells between ischemic to nonischemic hemispheres. 15 h prior to the onset of global cerebral ischemia (bilateral common carotid artery occlusion plus hypotension; n=9), similar vectors were injected into each CA1 hippocampal subsector. Reporter gene positive cells in CA1 were counted and compared to counts in sham operated rats injected with vector (n=4). RESULTS: Survival among HSP72 treated groups was significantly higher for both experiments. After post insult delivery in the MCA occlusion model, 54.7±8.6% of HSP72 treated cells remained versus 31.2±5.1% of control vector treated (P<0.03). Following global cerebral ischemia, 31±8% of HSP72 treated CA1 neurons remained compared to 10±4% among controls (P<0.05). CONCLUSIONS: To our knowledge, this is the first study to show that postischemic HSP72 overexpression is protective, and that HSP72 protects CA1 neurons from global cerebral ischemia. This suggests that this stress protein may be a useful therapeutic target because it protects against a variety of insults and is also effective when treatment is delayed.