Overexpression of rat heat shock protein 70 reduces neuronal injury after transient focal ischemia, transient global ischemia, or kainic acid-induced seizures.
OBJECTIVE
Transgenic (Tg) mice overexpressing rat heat shock protein 70 (hsp70) demonstrated less infarction than did wild-type (WT) littermates after permanent focal cerebral ischemia. The purpose of this study was to determine whether neuronal injury and apoptosis were reduced in hsp70 Tg mice after transient focal ischemia. The effects of hsp70 overexpression were also evaluated after transient global ischemia or kainic acid (KA)-induced seizures, to verify the results in other excitotoxic stress models.


METHODS
Transient focal ischemia was produced with middle cerebral artery occlusion via intraluminal suture cannulation. Infarction volumes were assessed 24 hours after 30 minutes of middle cerebral artery occlusion. Transient global ischemia was produced with 25 minutes of bilateral common carotid artery occlusion. KA (30 mg/kg) was administered subcutaneously, and seizure activity was evaluated. The number of eosinophilic neurons was assessed in the CA1 region 72 hours after bilateral common carotid artery occlusion and in the CA3 region 24 hours after KA administration.


RESULTS
The infarction volume after transient middle cerebral artery occlusion was significantly smaller in hsp70 Tg mice than in WT mice (9.1 +/- 5.7 mm(3) versus 22.4 +/- 16.8 mm(3), P < 0.05). The number of eosinophilic neurons in the CA1 area after bilateral common carotid artery occlusion and in CA3 after KA injection was significantly lower in hsp70 Tg mice than in WT mice (949.1 +/- 1095.5 versus 2406.9 +/- 1380.3, P < 0.05, and 33.8 +/- 45.3 versus 119.4 +/- 112.1, P < 0.05, respectively). Fewer terminal deoxynucleotidyl transferase-mediated biotinylated deoxyuridine triphosphate nick end-labeling-positive cells were observed in hsp70 Tg mice than in WT mice in each model.


CONCLUSIONS
The results demonstrate that overexpression of hsp70 reduces neuronal injury after ischemia and seizures. The reduction in the number of terminal deoxynucleotidyl transferase-mediated biotinylated deoxyuridine triphosphate nick end-labeling-positive cells in hsp70 Tg mice suggests that hsp70 overexpression might reduce apoptotic cell death.
Department of Neurological Surgery, University of California, San Francisco, California 94143-0112, USA.
Daisuke
D
Tsuchiya
Shwuhuey
S
Hong
Yasuhiko
Y
Matsumori
Takamasa
T
Kayama
Raymond A
RA
Swanson
Wolfgang H
WH
Dillman
Jialing
J
Liu
S Scott
SS
Panter
Philip R
PR
Weinstein
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D020520:Brain Infarction / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D018690:Excitatory Amino Acid Agonists; D015870:Gene Expression; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000502:physiology*; D002546:Ischemic Attack, Transient / Q000473:pathology / Q000503:physiopathology*; D007608:Kainic Acid; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000473:pathology*; D051381:Rats; D012640:Seizures / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*
D018690:Excitatory Amino Acid Agonists; D018840:HSP70 Heat-Shock Proteins; D007608:Kainic Acid