Hepatocyte growth factor attenuates cerebral ischemia-induced learning dysfunction.
Hepatocyte growth factor (HGF) acts as an organotropic factor for regeneration and protection in various organs and has the ability to attenuate cerebral ischemia-induced cell death. However, the effect of HGF on learning and memory function after a cerebral ischemic event is unknown. We demonstrate here that administration of human recombinant HGF (hrHGF) into the ventricle reduced the prolongation of the escape latency in the acquisition and retention tests in the water maze task on days 12-28 after microsphere embolism-induced cerebral ischemia. In addition, disruption of the blood-brain barrier at the early stage after microsphere embolism, which was determined by FITC-albumin leakage, was markedly reduced by treatment with hrHGF. We demonstrated that this effect of hrHGF on the blood-brain barrier was associated with protection against the apoptotic death of the cerebral endothelial cells at the early stage after the ischemia. These results suggest that hrHGF can prevent the learning and memory dysfunction soon after sustained cerebral ischemia by protecting against injury to the endothelial cells. The use of HGF may be a potent strategy for the treatment of cerebrovascular diseases, including cerebral infarct and vascular dementia.
Date
Ichiro
I
Department of Pharmacology, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
Takagi
Norio
N
Takagi
Keiko
K
Kago
Tomoyuki
T
Matsumoto
Kunio
K
Nakamura
Toshikazu
T
Takeo
Satoshi
S
D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology; D001921:Brain / Q000473:pathology / Q000502:physiology; D002545:Brain Ischemia / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020287:In Situ Nick-End Labeling; D007276:Injections, Intraventricular; D007859:Learning Disabilities / Q000378:metabolism* / Q000473:pathology; D008297:Male; D018782:Maze Learning / Q000502:physiology*; D008568:Memory / Q000502:physiology*; D008863:Microspheres; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; C494813:Bcl2l1 protein, rat; D018696:Neuroprotective Agents; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D017228:Hepatocyte Growth Factor