Transient forebrain
ischemia induces activation of
calpain and proteolysis of a neuronal cytoskeleton,
fodrin, in gerbil hippocampus. This phenomenon precedes delayed neuronal death in hippocampal CA1 neurons. We examined effects of a
calpain inhibitor on delayed neuronal death after transient forebrain
ischemia. In gerbils, a selective
calpain inhibitor entrapped in
liposome was given transvenously and 30 min later, 5-min forebrain
ischemia was produced by occlusion of both common carotid arteries. On day 7, CA1 neuronal damage was examined in the hippocampal slices stained with
cresyl violet.
Calpain-induced proteolysis of
fodrin was also examined by immunohistochemistry and immunoblot. Additionally, to assure entrapment of the inhibitor by CA1 neurons, the inhibitor-
liposome complex was labeled with
FITC and given to gerbils. Fluorescence in the hippocampal slices was examined by confocal
laser scanning microscope. Selective CA1 neuronal damage induced by forebrain
ischemia was prevented by administration of the inhibitor in a dose-dependent manner.
Calpain-induced proteolysis of
fodrin was also extinguished by the
calpain inhibitor in a dose-dependent manner. Bright fluorescence of the
FITC-labeled inhibitor was observed in the CA1 neurons. The data show an important role of
calpain in the development of the ischemic delayed neuronal death.
Calpain seems to produce neuronal damage by degrading neuronal cytoskeleton. Our data also show a palliative effect of the
calpain inhibitor on the neurotoxic damage, which offers a new and potent treatment of transient forebrain
cerebral ischemia.