We have previously shown that
cerebral Hypoxia-ischemia (HI) results in activation of
Src kinase in the newborn piglet brain. We investigated the regulatory mechanism by which the pre-apoptotic
proteins translocate from mitochondria to the cytosol during HI through the
Src kinase. Newborn piglets were divided into 3 groups (n = 5/group): normoxic (Nx), HI and HI pre-treated with
Src kinase inhibitor PP2 (PP2 + HI). Brain tissue HI was verified by neuropathological analysis and by
Adenosine Triphosphate (
ATP) and
Phosphocreatine (PCr) levels. We used western blots, immunohistochemistry, H&E and biochemical
enzyme assays to determine the role of
Src kinase on mitochondrial membrane apoptotic protein trafficking. HI resulted in decreased
ATP and PCr levels, neuropathological changes and increased levels of
cytochrome c, Smac/DIABLO and AIF in the cytosol while their levels were decreased in mitochondria compared to Nx. PP2 decreased the cytosolic levels of pre-apoptotic
proteins, attenuated the neuropathological changes and apoptosis and decreased the HI-induced increased activity of
caspase-3. Our data suggest that
Src kinase may represent a potential target that could interrupt the enzymatic activation of the
caspase dependent cell death pathway.