Downregulation of GRP78 chaperone protein triggers pro‐apoptotic CHOP signaling cascade in acute intracerebral hemorrhage rats

Abstract

Endoplasmic reticulum (ER) stress triggered‐apoptosis might play important role in many neurological disorders, leading to brain damage consequently. Glucose regulated protein (GRP) 78 or Bip, serves as a master controller in stabilizing the unfolded proteins resulted from various stimuli in the ER and thus reduces ER stress. Although upregulation of GRP78/Bip possesses neuroprotective effect in ischemic stroke animals, its role in the most deadly type of stroke ‐ intracerebral hemorrhage (ICH), remains unclear. The aim of this study work was to study the role of GRP78/Bip during ICH injury.ICH were induced in rats by intrastriatal infusion of 0.2 U collagenase VII‐S. The neurological severity was evaluated before and at 1‐, 3‐ and 7‐days after ICH. At 0, 1, 3, 6, 24, and 72 hours, brains were recovered for hematoma volume measurement, and molecular biological or histological studies.Our results demonstrated that GRP78/Bip rapidly decreased in the ipsilateral striata during 1 to 3 hours post‐ICH, and gradually restored to the basal level at 24 hours post‐ICH. The downregulation of GRP78/Bip was associated with the severity of the hemorrhagic volume. Reversed PCR of GRP78/Bip indicated the decrease of GRP78/Bip was not due to the decreased expression of GRP78/Bip gene, but was the result of increased ubiquitin‐mediated degradation. The decrease of GRP78/Bip triggers the pro‐apoptotic CHOP to be activated during the 24 to 72 hours post‐ICH. The activation of CHOP was associated with the volume of the hematoma and the severity of the ICH‐induced brain injury. Thus, the decrease of GRP78/Bip at the early phase was correlated with the severity of ICH injury, and treatment targeting on regulating Bip/GRP78 might has a clinical potential in reducing ICH‐induced brain injury.