Role of glucose-regulated protein 78 in early brain injury after experimental subarachnoid hemorrhage in rats

Abstract

Early brain injury (EBI) plays a key role in the pathogenesis of subarachnoid hemorrhage (SAH). This study investigated the role of glucose-regulated protein 78 (GRP78) in EBI after SAH. Male Sprague-Dawley rats (n=108) weighing 260±40 g were divided into control, sham-operated, and operated groups. Blood was injected into the prechiasmatic cistern of rats in the operated group. Neurological scores, ultrastructures of neurons, apoptosis, and GRP78 expression in the hippocampus were examined using Garcia scoring system, transmission electron microscopy, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling, and Western blotting at 1, 6, 12, 24, 48, and 72 h after SAH, respectively. The results showed that neurological scores were significantly decreased in the operated group as compared with those in control and sham-operated groups at 12, 24, 48, and 72 h. Metachromatin, chromatin pyknosis at the edge, endoplasmic reticulum swelling, and invagination of nuclear membrane were observed at 24 h in the operated group, indicating the early morphological changes of apoptosis. The number of apoptotic cells was significantly increased in the operated group as compared with that in control and sham-operated groups at 6, 12, 24, 48, and 72 h. The GRP78 protein expression levels in the operated group were significantly elevated at all time points and reached the peak at 12 h. GRP78 expression was positively associated with apoptosis cells and negatively with neurological scores. In conclusion, EBI was demonstrated to occur after SAH and GRP78 was involved in the development of EBI after SAH.

Spatiotemporal Expression of GRP78 in the Blood Vessels of Rats Treated With 3-Nitropropionic Acid Correlates With Blood–Brain Barrier Disruption

“…The neuronal functions of GRP78 have been investigated in various central nervous system (CNS) disease models, including ischemic insults ( Wang et al, 1993 ; Aoki et al, 2001 ; Ito et al, 2001 ; Shibata et al, 2003 ; Tajiri et al, 2004 ; Oida et al, 2008 ; Osada et al, 2010 ), epileptic seizures ( Wang et al, 1993 ; Chen et al, 2013 ), spinal cord injury ( Penas et al, 2007 , 2011 ; Ohri et al, 2012 ; Matsuyama et al, 2014 ), diabetic encephalopathy ( Zhao et al, 2015 ), and experimental subarachnoid hemorrhage ( Liu et al, 2016 ). GRP78 overexpression can have a neuroprotective effect by inhibiting the unfolded protein response, promoting autophagy, buffering calcium unbalance, and activating pro-survival signaling pathways ( Ouyang et al, 2011 ; Zhang et al, 2015 ; Casas, 2017 ).…”

The role and therapeutic potential of heat shock proteins in haemorrhagic stroke

“…HSP70 might be a potential target for SAH treatment and management, especially because no strategies explicitly targeting SAH have been developed yet . Additionally, HSP70 is a significant marker for cellular stress or damage and is also a crucial predictor of poor prognosis as it indicates the severity and extent of brain injury during SAH . Moreover, because it is expressed at lower levels in haemorrhagic stroke than in ischaemic stroke, HSP70 can be used as a blood biomarker for the early differential diagnosis of haemorrhagic stroke and ischaemic stroke …”

“…Cerebral vasospasm was once considered to be a prerequisite for DCI; however, DCI can develop without angiographic vasospasms, and vasospasms may also end with no ischaemic lesions . The EBI stage was proposed more recently and involves elevated intracranial pressure, decreased cerebral blood flow and cerebral perfusion pressure, cerebral deoxygenation, apoptosis of neural cells, destruction of the blood‐brain barrier (BBB), inflammation and encephaledema . The pathophysiological changes occurring during EBI might induce the development of DCI, but this has not yet been confirmed …”

“…As discussed previously, the development of DCI is not caused solely by delayed cerebral vasospasm, and there might be causality between EBI and DCI; thus, agents directed at treating DCI would not eliminate the root causes of DCI, and this may explain the frustrating results from new drugs to treat SAH . The alleviation of delayed vasospasm does not improve the clinical outcome in patients with SAH, which leads to a reasonable doubt as to whether delayed cerebral vasospasm affects the prognosis of SAH . Therefore, an increasing number of scholars have begun to support the theory that EBI is the chief cause of mortality and disability following SAH …”

Neuritin Attenuates Neuronal Apoptosis Mediated by Endoplasmic Reticulum Stress In Vitro

“…Apoptosis pathways mainly include death-receptor activation (exogenous pathway), mitochondrial-damage pathway (endogenous pathway), and apoptosis pathway initiated by endoplasmic reticulum stress (ERS). The first two are classical apoptotic pathways, but the ERS pathway is a recently discovered apoptotic pathway [ 3 ]. ERS can reportedly be activated in neurons damaged by cerebral ischemia [ 4 ].…”