The dynamic changes of endoplasmic reticulum stress pathway markers GRP78 and CHOP in the hippocampus of diabetic mice

Zhao, Yang; Yan, Ying; Zhao, Zhigang; Li, Sen; Yin, Jie

doi:10.1016/j.brainresbull.2014.12.006

Cited by 49 publications

(33 citation statements)

References 32 publications

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“…Interestingly, 4-PBA treatment increased the levels of UCHL1 in the diabetic rat brain. 42 Nevertheless, in line with the earlier studies, 43 4-PBA has no effect on ER stress markers in healthy (control) rats. 4-PBA interacts with hydrophobic domains of misfolded proteins and, thus, prevents their aggregation.…”

Section: Discussionsupporting

confidence: 75%

Ubiquitin‐proteasome system and ER stress in the brain of diabetic rats

Karnam

Reddy

Chitra

2018

J of Cellular Biochemistry

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The ubiquitin‐proteasome system (UPS) has been implicated in the pathogenesis of many neurodegenerative diseases. Endoplasmic reticulum (ER) stress is shown to play a pathological role in the development of diabetes and its complications. Hence, the current study is aimed to investigate the role of UPS and ER stress in the cerebral cortex of diabetic rats and examine the therapeutic effect of 4‐phenylbutyric acid (4‐PBA), an ER stress inhibitor. Male Sprague‐Dawley rats were divided into three groups: control, diabetes, and diabetes plus 4‐PBA treatment group. Diabetes was induced by single intraperitoneal streptozotocin injection (37 mg/kg body weight [bw]), and 4‐PBA was administered (40 mg/kg bw/d, intraperitoneal) for 2 months, starting from 2 months of diabetes induction. At the end of 4 months, cerebral cortex was collected for analysis. Declined proteasome activity and ubiquitin C‐terminal hydrolase (UCH)‐L1 expression, increased ubiquitinated proteins, and apoptosis were observed in the diabetic rats. The expression of the ubiquitin‐activating enzyme E1, UCHL5, and ER stress markers (ATF6, pPERK, and CHOP) was markedly elevated, whereas the expression of ER‐associated protein degradation (ERAD) components was downregulated in the diabetic rats. 4‐PBA intervention attenuated ER stress, alterations in UPS, and ERAD components in diabetic rats. Importantly, neuronal apoptosis was lowered in 4‐PBA‐treated diabetic rats. Our observations demonstrate that altered UPS could be one of the underlying mechanisms of neuronal apoptosis in diabetes and chemical chaperones such as 4‐PBA could be potential candidates for preventing these alterations under hyperglycemic conditions.

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Section: Discussionsupporting

confidence: 75%

Ubiquitin‐proteasome system and ER stress in the brain of diabetic rats

Karnam

Reddy

Chitra

2018

J of Cellular Biochemistry

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“…Recent study suggests that inhibition of endoplasmic reticulum stress pathway involving CHOP could attenuates brain ischemic injury in diabetic stroke [47]. While another research shown that the up-regulation of CHOP in hippocampal neurons of diabetic mice may promote neuronal apoptosis and account for the damaged learning and memory ability of diabetic mice [48]. However, how ER stress promotes inflammatory response and neuronal injury in diabetic hippocampi remains poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Endoplasmic reticulum stress-induced neuronal inflammatory response and apoptosis likely plays a key role in the development of diabetic encephalopathy

et al. 2016

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We assumed that diabetic encephalopathy (DEP) may be induced by endoplasmic reticulum (ER)-mediated inflammation and apoptosis in central nervous system. To test this notion, here we investigated the neuronal ER stress and associated inflammation and apoptosis in a type 2 diabetes model induced with high-fat diet/streptozotocin in Sprague-Dawley rats. Elevated expressions of ER stress markers, including glucose-regulated protein 78 (GRP78), activating transcription factor-6 (ATF-6), X-box binding protein-1 (XBP-1), and C/EBP homologous protein, and phosphor-Jun N-terminal kinase (p-JNK) were evident in the hippocampus CA1 of diabetic rats. These changes were also accompanied with the activation of NF-κB and the increased levels of inflammatory cytokines, tumor necrosis factor-α (TNF-α) and Interleukin-6 (IL-6). Mechanistic study with in vitro cultured hippocampus neurons exposed to high glucose (HG), which induced a diabetes-like effects, shown by increased ER stress, JNK and NF-κB activation, and inflammatory response. Inhibition of ER stress by 4-phenylbutyrate (4-PBA) or blockade of JNK activity by specific inhibitor or transfection of DN-JNK attenuated HG-induced inflammation and associated apoptosis. To validate the in vitro finding, in vivo application of 4-PBA resulted in a significant reduction of diabetes-induced neuronal ER stress, inflammation and cell death, leading to the prevention of DEP. These results suggest that diabetes-induced neuronal ER stress plays the critical role for diabetes-induced neuronal inflammation and cell death, leading to the development of DEP.

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“…It is understood that ERS is capable of inducing mitochondria-and death receptor-independent apoptosis (10). In these cases, the upregulation of ERS-related transcription factors, including glucose-regulated protein (GRP)78 and CCAAT-enhancer-binding homologous protein (CHOP) have been identified (11,12). The involvement of ERS has been widely observed in the brain pathogenesis of neurological disorders and neurodegenerative diseases, including cerebral ischemia, Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (9,13,14).…”

Section: Introductionmentioning

confidence: 99%

Edaravone improves spatial memory and modulates endoplasmic reticulum stress-mediated apoptosis after abdominal surgery in mice

Tian

Zhang

et al. 2017

Experimental and Therapeutic Medicine

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Abstract.Patients who receive major surgery often develop postoperative cognitive dysfunction (POCD); however, there is a lack of effective management as the pathogenesis of this disorder has not been fully elucidated. The neuroprotective effects of edaravone have been characterized in both in vitro cultured cells and in experimental animal models. The present study aimed to determine the potential role of edaravone in surgery-induced cognitive decline in mice. Animals were assigned to three groups: Control group (n=32), where mice received local anesthesia; surgery group (n=32), where mice underwent abdominal surgery under anesthesia; and edaravone group (n=32), where mice received abdominal surgery and were administered with edaravone (3 mg/kg). Morris water maze and T-maze tests demonstrated that edaravone attenuated surgery-induced cognitive impairment. Nissl staining indicated that edaravone prevented neuronal loss in the hippocampus of mice that underwent surgery. Furthermore, treatment with edaravone mitigated the surgery-induced upregulation of glucose-regulated protein 78 and CCAAT-enhancer-binding homologous protein and reduced the number of terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling-positive nuclei in mice hippocampi. In conclusion, edaravone may prevent POCD-induced neuronal apoptosis through attenuating endoplasmic reticulum stress.

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The dynamic changes of endoplasmic reticulum stress pathway markers GRP78 and CHOP in the hippocampus of diabetic mice

Cited by 49 publications

References 32 publications

Ubiquitin‐proteasome system and ER stress in the brain of diabetic rats

Ubiquitin‐proteasome system and ER stress in the brain of diabetic rats

Endoplasmic reticulum stress-induced neuronal inflammatory response and apoptosis likely plays a key role in the development of diabetic encephalopathy

Edaravone improves spatial memory and modulates endoplasmic reticulum stress-mediated apoptosis after abdominal surgery in mice

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