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

Abstract

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.

Zonisamide Ameliorates Cognitive Impairment by Inhibiting ER Stress in a Mouse Model of Type 2 Diabetes Mellitus

“…However, the Hrd1 protein expression under the ER stress in the brain remains unclear. It has been reported that the protein levels of Hrd1 in the cortex are decreased both in diabetic rats and in AD brain compared to the control group rat and non-AD subjects, and the brains of these diabetic rats and AD patients experienced ER stress (Kaneko et al, 2010 ; Shruthi et al, 2019 ). ER is involved in the processing and trafficking of amyloid precursor protein (APP); once in the ER, APP can generate Aβ due to the γ-secretases (Plácido et al, 2014 ).…”

Characterization of Retinal Microvascular Complications and the Effects of Endoplasmic Reticulum Stress in Mouse Models of Diabetic Atherosclerosis

“…[55][56][57] The ability of 4PBA to reduce acellular capillary density is consistent with previous studies. 19,58 Differences in pericyte ghost densities between controls and experimental groups, as well as between 4PBA and non-4PBA-treated mice within the same group, increased in significance moving outward from the optic disc. The trends observed with respect to pericyte ghost and microvessel vessel density in GlcN-supplemented mice are very similar to those in STZ-injected and ApoE −/− :Ins2 +/Akita mice, suggesting that ER stress, even in the absence of hyperglycemia, may be a contributor to DR pathogenesis.…”

“…74 In relation to diabetes, 4PBA has been found to improve diabetic encephalopathy and nephropathy, muscle atrophy, inflammation, and β-cell apoptosis. 58,[76][77][78][79][80][81] The reduction in CHOP expression with 4PBA suggests that 4PBA effectively alleviates ER stress to suppress the proapoptotic UPR. 68,82 Overall, this work characterizes the pathologic changes associated with DR in three different mouse models of diabetic atherosclerosis.…”

“… 55 – 57 The ability of 4PBA to reduce acellular capillary density is consistent with previous studies. 19 , 58 …”

“… 74 In relation to diabetes, 4PBA has been found to improve diabetic encephalopathy and nephropathy, muscle atrophy, inflammation, and β-cell apoptosis. 58 , 76 – 81 The reduction in CHOP expression with 4PBA suggests that 4PBA effectively alleviates ER stress to suppress the proapoptotic UPR. 68 , 82 …”