scholarly journals Oxidative Stress Underlies the Ischemia/Reperfusion-Induced Internalization and Degradation of AMPA Receptors

2021 ◽  
Vol 22 (2) ◽  
pp. 717
Author(s):  
Lindsay M. Achzet ◽  
Clara J. Davison ◽  
Moira Shea ◽  
Isabella Sturgeon ◽  
Darrell A. Jackson
Keyword(s):  
Oxidative Stress ◽  
Reperfusion Injury ◽  
Ampa Receptors ◽  
Neuronal Death ◽  
Ischemia Reperfusion ◽  
The United States ◽  
Delayed Neuronal Death ◽  
Rab Proteins ◽  
Ischemic Reperfusion Injury ◽  
Ischemic Reperfusion

Stroke is the fifth leading cause of death annually in the United States. Ischemic stroke occurs when a blood vessel supplying the brain is occluded. The hippocampus is particularly susceptible to AMPA receptor-mediated delayed neuronal death as a result of ischemic/reperfusion injury. AMPA receptors composed of a GluA2 subunit are impermeable to calcium due to a post-transcriptional modification in the channel pore of the GluA2 subunit. GluA2 undergoes internalization and is subsequently degraded following ischemia/reperfusion. The subsequent increase in the expression of GluA2-lacking, Ca2+-permeable AMPARs results in excitotoxicity and eventually delayed neuronal death. Following ischemia/reperfusion, there is increased production of superoxide radicals. This study describes how the internalization and degradation of GluA1 and GluA2 AMPAR subunits following ischemia/reperfusion is mediated through an oxidative stress signaling cascade. U251-MG cells were transiently transfected with fluorescently tagged GluA1 and GluA2, and different Rab proteins to observe AMPAR endocytic trafficking following oxygen glucose-deprivation/reperfusion (OGD/R), an in vitro model for ischemia/reperfusion. Pretreatment with Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP), a superoxide dismutase mimetic, ameliorated the OGD/R-induced, but not agonist-induced, internalization and degradation of GluA1 and GluA2 AMPAR subunits. Specifically, MnTMPyP prevented the increased colocalization of GluA1 and GluA2 with Rab5, an early endosomal marker, and with Rab7, a late endosomal marker, but did not affect the colocalization of GluA1 with Rab11, a marker for recycling endosomes. These data indicate that oxidative stress may play a vital role in AMPAR-mediated cell death following ischemic/reperfusion injury.

Abstract P800: Liposomal Delivery of PICK1 Inhibitor, FSC231, Prevents Ischemic/Reperfusion-Induced Degradation of GluA2 AMPA Receptor Subunit

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Lindsay Achzet ◽  
Darrell A Jackson
Keyword(s):  
Ischemic Stroke ◽  
Intracellular Calcium ◽  
Ampa Receptor ◽  
Neuronal Death ◽  
Research Effort ◽  
Ischemia Reperfusion ◽  
Hippocampal Slices ◽  
The United States ◽  
Delayed Neuronal Death ◽  
Ischemic Reperfusion

Stroke remains to be a leading cause of disability within the United States. Despite an enormous amount of research effort within the scientific community, very few therapeutics are available for stroke patients. Cytotoxic accumulation of intracellular calcium is a well-studied phenomenon that occurs following ischemic stroke. This intracellular calcium overload results from excessive release of the excitatory neurotransmitter glutamate, a process known as excitotoxicity, eventually leading to delayed neuronal death. The hippocampus is particularly susceptible to AMPA receptor-mediated delayed neuronal death. AMPA receptors (AMPARs) are homo- or hetero-tetramers composed of GluA1-4 subunits. The majority of AMPARs are impermeable to calcium due to a post-transcriptional modification in the channel pore of the GluA2 AMPAR subunit. Calcium-permeable AMPARs lacking the GluA2 subunit, contribute to calcium cytotoxicity and subsequent neuronal death. The internalization and subsequent degradation of GluA2 AMPAR subunits following oxygen-glucose deprivation/reperfusion (OGD/R) is, at least in part, mediated by protein-interacting with C Kinase-1 (PICK1). We hypothesize that disrupting the PICK1—GluA2 interaction will prevent the degradation of GluA2, thereby protecting neurons within the hippocampus from AMPAR-mediated delayed neuronal death. Pretreatment with liposome-encapsulated FSC231, an inhibitor of PICK1, in acute rodent hippocampal slices prevents the OGD/R-induced association of PICK1—GluA2. FSC231 treatment during OGD/R rescues total GluA2 AMPAR subunit protein levels. This work is the first to utilize a liposomal drug delivery system for the delivery of a small molecule in ex vivo acute rodent hippocampal slices exposed to ischemia/reperfusion injury. These results suggest that the interaction between GluA2 and PICK1 serves as an important step in the ischemic/reperfusion-induced reduction in total GluA2 levels and is a potential therapeutic target for the treatment of ischemic stroke.

Myocardial adaptation to ischemia by oxidative stress induced by endotoxin

1995 ◽  
Vol 269 (4) ◽  
pp. C907-C916 ◽  
Author(s):  
N. Maulik ◽  
M. Watanabe ◽  
D. Engelman ◽  
R. M. Engelman ◽  
V. E. Kagan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reperfusion Injury ◽  
Antioxidant Defense ◽  
Ischemia Reperfusion ◽  
Antioxidant Defense System ◽  
Left Ventricular ◽  
Antioxidant Enzyme Activities ◽  
Ischemic Reperfusion Injury ◽  
Ischemic Reperfusion ◽  
Antioxidant Reserve

In this study, we examined the effects of oxidative stress adaptation on myocardial ischemic reperfusion injury. Oxidative stress was induced by injecting endotoxin (0.5 mg/kg) into the rat. After 24 h, rats were killed, hearts were isolated, and the effects of ischemia-reperfusion were studied using an isolated working heart preparation. The development of oxidative stress was examined by assessing malonaldehyde production in the heart. The antioxidant defense system was studied by estimating antioxidant enzyme activities and ascorbate- as well as thiol-dependent antioxidant reserve. The results of our study indicated that endotoxin induced oxidative stress within 1 h of treatment; the stress was reduced progressively and steadily up to 24 h. The antioxidant enzymes superoxide dismutase, catalase, glutathione (GSH) peroxidase, and GSH reductase were lowered up to 2 h and then increased. Both thiol- and ascorbate-dependent antioxidant reserve were enhanced, but the enhancement of the former was only transitory. After 24 h, endotoxin provided adequate protection to the heart from the ischemic-reperfusion injury, as evidenced by improved left ventricular function and aortic flow. Our results suggest that the induction of oxidative stress by endotoxin-induced adaptive modification of the antioxidant defense in the heart, thereby reducing ischemic-reperfusion injury.

scholarly journals Protective Effect of Pharmacological Preconditioning of Total Flavones of Abelmoschl Manihot on Cerebral Ischemic Reperfusion Injury in Rats

2007 ◽  
Vol 35 (04) ◽  
pp. 653-661 ◽  
Author(s):  
Ji-Yue Wen ◽  
Zhi-Wu Chen
Keyword(s):  
Protective Effect ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Inos Mrna ◽  
Ischemic Reperfusion Injury ◽  
Ischemic Reperfusion ◽  
Infarction Volume ◽  
Cerebral Ischemic ◽  
Cerebral Ischemic Reperfusion ◽  
Pharmacological Preconditioning

The present study was to investigate the effect of pharmacological preconditioning of total flavones of Abelmoschl Manihot (TFA) on cerebral ischemic reperfusion injury in rats. Rat cerebral ischemia/reperfusion injury was induced by occluding the right middle cerebral artery (MCA). The infarct size was determined by staining with 2,3,5-triphenyl tetrazalium chloride (TTC). The serum malonaldehyde (MDA), nitric oxide (NO) and lactate dehydrogenase (LDH) levels were measured by using spectrophotometry; Inducible NO synthase (iNOS) mRNA expression was detected by RT-PCR method. The percentage of cerebral infarction volume was 28.1 ± 0.8 in the model group, while TFA or nimodipine (Nim) pretreatment 36 hours prior to the ischemic insult significantly decreased the infarction volume. Increases of serum LDH activity and MDA level were observed after ischemia/reperfusion, but these changes were inhibited in rats pretreated with either TFA (20, 40, 80, 160 mg/kg) or Nim, indicating a delayed protective effect of TFA preconditioning on cerebral ischemic reperfusion injury. In addition, the serum NO level and the cerebral iNOS mRNA were up-regulated, suggesting a possible mechanism for the protective effect of TFA pretreatment on cerebral ischemic reperfusion injury.

scholarly journals Myocardial ischemic reperfusion injury – A review

2020 ◽  
Vol 11 (2) ◽  
pp. 1305-1311
Author(s):  
Elanthendral R ◽  
Gayathri K ◽  
Saravana Kumar S
Keyword(s):  
Myocardial Infarction ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Significant Rise ◽  
High Rate ◽  
Cell Swelling ◽  
Ischemic Reperfusion Injury ◽  
Ongoing Research ◽  
Ischemic Reperfusion

Myocardial ischemic reperfusion injury leads to the development of myocardial infarction and cardiovascular disease. Death due to these diseases is increasing at a high rate. Tissue damage due to ischemia and reperfusion results in the development of the above-mentioned diseases in heart. During prolonged ischemia, various physiological changes such as a decrease in ATP levels and intracellular pH occur due to dysfunction of ATP ase, and accumulation of lactate in myocardial tissue. The consequences of these reactions include increased accumulation of mitochondrial calcium, followed by cell swelling and death. Due to NF-kappa-B signal pathway activation and severe Cx43 degradation, a serious myocardial infarction occurs after ischemia/reperfusion injury. Knowledge related to the mechanism of ischemia-reperfusion injury and its related treatments is important. This review explains the prevalence, risk factors, mechanism, modern medicine and traditional medicine for myocardial ischemia-reperfusion injury. Numerous medicinal plants have been scientifically evaluated for cardioprotective activity. Herbs that have been reported to exhibit therapeutic potency against Ischemic reperfusion injury are discussed in detail. There are a lot of diseases that are caused due to ischemic perfusion injury and end up in a significant rise in the rate of mortality. The details about ongoing research related to new drug development against myocardial ischemic perfusion injury are discussed here.

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