Ischemic preconditioning protects the brain against injury via inhibiting CaMKII–nNOS signaling pathway

Wang, Mei; Qi, Dashi; Zhou, Chaohui; Han, Dong; Li, Peipei; Zhang, Fang; Zhou, Xiaoyan; Han, Meng; Di, Jiehui; Ye, Jun-Song; Yu, Hong-Min; Song, Yuanjian; Zhang, Guangyi

doi:10.1016/j.brainres.2016.01.008

Cited by 17 publications

(14 citation statements)

References 50 publications

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“…These results indicate that enzymatic NO synthesis in the delayed IP phase is not regulated at the level of gene expression. In IP models NO synthesis can be suppressed by CaMKII-dependent negative regulatory phosphorylation of nNOS (Wang et al, 2010, 2016). However,

K_{ATP}^{+}

-channels openers diazoxide and BMS-191095 may initiate NO production by increasing nNOS and eNOS activity due to the activation of positive regulatory phosphorylation through the phosphoinositide-3-kinase/AKT serine/threonine kinase 1 (PI3K-Akt) pathway (Katakam et al, 2013, 2016).…”

Section: Discussionmentioning

confidence: 99%

Molecular Bases of Brain Preconditioning

et al. 2017

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Preconditioning of the brain induces tolerance to the damaging effects of ischemia and prevents cell death in ischemic penumbra. The development of this phenomenon is mediated by mitochondrial adenosine triphosphate-sensitive potassium (KATP+) channels and nitric oxide signaling (NO). The aim of this study was to investigate the dynamics of molecular changes in mitochondria after ischemic preconditioning (IP) and the effect of pharmacological preconditioning (PhP) with the KATP+-channels opener diazoxide on NO levels after ischemic stroke in rats. Immunofluorescence-histochemistry and laser-confocal microscopy were applied to evaluate the cortical expression of electron transport chain enzymes, mitochondrial KATP+-channels, neuronal and inducible NO-synthases, as well as the dynamics of nitrosylation and nitration of proteins in rats during the early and delayed phases of IP. NO cerebral content was studied with electron paramagnetic resonance (EPR) spectroscopy using spin trapping. We found that 24 h after IP in rats, there is a two-fold decrease in expression of mitochondrial KATP+-channels (p = 0.012) in nervous tissue, a comparable increase in expression of cytochrome c oxidase (p = 0.008), and a decrease in intensity of protein S-nitrosylation and nitration (p = 0.0004 and p = 0.001, respectively). PhP led to a 56% reduction of free NO concentration 72 h after ischemic stroke simulation (p = 0.002). We attribute this result to the restructuring of tissue energy metabolism, namely the provision of increased catalytic sites to mitochondria and the increased elimination of NO, which prevents a decrease in cell sensitivity to oxygen during subsequent periods of severe ischemia.

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K_{ATP}^{+}

Section: Discussionmentioning

confidence: 99%

Molecular Bases of Brain Preconditioning

et al. 2017

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“…TIA, prior to a cerebral infarction, has been shown in multiple studies to confer neuroprotection by decreasing the size of infarction and improving neurological outcomes ( 28 ). Extensive research shows that ischemic preconditioning treatment reduces cerebral damage ( 29 – 31 ); however, its use in the clinical setting has been limited due to the unpredictable nature of cerebral infarctions. Understanding the underlying mechanisms of how ischemic preconditioning offers protection against stroke-induced neuronal death is imperative for translation into medical practice.…”

Section: Introductionmentioning

confidence: 99%

“…Ischemic postconditioning is a process, following reperfusion of a vessel, in which transient episodes of ischemia are induced so as to limit reperfusion injury. This process stimulates protective factors thereby limiting inflammation and delayed cell death ( 31 , 32 ). Studies using experimental animal models have shown that postconditioning reduces myocardial I/R injury and proved its protective molecular functions ( 33 – 35 ).…”

Section: Introductionmentioning

confidence: 99%

Limb Remote Ischemic Conditioning: Mechanisms, Anesthetics, and the Potential for Expanding Therapeutic Options

et al. 2018

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Novel and innovative approaches are essential in developing new treatments and improving clinical outcomes in patients with ischemic stroke. Remote ischemic conditioning (RIC) is a series of mechanical interruptions in blood flow of a distal organ, following end organ reperfusion, shown to significantly reduce infarct size through inhibition of oxidation and inflammation. Ischemia/reperfusion (I/R) is what ultimately leads to the irreversible brain damage and clinical picture seen in stroke patients. There have been several reports and reviews about the potential of RIC in acute ischemic stroke; however, the focus here is a comprehensive look at the differences in the three types of RIC (remote pre-, per-, and postconditioning). There are some limited uses of preconditioning in acute ischemic stroke due to the unpredictability of the ischemic event; however, it does provide the identification of biomarkers for clinical studies. Remote limb per- and postconditioning offer a more promising treatment during patient care as they can be harnessed during or after the initial ischemic insult. Though further research is needed, it is imperative to discuss the importance of preclinical data in understanding the methods and mechanisms involved in RIC. This understanding will facilitate translation to a clinically feasible paradigm for use in the hospital setting.

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“…Ischemic preconditioning induces up regulation of phosphorylation at Ser847 of nNOS and Thr286 of CaMKII. Treatment of KN-62 [76] (an inhibitor of CaMKII) spoils the neuroprotective effect of ischemic preconditioning [57].…”

Section: Animal Modelsmentioning

confidence: 99%

Coordination between Calcium/Calmodulin-Dependent Protein Kinase II and Neuronal Nitric Oxide Synthase in Neurons

Araki

Osuka

Takata

et al. 2020

IJMS

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Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) is highly abundant in the brain and exhibits broad substrate specificity, thereby it is thought to participate in the regulation of neuronal death and survival. Nitric oxide (NO), produced by neuronal NO synthase (nNOS), is an important neurotransmitter and plays a role in neuronal activity including learning and memory processes. However, high levels of NO can contribute to excitotoxicity following a stroke and neurodegenerative disease. Aside from NO, nNOS also generates superoxide which is involved in both cell injury and signaling. CaMKII is known to activate and translocate from the cytoplasm to the post-synaptic density in response to neuronal activation where nNOS is predominantly located. Phosphorylation of nNOS at Ser847 by CaMKII decreases NO generation and increases superoxide generation. Conversely, NO-induced S-nitrosylation of CaMKII at Cys6 is a prominent determinant of the CaMKII inhibition in ATP competitive fashion. Thus, the “cross-talk” between CaMKII and NO/superoxide may represent important signal transduction pathways in brain. In this review, we introduce the molecular mechanism of and pathophysiological role of mutual regulation between CaMKII and nNOS in neurons.

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Ischemic preconditioning protects the brain against injury via inhibiting CaMKII–nNOS signaling pathway

Cited by 17 publications

References 50 publications

Molecular Bases of Brain Preconditioning

Molecular Bases of Brain Preconditioning

Limb Remote Ischemic Conditioning: Mechanisms, Anesthetics, and the Potential for Expanding Therapeutic Options

Coordination between Calcium/Calmodulin-Dependent Protein Kinase II and Neuronal Nitric Oxide Synthase in Neurons

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