Hibernation-like neuroprotection in stroke by attenuating brain metabolic dysfunction

Forreider, Brian; Pozivilko, David; Kawaji, Qingwen; Xu, Geng; Ding, Yuchuan

doi:10.1016/j.pneurobio.2016.03.002

Cited by 36 publications

(29 citation statements)

References 139 publications

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“…In previous studies, neuroprotection has been associated with reduced PKC, and increased Akt, expression [29] that is likely achieved through mitigation of oxidative stress resulting from ROS generation and hyperglycemia, which are well-known effects of ischemic injury [38]. PKC is upregulated during ischemic stroke concurrent with accumulation of ROS, which may indicate various glucose metabolism mechanisms involving Akt/PKC [39][40][41][42][43].…”

Section: Discussionmentioning

confidence: 98%

Reduced Apoptotic Injury by Phenothiazine in Ischemic Stroke through the NOX-Akt/PKC Pathway

et al. 2019

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Phenothiazine treatment has been shown to reduce post-stroke ischemic injury, though the underlying mechanism remains unclear. This study sought to confirm the neuroprotective effects of phenothiazines and to explore the role of the NOX (nicotinamide adenine dinucleotide phosphate oxidase)/Akt/PKC (protein kinase C) pathway in cerebral apoptosis. Sprague-Dawley rats underwent middle cerebral artery occlusion (MCAO) for 2 h and were randomly divided into 3 different cohorts: (1) saline, (2) 8 mg/kg chlorpromazine and promethazine (C+P), and (3) 8 mg/kg C+P as well as apocynin (NOX inhibitor). Brain infarct volumes were examined, and cell death/NOX activity was determined by assays. Western blotting was used to assess protein expression of kinase C-δ (PKC-δ), phosphorylated Akt (p-Akt), Bax, Bcl-XL, and uncleaved/cleaved caspase-3. Both C+P and C+P/NOX inhibitor administration yielded a significant reduction in infarct volumes and cell death, while the C+P/NOX inhibitor did not confer further reduction. In both treatment groups, anti-apoptotic Bcl-XL protein expression generally increased, while pro-apoptotic Bax and caspase-3 proteins generally decreased. PKC protein expression was decreased in both treatment groups, demonstrating a further decrease by C+P/NOX inhibitor at 6 and 24 h of reperfusion. The present study confirms C+P-mediated neuroprotection and suggests that the NOX/Akt/PKC pathway is a potential target for efficacious therapy following ischemic stroke.

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Section: Discussionmentioning

confidence: 98%

Reduced Apoptotic Injury by Phenothiazine in Ischemic Stroke through the NOX-Akt/PKC Pathway

et al. 2019

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“…; Nicholls ; Bélanger and Magistretti ; Forreider et al . ). However, the way by which A 1 R impact on brain metabolism is still poorly characterized, although it has been shown that A 1 R effectively control both neuronal and astrocytic intermediary metabolism (Daval and Nicolas ; Håberg et al .…”

Section: Role Of A1r In Neuroprotection: Prophylaxis and Preconditionmentioning

confidence: 97%

“…This implies that the recruitment of A 1 R can protect eukaryotic cells through a common general mechanism, which is obviously broader than synaptic effects, albeit these synaptic effects might also contribute to the protection of neurons. In fact, besides acting as a neuromodulator, adenosine also fulfills a general homeostatic role controlling intermediary metabolism, which is considered the basis of the non-brain tissue protective effects afforded by extracellular adenosine (reviewed in Cunha 2001aCunha , 2008b and is also well known to be crucial to determine neuronal degeneration (Nicotera et al 1999;Nicholls 2004;B elanger and Magistretti 2009;Forreider et al 2016). However, the way by which A 1 R impact on brain metabolism is still poorly characterized, although it has been shown that A 1 R effectively control both neuronal and astrocytic intermediary metabolism (Daval and Nicolas 1998;H aberg et al 2000;Blood et al 2003;Canals et al 2008;Duarte et al 2016).…”

Section: A 1 R As Metabolic Controllersmentioning

confidence: 99%

How does adenosine control neuronal dysfunction and neurodegeneration?

Cunha

2016

Journal of Neurochemistry

379

385

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The adenosine modulation system mostly operates through inhibitory A 1 (A 1 R) and facilitatory A 2A receptors (A 2A R) in the brain. The activity-dependent release of adenosine acts as a brake of excitatory transmission through A 1 R, which are enriched in glutamatergic terminals. Adenosine sharpens salience of information encoding in neuronal circuits: highfrequency stimulation triggers ATP release in the 'activated' synapse, which is locally converted by ecto-nucleotidases into adenosine to selectively activate A 2A R; A 2A R switch off A 1 R and CB1 receptors, bolster glutamate release and NMDA receptors to assist increasing synaptic plasticity in the 'activated' synapse; the parallel engagement of the astrocytic syncytium releases adenosine further inhibiting neighboring synapses, thus sharpening the encoded plastic change. Brain insults trigger a large outflow of adenosine and ATP, as a danger signal. A 1 R are a hurdle for damage initiation, but they desensitize upon prolonged activation. However, if the insult is near-threshold and/or of short-duration, A 1 R trigger preconditioning, which may limit the spread of damage. Brain insults also up-regulate A 2A R, probably to bolster adaptive changes, but this heightens brain damage since A 2A R blockade affords neuroprotection in models of epilepsy, depression, Alzheimer's, or Parkinson's disease. This initially involves a control of synaptotoxicity by neuronal A 2A R, whereas astrocytic and microglia A 2A R might control the spread of damage. The A 2A R signaling mechanisms are largely unknown since A 2A R are pleiotropic, coupling to different G proteins and non-canonical pathways to control the viability of glutamatergic synapses, neuroinflammation, mitochondria function, and cytoskeleton dynamics. Thus, simultaneously bolstering A 1 R preconditioning and preventing excessive A 2A R function might afford maximal neuroprotection. Keywords: A 1 receptor, A 2A receptor, astrocyte, microglia, synaptic plasticity, synaptotoxicity. This article is part of a mini review series: "Synaptic Function and Dysfunction in Brain Diseases". Relevance of modulation systems to tune information flow in brain circuitsThe goal of understanding the flow of information in neuronal circuits has traditionally been centered in studying the key processes sustaining synaptic transmission and plasticity -i.e. the role of glutamate and glutamate receptors, as well as to a lesser extent the role of GABA and its receptors. If one considers an analogy to the experience of watching TV, this corresponds to studying how the ON/OFF button impacts all Received April 4, 2016; revised manuscript received May 23, 2016; accepted June 23, 2016. Address correspondence and reprint requests to R. A. Cunha, Center for Neurosciences and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal. E-mail: cunharod@gmail.com Abbreviations used: A 1 R, adenosine A 1 receptor; A 2A R, adenosine A 2A receptor; ADHD, attention deficit and hyperactivity disorder; BDNF, brain-derived neurotrophi...

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“…HBO also downregulated NOX2 expression and NOX activity and improved functional outcome and neuronal survival due to the decrease in oxidative stress in a subarachnoid hemorrhage model (Ostrowski et al, 2006). Hibernation therapies, such as hypothermia or drug-induced hibernation such as ethanol, are also protective in stroke (Kim and Yenari, 2015; Forreider et al, 2016). Of these, ethanol, by itself and in conjunction with NBO, has been shown to decrease NOX levels and activity in a model of ischemic stroke.…”

Section: Potential Treatments On Nox Activationmentioning

confidence: 99%

NOX Activation by Subunit Interaction and Underlying Mechanisms in Disease

Rastogi

et al. 2017

Front. Cell. Neurosci.

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182

167

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Nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase (NOX) is an enzyme complex with the sole function of producing superoxide anion and reactive oxygen species (ROS) at the expense of NADPH. Vital to the immune system as well as cellular signaling, NOX is also involved in the pathologies of a wide variety of disease states. Particularly, it is an integral player in many neurological diseases, including stroke, TBI, and neurodegenerative diseases. Pathologically, NOX produces an excessive amount of ROS that exceed the body’s antioxidant ability to neutralize them, leading to oxidative stress and aberrant signaling. This prevalence makes it an attractive therapeutic target and as such, NOX inhibitors have been studied and developed to counter NOX’s deleterious effects. However, recent studies of NOX have created a better understanding of the NOX complex. Comprised of independent cytosolic subunits, p47-phox, p67-phox, p40-phox and Rac, and membrane subunits, gp91-phox and p22-phox, the NOX complex requires a unique activation process through subunit interaction. Of these subunits, p47-phox plays the most important role in activation, binding and translocating the cytosolic subunits to the membrane and anchoring to p22-phox to organize the complex for NOX activation and function. Moreover, these interactions, particularly that between p47-phox and p22-phox, are dependent on phosphorylation initiated by upstream processes involving protein kinase C (PKC). This review will look at these interactions between subunits and with PKC. It will focus on the interaction involving p47-phox with p22-phox, key in bringing the cytosolic subunits to the membrane. Furthermore, the implication of these interactions as a target for NOX inhibitors such as apocynin will be discussed as a potential avenue for further investigation, in order to develop more specific NOX inhibitors based on the inhibition of NOX assembly and activation.

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Hibernation-like neuroprotection in stroke by attenuating brain metabolic dysfunction

Cited by 36 publications

References 139 publications

Reduced Apoptotic Injury by Phenothiazine in Ischemic Stroke through the NOX-Akt/PKC Pathway

Reduced Apoptotic Injury by Phenothiazine in Ischemic Stroke through the NOX-Akt/PKC Pathway

How does adenosine control neuronal dysfunction and neurodegeneration?

NOX Activation by Subunit Interaction and Underlying Mechanisms in Disease

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