A Combination of Three Repurposed Drugs Administered at Reperfusion as a Promising Therapy for Postischemic Brain Injury

Yu, I‐Chen; Kuo, Ping‐Chang; Yen, Jui‐Hung; Paraiso, Hallel C.; Curfman, Eric; Hong-Goka, Benecia C.; Sweazey, Robert D.; Chang, Fen‐Lei

doi:10.1007/s12975-017-0543-5

Cited by 15 publications

(16 citation statements)

References 69 publications

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“…Primary MG cells were obtained as previously described with some modifications [ 21 ]. Briefly, cells were cultured in medium DMEM/F12 containing 10% heated-inactivated fetal bovine serum, 2 mM l -glutamine, and 1X antibiotic/antimycotic.…”

Section: Methodsmentioning

confidence: 99%

“…The fluorescence microscope BX53 (Olympus, PA), Nuance FX multispectral imaging system, and Nuance software (PerkinElmer) were used for image acquisition and analysis. For FACS analysis, brain mononuclear cells were isolated as previously described [ 21 , 25 ]. The isolated cells were incubated with an antibody cocktail containing anti-CD86, CD80, and CD40.…”

Section: Methodsmentioning

confidence: 99%

“…The microglial CM was applied to differentiate HT22 hippocampal neurons. Mouse HT22 hippocampal neurons were differentiated as previously described before exposed to microglial CM [ 21 ]. At 24 h after incubating with microglial CM, the viability of neurons was examined using a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay.…”

Section: Methodsmentioning

confidence: 99%

“…The mouse brains were harvested and processed to prepare brain sections as previously described [ 21 , 25 ]. Brain sections were blocked and incubated with primary antibodies, rabbit anti-Iba1 (1:2500, WAKO, VA), or rabbit anti-GFAP (1:3000, Cell Signaling, Danvers, MA) for 2 h at RT.…”

Section: Methodsmentioning

confidence: 99%

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Dimethyl fumarate attenuates reactive microglia and long-term memory deficits following systemic immune challenge

Paraiso

Kuo

Curfman

et al. 2018

J Neuroinflammation

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BackgroundSystemic inflammation is associated with increased cognitive decline and risk for Alzheimer’s disease. Microglia (MG) activated during systemic inflammation can cause exaggerated neuroinflammatory responses and trigger progressive neurodegeneration. Dimethyl fumarate (DMF) is a FDA-approved therapy for multiple sclerosis. The immunomodulatory and anti-oxidant properties of DMF prompted us to investigate whether DMF has translational potential for the treatment of cognitive impairment associated with systemic inflammation.MethodsPrimary murine MG cultures were stimulated with lipopolysaccharide (LPS) in the absence or presence of DMF. MG cultured from nuclear factor (erythroid-derived 2)-like 2-deficient (Nrf2−/−) mice were used to examine mechanisms of DMF actions. Conditioned media generated from LPS-primed MG were used to treat hippocampal neuron cultures. Adult C57BL/6 and Nrf2−/− mice were subjected to peripheral LPS challenge. Acute neuroinflammation, long-term memory function, and reactive astrogliosis were examined to assess therapeutic effects of DMF.ResultsDMF suppressed inflammatory activation of MG induced by LPS. DMF suppressed NF-κB activity through Nrf2-depedent and Nrf2-independent mechanisms in MG. DMF treatment reduced MG-mediated toxicity towards neurons. DMF suppressed brain-derived inflammatory cytokines in mice following peripheral LPS challenge. The suppressive effect of DMF on neuroinflammation was blunted in Nrf2−/− mice. Importantly, DMF treatment alleviated long-term memory deficits and sustained reactive astrogliosis induced by peripheral LPS challenge. DMF might mitigate neurotoxic astrocytes associated with neuroinflammation.ConclusionsDMF treatment might protect neurons against toxic microenvironments produced by reactive MG and astrocytes associated with systemic inflammation.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1125-5) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Dimethyl fumarate attenuates reactive microglia and long-term memory deficits following systemic immune challenge

Paraiso

Kuo

Curfman

et al. 2018

J Neuroinflammation

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“…A combination of three drugs (lovastatin, minocycline and lamotrigine) was also studied in a mouse model after brain ischemia provoked by artery carotid occlusion [40]. As a result a decreased neurological deficit was reached suggesting a potential beneficial effect of this treatment in post-cardiac arrest therapy.…”

Section: Pharmacologic Strategiesmentioning

confidence: 99%

Strategies of Neuroprotection after Successful Resuscitation

Kovács¹,

Zima²

2017

Resuscitation Aspects

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Post-cardiac arrest syndrome (PCAS) incorporates post-cardiac arrest brain injury, postcardiac arrest myocardial dysfunction, systemic ischemia/reperfusion syndrome and the precipitating pathology. Brain injury remains the leading cause of death in the postcardiac arrest period. One of our main goals during post-resuscitation care is to guide a proper neuroprotective strategy. We are going to summarize the tools of neuroprotection in post-cardiac arrest therapy. The role of normoxia/normocapnia, normoglycemia, seizure control, sedation and pharmacologic strategies will be discussed in brief. The handling of temperature management and the management of hemodynamic variables to secure satisfactory cerebral perfusion will be worked out in details. Targeted temperature management is the main tool of neuroprotection in post-cardiac arrest therapy. We are going to conclude the principles of temperature control after successful resuscitation pointing out its beneficial effects. This method has also several complications that are going to be discussed highlighting its hemodynamic impacts. There is no evidence about target hemodynamic parameters during post-cardiac arrest syndrome to maintain cerebral perfusion neither about the most effective hemodynamic monitoring system. We are presenting preliminary data of our study where we investigate the effect of PiCCO™ (Pulse index Continous Cardiac Output) monitoring on the outcome in this patient group.Keywords: post-cardiac arrest syndrome, post-cardiac arrest brain injury, post-resuscitation therapy, targeted temperature management, hemodynamic parameters IntroductionSudden cardiac arrest is one of the leading causes of death in Europe [1]. The outcome is still very poor: the hospital discharge varies between 7 and 10% after out-of-hospital cardiac arrest (OHCA) and it is approximately 25% after in-hospital cardiac arrest (IHCA) [1]. The chain of © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.survival describes links that lead to a successful resuscitation [2]. The fourth element covers proper post-resuscitation care to restore quality of life. It is well known that the management of post-resuscitation cardiac arrest syndrome affects outcome and it is an important part of the resuscitation process. Pointing out the growing importance of post-resuscitation therapy, the European Resuscitation Council (ERC) introduced a separate chapter about post-resuscitation care in the 2015 guidelines [3]. One of the key elements to improve survival rate after sudden cardiac arrest may be the enhancement of post-resuscitation therapy.The post-cardiac arrest brain injury remains the main cause of mortality in the post-cardiac arrest period, being as high as 68% after OHCA and 25% after IHCA [4]. These data show that one of our leading goa...

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The arousal effect of hyperbaric oxygen through orexin/hypocretin an upregulation on ketamine/ethanol‐induced unconsciousness in male rats

Bian

Huang

et al. 2019

J of Neuroscience Research

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Approaches that facilitate the recovery from coma would have enormous impacts on patient outcomes and medical economics. Orexin-producing neurons release orexins (also known as hypocretins) energy-dependently to maintain arousal. Hyperbaric oxygen (HBO) could increase ATP levels by preserving mitochondrial function. We investigated, for the first time, the arousal effects of HBO and orexins mechanisms in a rat model of unconsciousness induced by ketamine or ethanol. A total of 120 Sprague-Dawley male rats were used in this study. Unconsciousness was induced either by intraperitoneal injection of ketamine or ethanol. The HBO treatment (100% O2 at 3 ATA) was administered immediately after unconsciousness induction for 1 hr. SB334867, orexin-1 receptor (OX1R) inhibitor, or JNJ10397049, orexin-2 receptor (OX2R) inhibitor was administered 30 min intraperitoneally before unconsciousness induction. Loss of righting reflex test (LORR) and Garcia test were used to evaluate the unconsciousness duration and neurological deficits after recovering from unconsciousness, respectively. Enzyme-linked immunosorbent assay was used to measure brain tissue ATP and orexin A levels. Ketamine or ethanol injection resulted in LORR immediately and neurological deficits 6 hr after unconsciousness induction. HBO treatment significantly reduced the LORR duration, improved Garcia scores and unregulated ATP and orexin A levels in the brain tissue. Administration of OX1R inhibitor or OX2 R inhibitor abolished arousal and neurological benefits of HBO. In conclusion, HBO exerted arousal-promoting effects on unconscious rats induced by ketamine or ethanol. The underlying mechanism was via, at least in part, ATP/orexin A upregulation. HBO may be a practical clinical approach to accelerate unconsciousness recovery in patients.

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A Combination of Three Repurposed Drugs Administered at Reperfusion as a Promising Therapy for Postischemic Brain Injury

Cited by 15 publications

References 69 publications

Dimethyl fumarate attenuates reactive microglia and long-term memory deficits following systemic immune challenge

Dimethyl fumarate attenuates reactive microglia and long-term memory deficits following systemic immune challenge

Strategies of Neuroprotection after Successful Resuscitation

The arousal effect of hyperbaric oxygen through orexin/hypocretin an upregulation on ketamine/ethanol‐induced unconsciousness in male rats

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