Single administration of soluble epoxide hydrolase inhibitor suppresses neuroinflammation and improves neuronal damage after cardiac arrest in mice

Taguchi, Noriko; Nakayama, Shin; Tanaka, Makoto

doi:10.1016/j.neures.2016.05.002

Cited by 24 publications

(26 citation statements)

References 40 publications

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“…Previous pharmacokinetic data suggest that TPPU, a very well characterized sEH inhibitor, can enter into the brain (21)(22). It is known that AS-2586114 has a prolonged action in vivo and ability to cross the blood-brain barrier (23)(24). UB-EV-52 is a new inhibitor somewhat related with previously reported adamantane-derived sEH inhibitors such as t-AUCB (25) and the clinically studied AR9281 (UC1153) (26).…”

Section: On-target Drug Inhibition Of Sehmentioning

confidence: 90%

Pharmacological inhibition of soluble epoxide hydrolase as a new therapy for Alzheimer’s Disease

Griñán-Ferré

Codony

Pujol

et al. 2019

Preprint

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The inhibition of the enzyme soluble epoxide hydrolase (sEH) has demonstrated clinical therapeutic effects in several peripheral inflammatory-related diseases, with two compounds that have entered clinical trials. However, the role of this enzyme in the neuroinflammation process has been largely neglected. Herein, we disclose the pharmacological validation of sEH as a novel target for the treatment of Alzheimer's Disease (AD). Of interest, we have found that sEH is upregulated in brains from AD patients. We have evaluated the cognitive impairment and the pathological hallmarks in two models of age-related cognitive decline and AD using three structurally different and potent sEH inhibitors as chemical probes. Our findings supported our expectations on the beneficial effects of central sEH inhibition, regarding of reducing cognitive impairment, tau hyperphosphorylation pathology and the number of amyloid plaques.Interestingly, our results suggest that reduction of inflammation in the brain is a relevant therapeutic strategy for all stages of AD.

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Section: On-target Drug Inhibition Of Sehmentioning

confidence: 90%

Pharmacological inhibition of soluble epoxide hydrolase as a new therapy for Alzheimer’s Disease

Griñán-Ferré

Codony

Pujol

et al. 2019

Preprint

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“…Furthermore, treatment with TPPU does not improve daily neurologic deficit scores above those observed in piglets administered vehicle after CA. Despite efficacy in rodent models of global [ 16 , 17 ] and focal hypoxic brain injury [ 15 , 27 , 28 ], short-term therapy with an sEH inhibitor is not neuroprotective after CA in this pediatric swine model.…”

Section: Discussionmentioning

confidence: 99%

“…However, other drugs have been shown to be neuroprotective in a similar piglet model with comparable therapeutic timing [ 22 , 23 ]. We chose to administer the first dose of TPPU at 30 min after ROSC to mimic clinical delays that occur when an unstable patient is in the intensive care setting, and based on demonstrated neuroprotection with this dosing regimen after CA in mice [ 17 ]. However, it is possible that earlier administration after CA is necessary for neuroprotection, especially since molecular pathways of cell death are activated within 15 min of injury in this swine model [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

“…Another explanation for the apparent species differences in the neuroprotective efficacy of TPPU could be that neuronal responses and cell death mechanisms are differential and nuanced in rodents and pigs [ 39 ] or depend upon developmental stage. In an adult mouse CA model, sEH inhibitors provided benefit to the hippocampus but not to the caudate-putamen [ 16 , 17 ]. In immature piglets, however, the CA1 hippocampus undergoes very little delayed neurodegeneration after CA [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

“…Genetic deletion or pharmacologic inhibition of sEH protects against hypoxic injury in adult rodent models of ischemic cardiomyopathy [ 14 ], ischemic stroke [ 13 , 15 ], and cardiac arrest [ 16 , 17 ]. The mechanism of this protection is unknown, but increasing evidence suggests that attenuation of endoplasmic reticulum (ER) stress might be one possibility [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

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Neurologic effects of short-term treatment with a soluble epoxide hydrolase inhibitor after cardiac arrest in pediatric swine

et al. 2020

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Background Cardiac arrest (CA) is the most common cause of acute neurologic insult in children. Many survivors have significant neurocognitive deficits at 1 year of recovery. Epoxyeicosatrienoic acids (EETs) are multifunctional endogenous lipid signaling molecules that are involved in brain pathobiology and may be therapeutically relevant. However, EETs are rapidly metabolized to less active dihydroxyeicosatrienoic acids by soluble epoxide hydrolase (sEH), limiting their bioavailability. We hypothesized that sEH inhibition would improve outcomes after CA in an infant swine model. Male piglets (3–4 kg, 2 weeks old) underwent hypoxic-asphyxic CA. After resuscitation, they were randomized to intravenous treatment with an sEH inhibitor (TPPU, 1 mg/kg; n = 8) or vehicle (10% poly(ethylene glycol); n = 9) administered at 30 min and 24 h after return of spontaneous circulation. Two sham-operated groups received either TPPU (n = 9) or vehicle (n = 8). Neurons were counted in hematoxylin- and eosin-stained sections from putamen and motor cortex in 4-day survivors. Results Piglets in the CA + vehicle groups had fewer neurons than sham animals in both putamen and motor cortex. However, the number of neurons after CA did not differ between vehicle- and TPPU-treated groups in either anatomic area. Further, 20% of putamen neurons in the Sham + TPPU group had abnormal morphology, with cell body attrition and nuclear condensation. TPPU treatment also did not reduce neurologic deficits. Conclusion Treatment with an sEH inhibitor at 30 min and 24 h after resuscitation from asphyxic CA does not protect neurons or improve acute neurologic outcomes in piglets.

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Systemic administration of dendrimer N‐acetyl cysteine improves outcomes and survival following cardiac arrest

Modi

Wang

Olmstead

et al. 2021

Bioengineering & Transla Med

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Cardiac arrest (CA), the sudden cessation of effective cardiac pumping function, is still a major clinical problem with a high rate of early and long‐term mortality. Post‐cardiac arrest syndrome (PCAS) may be related to an early systemic inflammatory response leading to exaggerated and sustained neuroinflammation. Therefore, early intervention with targeted drug delivery to attenuate neuroinflammation may greatly improve therapeutic outcomes. Using a clinically relevant asphyxia CA model, we demonstrate that a single (i.p.) dose of dendrimer‐N‐acetylcysteine conjugate (D‐NAC), can target “activated” microglial cells following CA, leading to an improvement in post‐CA survival rate compared to saline (86% vs. 45%). D‐NAC treatment also significantly improved gross neurological score within 4 h of treatment ( p < 0.05) and continued to show improvement at 48 h ( p < 0.05). Specifically, there was a substantial impairment in motor responses after CA, which was subsequently improved with D‐NAC treatment ( p < 0.05). D‐NAC also mitigated hippocampal cell density loss seen post‐CA in the CA1 and CA3 subregions ( p < 0.001). These results demonstrate that early therapeutic intervention even with a single D‐NAC bolus results in a robust sustainable improvement in long‐term survival, short‐term motor deficits, and neurological recovery. Our current work lays the groundwork for a clinically relevant therapeutic approach to treating post‐CA syndrome.

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Single administration of soluble epoxide hydrolase inhibitor suppresses neuroinflammation and improves neuronal damage after cardiac arrest in mice

Cited by 24 publications

References 40 publications

Pharmacological inhibition of soluble epoxide hydrolase as a new therapy for Alzheimer’s Disease

Pharmacological inhibition of soluble epoxide hydrolase as a new therapy for Alzheimer’s Disease

Neurologic effects of short-term treatment with a soluble epoxide hydrolase inhibitor after cardiac arrest in pediatric swine

Systemic administration of dendrimer N‐acetyl cysteine improves outcomes and survival following cardiac arrest

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