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

Griñán-Ferré, Christian; Codony, Sandra; Pujol, Eugènia; Yang, Jun; Leiva, Rosana; Escolano, Carmen; Companys-Alemany, Júlia; Corpas, Rubén; Sanfeliu, Coral; Loza, Marı́a Isabel; Brea, José; Morisseau, Christophe; Hammock, Bruce D.; Pallàs, Mercè; Galdeano, Carles

doi:10.1101/605055

Cited by 12 publications

(23 citation statements)

References 48 publications

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“…Orally administrated N-[1-(1-oxopropyl)-4-piperidinyl]-N’-[4-(trifluoromethoxy)phenyl)-urea (TPPU), a potent sEH inhibitor, in the 5xFAD mice reinstated the Ep-PUFA levels and reversed astrocyte and microglia reactivity as well as immune pathway dysregulation [ 228 ]. Consistent with this result, another study examined administration of three structural different sEH inhibitors in two AD mouse models (5XFAD and SAMP8, paradigms of early-onset and late-onset AD) [ 230 ]. They found a reduction in gene expression and brain protein levels of pro-inflammatory cytokines, including tumor necrosis factor–α (TNF-α), IL-1β, C-C motif ligand 3(CCL3), in both mouse models.…”

Section: Ep-pufas and Neuroinflammationmentioning

confidence: 81%

Cytochrome P450 Metabolism of Polyunsaturated Fatty Acids and Neurodegeneration

et al. 2020

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Due to the aging population in the world, neurodegenerative diseases have become a serious public health issue that greatly impacts patients’ quality of life and adds a huge economic burden. Even after decades of research, there is no effective curative treatment for neurodegenerative diseases. Polyunsaturated fatty acids (PUFAs) have become an emerging dietary medical intervention for health maintenance and treatment of diseases, including neurodegenerative diseases. Recent research demonstrated that the oxidized metabolites, particularly the cytochrome P450 (CYP) metabolites, of PUFAs are beneficial to several neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease; however, their mechanism(s) remains unclear. The endogenous levels of CYP metabolites are greatly affected by our diet, endogenous synthesis, and the downstream metabolism. While the activity of omega-3 (ω-3) CYP PUFA metabolites and omega-6 (ω-6) CYP PUFA metabolites largely overlap, the ω-3 CYP PUFA metabolites are more active in general. In this review, we will briefly summarize recent findings regarding the biosynthesis and metabolism of CYP PUFA metabolites. We will also discuss the potential mechanism(s) of CYP PUFA metabolites in neurodegeneration, which will ultimately improve our understanding of how PUFAs affect neurodegeneration and may identify potential drug targets for neurodegenerative diseases.

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Section: Ep-pufas and Neuroinflammationmentioning

confidence: 81%

Cytochrome P450 Metabolism of Polyunsaturated Fatty Acids and Neurodegeneration

et al. 2020

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“…The design of new compounds with high efficacy and potency to inhibit sEH, but also with adequate pharmacokinetic properties to enter the CNS, is a challenge that must be faced. Recent studies have been described, such as the use of sEH as a new pharmacological target for neurodegenerative diseases such as PD [108] and AD [109,110]. Recently it has been demonstrated in two mice models of early-and late-onset AD (5XFAD and SAMP8) that treatment with several sEHi reduced neuroinflammation markers, OS and endoplasmic reticulum (ER) stress, after modifying the oxylipin profile, including EETs, the levels of which increased.…”

Section: Soluble Epoxide Hydrolase In Central Nervous System Disordersmentioning

confidence: 99%

“…Recently it has been demonstrated in two mice models of early-and late-onset AD (5XFAD and SAMP8) that treatment with several sEHi reduced neuroinflammation markers, OS and endoplasmic reticulum (ER) stress, after modifying the oxylipin profile, including EETs, the levels of which increased. Interestingly, sEHi impacted on AD hallmarks as amyloid plaques and tau hyperphosphorylation, preventing cognitive decline after oral administration [110]. Additionally, Lee et al (2019) [111] demonstrated that sEH deletion in an AD mice model (APP/PS1) reduced and delayed the development of cognitive impairment and specific markers of the disease such as β-amyloid deposition and apoE expression.…”

Section: Soluble Epoxide Hydrolase In Central Nervous System Disordersmentioning

confidence: 99%

“…sEH could likely represent a promising therapeutic target for neurological disorders such as depression, PD, LBD, and AD [108,110,111,147]. In the recent past, several reports demonstrated the usefulness of small molecules for inhibiting sEH activity, which was effective against several illness conditions such as cancer, hypertension, heart diseases (ischemia, cardiac, and renocardiac failures), obesity, and diabetic neuropathy [148][149][150][151][152][153][154][155][156].…”

Section: Therapeutic Use Of Seh Modulation In Parkinson's Diseasementioning

confidence: 99%

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Soluble Epoxide Hydrolase Inhibition to Face Neuroinflammation in Parkinson’s Disease: A New Therapeutic Strategy

et al. 2020

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Neuroinflammation is a crucial process associated with the pathogenesis of neurodegenerative diseases, including Parkinson’s disease (PD). Several pieces of evidence suggest an active role of lipid mediators, especially epoxy-fatty acids (EpFAs), in the genesis and control of neuroinflammation; 14,15-epoxyeicosatrienoic acid (14,15-EET) is one of the most commonly studied EpFAs, with anti-inflammatory properties. Soluble epoxide hydrolase (sEH) is implicated in the hydrolysis of 14,15-EET to its corresponding diol, which lacks anti-inflammatory properties. Preventing EET degradation thus increases its concentration in the brain through sEH inhibition, which represents a novel pharmacological approach to foster the reduction of neuroinflammation and by end neurodegeneration. Recently, it has been shown that sEH levels increase in brains of PD patients. Moreover, the pharmacological inhibition of the hydrolase domain of the enzyme or the use of sEH knockout mice reduced the deleterious effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration. This paper overviews the knowledge of sEH and EETs in PD and the importance of blocking its hydrolytic activity, degrading EETs in PD physiopathology. We focus on imperative neuroinflammation participation in the neurodegenerative process in PD and the putative therapeutic role for sEH inhibitors. In this review, we also describe highlights in the general knowledge of the role of sEH in the central nervous system (CNS) and its participation in neurodegeneration. We conclude that sEH is one of the most promising therapeutic strategies for PD and other neurodegenerative diseases with chronic inflammation process, providing new insights into the crucial role of sEH in PD pathophysiology as well as a singular opportunity for drug development.

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“…Object novel recognition was performed in a 90-degree, two-arm, 25-cm-long, 20-cm-high maze as previously described [38]. The walls could be easily removed for cleaning.…”

Section: Novel Object Recognition Test (Nort)mentioning

confidence: 99%

Anxiety, Impaired Social and Aggressive Behaviour Correlates with Cognitive and Molecular Changes in Older SAMP8 Males

Vasilipoulou¹,

Companys-Alemany²,

Canudas³

et al. 2020

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Alzheimer’s disease (AD) is characterized by cognitive impairment and different non-cognitive deficits called “Behavioural and psychological symptoms of dementia” (BPSD) related to neurotrophin alterations, which differ from those presented in normal aging. Mouse models, both transgenics and inbreed mice models of AD, are a useful tool in understanding the underlying mechanisms of the disease. The SAMP8 (senescence-accelerated mouse prone 8) mice line was generated from AKR/J strain by Professor Toshio Takeda at the University of Kyoto. This strain exhibited a particular early-onset and accelerated aging phenotype. The present study characterizes and provides information regarding the non-cognitive, cognitive and neurotrophin alterations and their correlation, demonstrating the AD-like symptoms presented in older males SAMP8. The cognitive impairment presented was accompanied by a reduction in sociability and an increase in aggressive as well as anxiety behaviours. Furthermore, changes in two of the most important neurotrophins, such as brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3) were found. Thus, the present results reveal new insights in this useful inbred mouse model of neurodegeneration and AD, demonstrating the potential relationship between neurotrophin modifications, cognitive impairment and neuropsychiatric disorders (ND).

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

Cited by 12 publications

References 48 publications

Cytochrome P450 Metabolism of Polyunsaturated Fatty Acids and Neurodegeneration

Cytochrome P450 Metabolism of Polyunsaturated Fatty Acids and Neurodegeneration

Soluble Epoxide Hydrolase Inhibition to Face Neuroinflammation in Parkinson’s Disease: A New Therapeutic Strategy

Anxiety, Impaired Social and Aggressive Behaviour Correlates with Cognitive and Molecular Changes in Older SAMP8 Males

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