An inhibitor of soluble epoxide hydrolase ameliorates diabetes-induced learning and memory impairment in rats

Minaz, Nathani; Razdan, Rema; Hammock, Bruce D.; Goswami, Sumanta

doi:10.1016/j.prostaglandins.2018.05.004

Cited by 21 publications

(28 citation statements)

References 56 publications

(61 reference statements)

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“…It was found that a soluble epoxide hydrolase inhibitor (sEHI) alleviates transmissible spongiform encephalopathies (TSEs) associated with neuronal loss and inflammation (Poli et al, 2013). Earlier, we demonstrated that the sEHI, TPPU, minimizes memory impairment in diabetic rats (Minaz et al, 2018). These lines of research suggest that sEHIs may have potential therapeutic effect in managing AD associated memory impairment.…”

Section: Introductionmentioning

confidence: 77%

“…Diabetic rats were administered edaravone/EDV (3 mg/kg), edaravone (10 mg/kg), TPPU (1 mg/kg) or TPPU + DHA (100 mg/kg). The dose of TPPU was selected based on our previous studies on anti-inflammatory and memory protective activity of the enzyme inhibitor (Goswami et al, 2016; Minaz et al, 2018). Epoxy fatty acids generated from DHA were more stable and potent in the presence of the sEHI.…”

Section: Methodsmentioning

confidence: 99%

“…Diabetes mellitus (DM) is a complex metabolic disorder which adversely affects multiple physiological systems including the central nervous system and cardiovascular system, and the disease is associated with altered memory function, cardiac stress, endothelial dysfunction and neuropathy (Islam et al, 2017; Bhadri et al, 2018; Minaz et al, 2018). Both type 1 and type 2 diabetes induce changes in the neurones, brain and memory as seen in the case of Alzheimer’s disease (Zhao and Townsend, 2009; Ouwens et al, 2014; Rdzak and Abdelghany, 2014; King et al, 2015; Meneilly and Tessier, 2016; Morales-Corraliza et al, 2016; Chen et al, 2018; Pappas et al, 2018; Takeuchi et al, 2018; Yashkin et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…These lines of research suggest that sEHIs may have potential therapeutic effect in managing AD associated memory impairment. We have previously demonstrated the anti-inflammatory property (Goswami et al, 2016, 2017) of TPPU in addition to its ability to reduce oxidative stress (Goswami et al, 2016) including the diabetes-induced oxidative stress in the brain (Minaz et al, 2018), but it has not been evaluated in AD-like condition. We hypothesized that TPPU could alleviate diabetes-induced Alzheimer-like complexities by decreasing the oxidative stress and inflammation.…”

Section: Introductionmentioning

confidence: 99%

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Docosahexaenoic Acid Increases the Potency of Soluble Epoxide Hydrolase Inhibitor in Alleviating Streptozotocin-Induced Alzheimer’s Disease-Like Complications of Diabetes

et al. 2019

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Diabetes is a risk factor for Alzheimer’s disease and it is associated with significant memory loss. In the present study, we hypothesized that the soluble epoxide hydrolase (sEH) inhibitor N-[1-(1-oxopropyl)-4-piperidinyl]-N’-[4-(trifluoromethoxy)phenyl)-urea (also known as TPPU) could alleviate diabetes-aggravated Alzheimer’s disease-like symptoms by improving memory and cognition, and reducing the oxidative stress and inflammation associated with this condition. Also, we evaluated the effect of edaravone, an antioxidant on diabetes-induced Alzheimer’s-like complications and the additive effect of docosahexaenoic acid (DHA) on the efficacy of TPPU. Diabetes was induced in male Sprague-Dawley rats by intraperitoneally administering streptozotocin (STZ). Six weeks after induction of diabetes, animals were either treated with vehicle, edaravone (3 or 10 mg/kg), TPPU (1 mg/kg) or TPPU (1 mg/kg) + DHA (100 mg/kg) for 2 weeks. The results demonstrate that the treatments increased the memory response of diabetic rats, in comparison to untreated diabetic rats. Indeed, DHA + TPPU were more effective than TPPU alone in reducing the symptoms monitored. All drug treatments reduced oxidative stress and minimized inflammation in the brain of diabetic rats. Expression of the amyloid precursor protein (APP) was increased in the brain of diabetic rats. Treatment with edaravone (10 mg/kg), TPPU or TPPU + DHA minimized the level of APP. The activity of acetylcholinesterase (AChE) which metabolizes acetylcholine was increased in the brain of diabetic rats. All the treatments except edaravone (3 mg/kg) were effective in decreasing the activity of AChE and TPPU + DHA was more efficacious than TPPU alone. Intriguingly, the histological changes in hippocampus after treatment with TPPU + DHA showed significant protection of neurons against STZ-induced neuronal damage. Overall, we found that DHA improved the efficacy of TPPU in increasing neuronal survival and memory, decreasing oxidative stress and inflammation possibly by stabilizing anti-inflammatory and neuroprotective epoxides of DHA. In the future, further evaluating the detailed mechanisms of action of sEH inhibitor and DHA could help to develop a strategy for the management of Alzheimer’s-like complications in diabetes.

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Section: Introductionmentioning

confidence: 77%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Docosahexaenoic Acid Increases the Potency of Soluble Epoxide Hydrolase Inhibitor in Alleviating Streptozotocin-Induced Alzheimer’s Disease-Like Complications of Diabetes

et al. 2019

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“…This mechanism – disrupting endothelial cell junctions of the BRB by sEH-dependent production of 19,20-DHDP – is worth investigating further since defects in the BRB contribute to other eye diseases (Campochiaro et al, 1999; Green, 1999). Furthermore, a recent study reported that sEH inhibitor TPPU reduces fasting glucose level in rats (Minaz et al, 2018). Given this, the antihyperglycemic effect of sEH inhibitors in relation to diabetic retinopathy is also worth exploring.…”

Section: Non-proliferative Diabetic Retinopathymentioning

confidence: 99%

Soluble Epoxide Hydrolase Inhibition for Ocular Diseases: Vision for the Future

Park

Corson

2019

Front. Pharmacol.

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Ocular diseases cause visual impairment and blindness, imposing a devastating impact on quality of life and a substantial societal economic burden. Many such diseases lack universally effective pharmacotherapies. Therefore, understanding the mediators involved in their pathophysiology is necessary for the development of therapeutic strategies. To this end, the hydrolase activity of soluble epoxide hydrolase (sEH) has been explored in the context of several eye diseases, due to its implications in vascular diseases through metabolism of bioactive epoxygenated fatty acids. In this mini-review, we discuss the mounting evidence associating sEH with ocular diseases and its therapeutic value as a target. Substantial data link sEH with the retinal and choroidal neovascularization underlying diseases such as wet age-related macular degeneration, retinopathy of prematurity, and proliferative diabetic retinopathy, although some conflicting results pose challenges for the synthesis of a common mechanism. sEH also shows therapeutic relevance in non-proliferative diabetic retinopathy and diabetic keratopathy, and sEH inhibition has been tested in a uveitis model. Various approaches have been implemented to assess sEH function in the eye, including expression analyses, genetic manipulation, pharmacological targeting of sEH, and modulation of certain lipid metabolites that are upstream and downstream of sEH. On balance, sEH inhibition shows considerable promise for treating multiple eye diseases. The possibility of local delivery of inhibitors makes the eye an appealing target for future sEH drug development initiatives.

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Use of AD Informer Set compounds to explore validity of novel targets in Alzheimer's disease pathology

Potjewyd

Annor-Gyamfi

Aubé

et al. 2022

A&D Transl Res & Clin Interv

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Introduction A chemogenomic set of small molecules with annotated activities and implicated roles in Alzheimer's disease (AD) called the AD Informer Set was recently developed and made available to the AD research community: https://treatad.org/data-tools/ad-informer-set/. Methods Small subsets of AD Informer Set compounds were selected for AD‐relevant profiling. Nine compounds targeting proteins expressed by six AD‐implicated genes prioritized for study by Target Enablement to Accelerate Therapy Development for Alzheimer's Disease (TREAT‐AD) teams were selected for G‐protein coupled receptor (GPCR), amyloid beta (Aβ) and tau, and pharmacokinetic (PK) studies. Four non‐overlapping compounds were analyzed in microglial cytotoxicity and phagocytosis assays. Results The nine compounds targeting CAPN2, EPHX2, MDK, MerTK/FLT3, or SYK proteins were profiled in 46 to 47 primary GPCR binding assays. Human induced pluripotent stem cell (iPSC)‐derived neurons were treated with the same nine compounds and secretion of Aβ peptides (Aβ40 and Aβ42) as well as levels of phosphophorylated tau (p‐tau, Thr231) and total tau (t‐tau) peptides measured at two concentrations and two timepoints. Finally, CD1 mice were dosed intravenously to determine preliminary PK and/or brain‐specific penetrance values for these compounds. As a final cell‐based study, a non‐overlapping subset of four compounds was selected based on single‐concentration screening for analysis of both cytotoxicity and phagocytosis in murine and human microglia cells. Discussion We have demonstrated the utility of the AD Informer Set in the validation of novel AD hypotheses using biochemical, cellular (primary and immortalized), and in vivo studies. The selectivity for their primary targets versus essential GPCRs in the brain was established for our compounds. Statistical changes in tau, p‐tau, Aβ40, and/or Aβ42 and blood–brain barrier penetrance were observed, solidifying the utility of specific compounds for AD. Single‐concentration phagocytosis results were validated as predictive of dose–response findings. These studies established workflows, validated assays, and illuminated next steps for protein targets and compounds.

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An inhibitor of soluble epoxide hydrolase ameliorates diabetes-induced learning and memory impairment in rats

Abstract: Inhibition of the sEH alleviates diabetes-induced decline in learning and memory.

Cited by 21 publications

References 56 publications

Docosahexaenoic Acid Increases the Potency of Soluble Epoxide Hydrolase Inhibitor in Alleviating Streptozotocin-Induced Alzheimer’s Disease-Like Complications of Diabetes

Docosahexaenoic Acid Increases the Potency of Soluble Epoxide Hydrolase Inhibitor in Alleviating Streptozotocin-Induced Alzheimer’s Disease-Like Complications of Diabetes

Soluble Epoxide Hydrolase Inhibition for Ocular Diseases: Vision for the Future

Use of AD Informer Set compounds to explore validity of novel targets in Alzheimer's disease pathology

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