The impact of soluble epoxide hydrolase inhibition and epoxyeicosatrienoic acids on early-life microglia activation and neuroinflammatory responses in the brain

Abstract

[eng] Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive cognitive decline and is the most common cause of dementia worldwide. AD has a complex multifactorial aetiology influenced by both genetic and environmental factors that may contribute to its onset. Several biological processes are implicated in the pathogenesis of AD, acting as potential triggers for cognitive impairment. Neuroinflammation, primarily driven by microglia, has been identified as one of the neuropathological characteristics of AD, although it is also believed to be one of its triggers. Concurrently, some oxylipins including the epoxyeicosatrienoic acids (EETs) derived from arachidonic acid, present beneficial anti-inflammatory properties. Since EETs are rapidly metabolized by the soluble epoxide hydrolase (sEH) into less bioactive metabolites, the inhibition of this enzyme has been proposed as a therapeutic pharmacological strategy for AD treatment. A first study was conducted to assess the effects of maternal administration of the sEH inhibitor (sEHI) TPPU during pregnancy and lactation on their wild-type and 5XFAD offspring. Interestingly, TPPU prevented cognitive and behavioural changes in offspring with a 5XFAD genotype. Additionally, TPPU also induced neuroprotective epigenetic changes, mitigated p-tau levels, and reduced neuroinflammatory markers, thus highlighting the potential of sEHI as a promising therapeutic approach for AD and suggesting beneficial effects of EETs. In a subsequent study, we wanted to study the role of EETs and other oxylipins in the neurodevelopmental outcome of children exposed to low or high levels of environmental mercury (Hg) contamination. The primary contaminant form of Hg is methylmercury, which has neurotoxic effects during brain development. Prenatal exposure to methylmercury, as indicated by Hg levels in cord blood, induces changes in PUFA metabolites that can be associated to postnatal neurodevelopment in children. Subsequently, we wondered whether the observed benefits of sEHI could be attributed to their impact on microglia. In the third study, we explored their anti-inflammatory effect on microglia following an inflammatory insult. To simulate an AD-like inflammatory environment, we utilized monomeric C-reactive protein (mCRP), which has been previously linked to the AD pathology. mCRP induced a pro-inflammatory phenotype in microglia, activating key inflammatory pathways and the release of pro-inflammatory cytokines. Successfully, newly-synthesized sEHI effectively countered microglial pro-inflammatory mechanisms, confirming their direct pharmaceutical benefits through the modulation of microglial activity. To investigate more deeply into therapies against aberrant microglial inflammatory responses, in the last study, we investigated whether a nutraceutical treatment could mitigate the activation of microglia induced by our inflammatory agent mCRP. Resveratrol successfully countered the activation of microglia due to its antioxidant and anti-inflammatory properties, highlighting how dietary interventions with nutraceuticals can directly benefit the brain. In summary, we have confirmed the anti-inflammatory and neuroprotective effects of sEHI, highlighting them as promising pharmacological agents. Our findings demonstrate that PUFA- derived oxylipins, specially EETs, can shape our health outcomes already from prenatal stages. Additionally, oxylipins may influence our susceptibility and resilience to both external and internal pathological insults. By understanding how microglia responds in front of endogenous inflammatory stimulus and the direct impact of sEHI in microglia activation, we can provide valuable insights for future therapies targeting neurodegenerative diseases with a neuroinflammatory basis. Given the complex aetiology of AD, a combinatory treatment strategy tackling several pathological aspects of the disease, along with healthy lifestyle interventions from an early age, particularly focusing on diet, would represent a significant step towards improving the overall outcome of AD.

[cat] La neuroinflamació, modulada principalment per la micròglia, s'ha identificat com un contribuent important en la malaltia d'Alzheimer (AD), convertint-la en una diana terapèutica prometedora. Per altra banda, les oxilipines, especialment els àcids epoxieicosatrienoics (EET), presenten propietats antiinflamatòries beneficioses. Tot i així, com que els EET es metabolitzen ràpidament per l'epòxid hidrolasa soluble (sEH), s'ha proposat inhibir aquest enzim com a estratègia terapèutica per al tractament de l’AD. D’entrada, en un primer estudi, vam avaluar els efectes de l'administració materna de l’inhibidor de la sEH (sEHI) TPPU durant l'embaràs i la lactància en les cries de fenotip de tipus salvatge o 5XFAD. El TPPU va protegir els ratolins 5XFAD contra el deteriorament cognitiu i va reduir la p-tau i la reactivitat microglial. En un estudi posterior, vam investigar el paper de les oxilipines en el neurodesenvolupament d’infants exposats a nivells baixos o alts de mercuri (Hg) ambiental. Vam trobar que l'exposició prenatal al metilmercuri, mesurada pels nivells de Hg en la sang del cordó umbilical, indueix canvis en els metabòlits dels PUFA que s’associen amb el neurodesenvolupament postnatal dels nens. En el tercer estudi, vam investigar si els beneficis dels sEHI eren deguts al seu efecte sobre la micròglia. Utilitzant la proteïna C-reactiva monomèrica per simular un entorn inflamatori com en l'AD, vam induir un fenotip proinflamatori a la micròglia. Els sEHI van contrarestar efectivament aquest efecte, confirmant el seu impacte positiu en la micròglia. Finalment, a l'últim estudi, vam analitzar el resveratrol contra les respostes inflamatòries aberrants de la micròglia. Amb èxit, va aconseguir contrastar l'activació de la microglia gràcies a les seves propietats antioxidants i antiinflamatòries, destacant així com les intervencions dietètiques amb nutracèutics poden ser beneficiosos pel cervell. Breument, podem confirmar els efectes antiinflamatoris i neuroprotectors dels sEHI, revelant una estratègia farmacològica prometedora. Els nostres resultats demostren que les oxilipines, especialment els EETs, poden modelar la nostra salut ja des d'etapes primerenques de la vida. L'impacte dels sEHI en l'activació de la micròglia és rellevant per a futures teràpies de malalties neuroinflamatòries. La combinació de tractaments i intervencions en l'estil de vida podrien millorar el desenvolupament de l'AD.