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Resveratrol is a natural phenolic compound with known benefits against neurodegeneration. We analyzed in vitro the protective mechanisms of resveratrol against the proinflammatory monomeric C-reactive protein (mCRP). mCRP increases the risk of AD after stroke and we previously demonstrated that intracerebral mCRP induces AD-like dementia in mice. Here, we used BV2 microglia treated with mCRP for 24 h in the presence or absence of resveratrol. Cells and conditioned media were collected for analysis. Lipopolysaccharide (LPS) has also been implicated in AD progression and so LPS was used as a resveratrol-sensitive reference agent. mCRP at the concentration of 50 µg/mL activated the nitric oxide pathway and the NLRP3 inflammasome pathway. Furthermore, mCRP induced cyclooxygenase-2 and the release of proinflammatory cytokines. Resveratrol effectively inhibited these changes and increased the expression of the antioxidant enzyme genes Cat and Sod2. As central mechanisms of defense, resveratrol activated the hub genes Sirt1 and Nfe2l2 and inhibited the nuclear translocation of the signal transducer NF-ĸB. Proinflammatory changes induced by mCRP in primary mixed glial cultures were also protected by resveratrol. This work provides a mechanistic insight into the protective benefits of resveratrol in preventing the risk of AD induced by proinflammatory agents.

Resveratrol is a natural phenolic compound with known benefits against neurodegeneration. We analyzed in vitro the protective mechanisms of resveratrol against the proinflammatory monomeric C-reactive protein (mCRP). mCRP increases the risk of AD after stroke and we previously demonstrated that intracerebral mCRP induces AD-like dementia in mice. Here, we used BV2 microglia treated with mCRP for 24 h in the presence or absence of resveratrol. Cells and conditioned media were collected for analysis. Lipopolysaccharide (LPS) has also been implicated in AD progression and so LPS was used as a resveratrol-sensitive reference agent. mCRP at the concentration of 50 µg/mL activated the nitric oxide pathway and the NLRP3 inflammasome pathway. Furthermore, mCRP induced cyclooxygenase-2 and the release of proinflammatory cytokines. Resveratrol effectively inhibited these changes and increased the expression of the antioxidant enzyme genes Cat and Sod2. As central mechanisms of defense, resveratrol activated the hub genes Sirt1 and Nfe2l2 and inhibited the nuclear translocation of the signal transducer NF-ĸB. Proinflammatory changes induced by mCRP in primary mixed glial cultures were also protected by resveratrol. This work provides a mechanistic insight into the protective benefits of resveratrol in preventing the risk of AD induced by proinflammatory agents.

The high prevalence of neurodegenerative diseases is an unintended consequence of the high longevity of the population, together with the lack of effective preventive and therapeutic options. There is great pressure on preclinical research, and both old and new models of neurodegenerative diseases are required to increase the pipeline of new drugs for clinical testing. We review here the main models of neurotoxicity-based animal models leading to central neurodegeneration. Our main focus was on studying how changes in neurotransmission and neuroinflammation, mainly in rodent models, contribute to harmful processes linked to neurodegeneration. The majority of the models currently in use mimic Parkinson's disease (PD) and Alzheimer's disease (AD), which are the most common neurodegenerative conditions in older adults. AD is the most common age-related dementia, whereas PD is the most common movement disorder with also cases of dementia. Several natural toxins and xenobiotic agents induce dopaminergic neurodegeneration and can reproduce neuropathological traits of PD. The literature analysis of MPTP, 6-OH-dopamine, and rotenone models suggested the latter as a useful model when specific doses of rotenone were administrated systemically to C57BL/6 mice. Cholinergic neurodegeneration is mainly modelled with the toxin scopolamine, which is a useful rodent model for the screening of protective drugs against cognitive decline and AD. Several agents have been used to model neuroinflammation-based neurodegeneration and dementia in AD, including lipopolysaccharide (LPS), streptozotocin, and monomeric C-reactive protein. The bacterial agent LPS makes a useful rodent model for testing anti-inflammatory therapies to halt the development and severity of AD. However, neurotoxin models might be more useful than genetic models for drug discovery in PD but that is not the case in AD where they cannot beat the new developments in transgenic mouse models. Overall, we should work using a

Neuroinflammation is a crucial neuropathological trait in Alzheimer’s disease (AD), although its role in the development of AD is not clarified. We previously proposed the monomeric C-reactive protein (mCRP), which is generated by activation and further disaggregation of circulating CRP, as a trigger of AD neuropathology after cerebrovascular damage. mCRP is a potent pro-inflammatory agent found deposited in AD brain tissue and proved to induce AD-like dementia and tau and amyloid neuropathology when injected into mouse hippocampus [1]. Furthermore, treatment of pregnant mice with TPPU, an inhibitor of the soluble epoxide hydrolase enzyme (sEH) with anti-inflammatory properties, successfully prevented memory loss and AD pathology in the offspring by inducing long-term modifications in the epigenetic machinery [2].

Introduction: Resveratrol is a polyphenol with known health benefits. We had demonstrated its antioxidant and antiaging effects in lymphocytes from Alzheimer¿s disease (AD) patients (1) and its cognitive enhancement and anti-amyloid and anti-tau pathology mechanisms in mouse models of AD (2). Here we analyzed in vitro the anti-inflammatory mechanisms of resveratrol against dementia-inducing monomeric Creactive protein (mCRP) (3). We also tested the anti-senescence effects of resveratrol in saturated fat models of neurodegeneration.

Neuroinflammation is a crucial neuropathological trait in Alzheimer’s disease (AD), although its role in the development of AD is not clarified. We previously proposed the monomeric C-reactive protein (mCRP), which is generated by activation and further disaggregation of circulating CRP, as a trigger of AD neuropathology after cerebrovascular damage. mCRP is a potent pro-inflammatory agent found deposited in AD brain tissue and proved to induce AD-like dementia and tau and amyloid neuropathology when injected into mouse hippocampus [1]. Furthermore, treatment of pregnant mice with TPPU, an inhibitor of the soluble epoxide hydrolase enzyme (sEH) with anti-inflammatory properties, successfully prevented memory loss and AD pathology in the offspring by inducing long-term modifications in the epigenetic machinery [2].

Soluble epoxide hydrolase inhibitors (sEHI) are a new class of non-opioid analgesics, with a representative compound, EC5026, currently in clinical trials for the management of neuropathic pain [1]. Our group has recently designed, synthesized and pharmacologically evaluated novel series of potent benzohomoadamantane-based sEHI [2]. Herein, we report further medicinal chemistry around the abovementioned polycyclic scaffold to improve the potency and, particularly, the DMPK properties of previous hits. After an extensive in vitro screening cascade, molecular modeling, and in vivo pharmacokinetics studies, three candidates were selected for in vivo studies. Two compounds evaluated in a murine model of capsaicin-induced allodynia displayed potent anti-allodynic effect in a dose-dependent manner. Next, the most potent compound was evaluated in the cyclophosphamide-induced murine model of cystitis, a well-established model of visceral pain, presenting robust analgesic efficacy [3]. Finally, considering that chemotherapy-induced neuropathic pain (CINP), a severe side effect of several anticancer agents, is a largely unmet medical need [4], our third candidate was evaluated in a murine model of paclitaxel-induced neuropathic pain. CINP was performed by a daily injection of paclitaxel via i.p. (2 mg/kg), for 5 consecutive days. Mice developed neuropathic mechanical allodynia, which peaked on day 10 after the first paclitaxel administration ¿time when the acute effects of sEHI were tested. Subcutaneous administration of this candidate (2.5-5 mg/kg) completely reversed in a dose dependent manner the sensory hypersensitivity. Additionally, administration of the sEHI (5 mg/kg, s.c.) 30 min before each paclitaxel injection completely prevented the development of neuropathic allodynia. Collectively, these results suggest interstitial cystitis/pain bladder syndrome and CINP as possible new indications for sEHI. Acknowledgements: This work was funded by the Grant PID2020-118127RB-I

Alzheimer's disease (AD) is a dire unmet medical need, in part due to its multifactorial nature, which makes very challenging the development of efficacious drugs. Thus, new therapeutic approaches modulating multiple biological targets with a key pathogenic role are necessary. In this context, our group recently reported the discovery of a novel class of dual inhibitors of the enzymes soluble epoxide hydrolase (sEH) and acetylcholinesterase (AChE) [1], with a multitarget profile in vitro and beneficial effects against neuroinflammation and memory impairment. Although the lead compound showed well-balanced nanomolar potencies at both targets, good blood-brain barrier permeability and no cytotoxicity, its suboptimal solubility and metabolic stability might hamper its applicability for the treatment of AD. Here we report a lead optimization campaign, aiming to achieve more favourable DMPK properties, while retaining the high dual potencies and brain permeation of the initial lead. To this end, we have explored the effects of the introduction of different polar substituents in diverse positions of the molecule of the first-generation lead. Chronic oral administration of a low dose (2 mg/kg) of the optimized lead (JM-039) to a transgenic mouse model of AD leads to beneficial effects on cognition and biological markers of neuroinflammation and synaptic plasticity. Thus, JM-039 emerges as a promising anti-AD drug candidate, able to address the early disease mechanisms.

The irreversible block of the cell cycle, cellular senescence, has recently gained interest in the aging field. Senescence has been found to contribute to Alzheimer’s Disease (AD) pathology and the resulting loss of cognition that patients go through. Considering that lifestyle interventions such as exercise, diet or anti-inflammatory supplementation have been linked with improved symptomatology in AD patients, we assessed how senescence markers behaved under these regimens. Analysis of whole blood from patients suffering from AD demonstrated a sex-specific difference in the senescence marker p16. In the same line, 5XFAD male mice also displayed more p16 transcription and protein content. Despite a marked pathological and cognitive improvement following exercise, senescence markers remained unchanged in this AD model. High-fat diet, which is described to be pro-inflammatory, increased senescence in the 5XFAD background. Complementary, anti-inflammatory perinatal treatment was also able to decrease senescence in young mice, highlighting how inflammation and senescence are intertwined. In the present work, we propose an inflammation–based model, in which lifestyle interventions are able to decrease senescent cells by indirectly mediating senomorphic capabilities. Whether these observations will prove to be critical in the clinical practice is yet unknown, but understanding cellular senescence in the context of neuroinflammation will be critical for AD and age-related diseases.

A balanced concentration of polyunsaturated fatty acids (PUFA) in the prenatal stage is essential for children¿s neurodevelopment. Also, animal studies showed that high levels of anti-inflammatory PUFA metabolites in the embryonic brain protect against genetic or environmental insults that would otherwise cause cognitive impairment. Here we used liquid chromatography - mass spectrometry to analyze oxylipins, the oxygenated metabolites of PUFA, in the placenta tissue (N=12) and cord blood plasma (N=39) of children from the INMA cohort (Valencia, Spain). Both tissues were characterized for total Hg levels as a reference for developmental neurotoxic MeHg exposure during pregnancy and distributed in low and high Hg groups. Deleterious effects of high Hg were confirmed in the placenta as decreased proteasome activity and inhibitory epigenetic changes. Children¿s neurodevelopment was assessed using the Bayley (14 months) and McCarthy (5 years) scales. Spearman correlation coefficients were calculated between scores and oxylipin levels. We also analyzed cortical brain tissue from wild type and transgenic Alzheimer's disease (5XFAD) mice dosed for 2 months with vehicle or a soluble epoxide hydrolase enzyme (sEH) inhibitor, UB-BJ-02 (5 mg/Kg, N=5/group). Inhibition of sEH increases levels of the potent anti-inflammatory epoxyeicosatrienoic acids (EETs) by inhibiting their hydrolysis to dihydro-EETs (DiHETs). We found that DiHETs were increased in the placenta of high Hg group. Furthermore, the mental and psychomotor development of 14-month-old children correlates positively with DiHETs levels in both placenta and cord blood tissues. Interestingly, cord blood DiEHTs positively correlate with working memory at 5 years. Thus we suggest that higher levels of DiHETs indicate higher synthesis of their anti-inflammatory EETs precursors. Accordingly, placenta levels of EETs correlate with mental development at 14 months of age. Other oxylipin changes also suggested an involvement of

With innumerable clinical failures of target-specific drug candidates for multifactorial diseases, such as Alzheimer's disease (AD), which remains inefficiently treated, the advent of multitarget drug discovery has brought a new breath of hope. Here, we disclose a class of 6-chlorotacrine (huprine)-TPPU hybrids as dual inhibitors of the enzymes soluble epoxide hydrolase (sEH) and acetylcholinesterase (AChE), a multitarget profile to provide cumulative effects against neuroinflammation and memory impairment. Computational studies confirmed the gorge-wide occupancy of both enzymes, from the main site to a secondary site, including a so far non-described AChE cryptic pocket. The lead compound displayed in vitro dual nanomolar potencies, adequate brain permeability, aqueous solubility, human microsomal stability, lack of neurotoxicity, and it rescued memory, synaptic plasticity, and neuroinflammation in an AD mouse model, after low dose chronic oral administration.