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1.
Regen Med ; 19(4): 171-187, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37818696

RESUMO

Background: Efficacious repair of peripheral nerve injury is an unmet clinical need. The implantation of biomaterials containing neurotrophic drugs at the injury site could promote nerve regeneration and improve outcomes for patients. Materials & methods: Random and aligned electrospun poly-ε-caprolactone scaffolds containing encapsulated tacrolimus were fabricated, and the gene expression profile of Schwann cells (SCs) cultured on the surface was elucidated. On aligned fibers, the morphology of SCs and primary rat neurons was investigated. Results: Both scaffold types exhibited sustained release of drug, and the gene expression of SCs was modulated by both nanofibrous topography and the presence of tacrolimus. Aligned fibers promoted the alignment of SCs and orientated outgrowth from neurons. Conclusion: Electrospun PCL scaffolds with tacrolimus hold promise for the repair of peripheral nerve injury.


This article reports the production and testing of fibrous materials loaded with tacrolimus, a drug known to improve nerve regeneration, for the surgical repair of peripheral nerve injury. Materials were created with either a randomly orientated structure or an aligned structure that mimics the anatomy of native nerve, and both displayed long-term release of the loaded drug. Schwann cells, which are a critical cell type in nerve regeneration, were grown on the materials and their behaviour was positively influenced by the fibrous surfaces and/or the presence of tacrolimus. Neurons grown on the aligned materials demonstrated directional outgrowth, which may be also beneficial for increasing the rate of regeneration. These materials have the potential to improve outcomes of nerve repair for patients.


Assuntos
Nanofibras , Traumatismos dos Nervos Periféricos , Animais , Ratos , Materiais Biocompatíveis , Regeneração Nervosa , Poliésteres , Células de Schwann , Tacrolimo/metabolismo , Engenharia Tecidual , Alicerces Teciduais
2.
Biomater Adv ; 154: 213623, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37837905

RESUMO

The development of nerve wraps for use in the repair of peripheral nerves has shown promise over recent years. A pharmacological effect to improve regeneration may be achieved by loading such materials with therapeutic agents, for example ibuprofen, a non-steroidal anti-inflammatory drug with neuroregenerative properties. In this study, four commercially available polymers (polylactic acid (PLA), polycaprolactone (PCL) and two co-polymers containing different ratios of PLA to PCL) were used to fabricate ibuprofen-loaded nerve wraps using blend electrospinning. In vitro surgical handling experiments identified a formulation containing a PLA/PCL 70/30 molar ratio co-polymer as the most suitable for in vivo implantation. In a rat model, ibuprofen released from electrospun materials significantly improved the rate of axonal growth and sensory recovery over a 21-day recovery period following a sciatic nerve crush. Furthermore, RT-qPCR analysis of nerve segments revealed that the anti-inflammatory and neurotrophic effects of ibuprofen may still be observed 21 days after implantation. This suggests that the formulation developed in this work could have potential to improve nerve regeneration in vivo.


Assuntos
Ibuprofeno , Traumatismos dos Nervos Periféricos , Ratos , Animais , Ibuprofeno/farmacologia , Ibuprofeno/uso terapêutico , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Traumatismos dos Nervos Periféricos/cirurgia , Poliésteres , Anti-Inflamatórios/farmacologia , Nervo Isquiático/cirurgia
3.
J Steroid Biochem Mol Biol ; 234: 106376, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37604319

RESUMO

Oxysterols are oxidized derivatives of cholesterol that are formed by enzymatic processes or through the action of reactive oxygen species. Several of these bioactive lipids have been shown to be affected and/or play a role in inflammatory processes. 4ß-hydroxycholesterol is one of the major oxysterols in mice and humans and its levels are affected by inflammatory diseases. However, apart from its long half-life, little is known about its catabolism. By incubating 4ß-hydroxycholesterol with mouse mitochondria-enriched liver fractions, as well as 25-hydroxycholesterol and 27-hydroxycholesterol with recombinant CYP3A4, we identified 4ß,25-dihydroxycholesterol and 4ß,27-dihydroxycholesterol as 4ß-hydroxycholesterol metabolites. Supporting the biological relevance of this metabolism, we detected both metabolites after incubation of J774, primary mouse peritoneal macrophages and PMA-differentiated THP-1 cells with 4ß-hydroxycholesterol. Across our experiments, the incubation of cells with lipopolysaccharides differentially affected the levels of the 25- and 27-hydroxylated metabolites of 4ß-hydroxycholesterol. Finally, 4ß,27-dihydroxycholesterol was also detected in mice liver and plasma after intraperitoneal administration of 4ß-hydroxycholesterol. To our knowledge, this is the first report of the in vitro and in vivo detection and quantification of 4ß-hydroxycholesterol metabolites.


Assuntos
Hidroxicolesteróis , Oxisteróis , Humanos , Animais , Camundongos , Hidroxicolesteróis/metabolismo , Colesterol , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Meia-Vida
4.
Int J Mol Sci ; 24(15)2023 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-37569473

RESUMO

Peripheral nerve injuries are quite common and often require a surgical intervention. However, even after surgery, patients do not often regain satisfactory sensory and motor functions. This, in turn, results in a heavy socioeconomic burden. To some extent, neurons can regenerate from the proximal nerve stump and try to reconnect to the distal stump. However, this regenerating capacity is limited, and depending on the type and size of peripheral nerve injury, this process may not lead to a positive outcome. To date, no pharmacological approach has been used to improve nerve regeneration following repair surgery. We elected to investigate the effects of local delivery of minocycline on nerve regeneration. This molecule has been studied in the central nervous system and was shown to improve the outcome in many disease models. In this study, we first tested the effects of minocycline on SCL 4.1/F7 Schwann cells in vitro and on sciatic nerve explants. We specifically focused on the Schwann cell repair phenotype, as these cells play a central role in orchestrating nerve regeneration. Finally, we delivered minocycline locally in two different rat models of nerve injury, a sciatic nerve transection and a sciatic nerve autograft, demonstrating the capacity of local minocycline treatment to improve nerve regeneration.

5.
J Peripher Nerv Syst ; 28(3): 500-507, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37349878

RESUMO

BACKGROUND: Optimal functional recovery following peripheral nerve injuries (PNIs) is dependent upon early recognition and prompt referral to specialist centres for appropriate surgical intervention. Technologies which facilitate the early detection of PNI would allow faster referral rates and encourage improvements in patient outcomes. Serum Neurofilament light chain (NfL) measurements are cheaper to perform, easier to access and interpret than many conventional methods used for nerve injury diagnosis, such as electromyography and/or magnetic resonance imaging assessments, but changes in serum NfL levels following traumatic PNI have not been investigated. This pre-clinical study aimed to determine whether serum NfL levels can: (1) detect the presence of a nerve trauma and (2) delineate between different severities of nerve trauma. METHODS: A rat sciatic nerve crush and common peroneal nerve crush were implemented as controlled animal models of nerve injury. At 1-, 3-, 7- and 21-days post-injury, serum samples were retrieved for analysis using the SIMOA® NfL analyser kit. Nerve samples were also retrieved for histological analysis. Static sciatic index (SSI) was measured at regular time intervals following injury. RESULTS: Significant 45-fold and 20-fold increases in NfL serum levels were seen 1-day post-injury following sciatic and common peroneal nerve injury, respectively. This corresponded with an eightfold higher volume of axons injured in the sciatic compared to the common peroneal nerve (p < .001). SSI measurements post-injury revealed greater reduction in function in the sciatic crush group compared with the common peroneal crush group. CONCLUSIONS: NfL serum measurements represent a promising method for detecting traumatic PNI and stratifying their severity. Clinical translation of these findings could provide a powerful tool to improve the surgical management of nerve-injured patients.


Assuntos
Filamentos Intermediários , Traumatismos dos Nervos Periféricos , Ratos , Animais , Filamentos Intermediários/patologia , Nervo Isquiático/lesões , Axônios/patologia , Recuperação de Função Fisiológica/fisiologia , Regeneração Nervosa/fisiologia
6.
Br J Pharmacol ; 179(21): 4917-4940, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-33817775

RESUMO

Oxysterols have gained attention over the last decades and are now considered as fully fledged bioactive lipids. The study of their levels in several conditions, including atherosclerosis, obesity and neurodegenerative diseases, led to a better understanding of their involvement in (patho)physiological processes such as inflammation and immunity. For instance, the characterization of the cholesterol-7α,25-dihydroxycholesterol/GPR183 axis and its implication in immunity represents an important step in the oxysterome study. Besides this axis, others were identified as important in several inflammatory pathologies (such as colitis, lung inflammation and atherosclerosis). However, the oxysterome is a complex system notably due to a redundancy of metabolic enzymes and a wide range of receptors. Indeed, deciphering oxysterol roles and identifying the potential receptor(s) involved in a given pathology remain challenging. Oxysterol properties are very diverse, but most of them could be connected by a common component: inflammation. Here, we review the implication of oxysterol receptors in inflammatory diseases. LINKED ARTICLES: This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.


Assuntos
Aterosclerose , Colite , Oxisteróis , Aterosclerose/tratamento farmacológico , Humanos , Inflamação/tratamento farmacológico
7.
Cells ; 12(1)2022 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-36611836

RESUMO

Damage to peripheral nerves can cause debilitating consequences for patients such as lifelong pain and disability. At present, no drug treatments are routinely given in the clinic following a peripheral nerve injury (PNI) to improve regeneration and remyelination of damaged nerves. Appropriately targeted therapeutic agents have the potential to be used at different stages following nerve damage, e.g., to maintain Schwann cell viability, induce and sustain a repair phenotype to support axonal growth, or promote remyelination. The development of therapies to promote nerve regeneration is currently of high interest to researchers, however, translation to the clinic of drug therapies for PNI is still lacking. Studying the effect of PPARγ agonists for treatment of peripheral nerve injures has demonstrated significant benefits. Ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), has reproducibly demonstrated benefits in vitro and in vivo, suggested to be due to its agonist action on PPARγ. Other NSAIDs have demonstrated differing levels of PPARγ activation based upon their affinity. Therefore, it was of interest to determine whether affinity for PPARγ of selected drugs corresponded to an increase in regeneration. A 3D co-culture in vitro model identified some correlation between these two properties. However, when the drug treatments were screened in vivo, in a crush injury model in a rat sciatic nerve, the same correlation was not apparent. Further differences were observed between capacity to increase axon number and improvement in functional recovery. Despite there not being a clear correlation between affinity and size of effect on regeneration, all selected PPARγ agonists improved regeneration, providing a panel of compounds that could be explored for use in the treatment of PNI.


Assuntos
PPAR gama , Traumatismos dos Nervos Periféricos , Ratos , Animais , Regeneração Nervosa/fisiologia , Células de Schwann , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Nervo Isquiático , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico
8.
Neurotherapeutics ; 18(3): 1815-1833, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34235639

RESUMO

N-acylethanolamines (NAEs) are endogenous bioactive lipids reported to exert anti-inflammatory and neuroprotective effects mediated by cannabinoid receptors and peroxisome proliferator-activated receptors (PPARs), among others. Therefore, interfering with NAE signaling could be a promising strategy to decrease inflammation in neurological disorders such as multiple sclerosis (MS). Fatty acid amide hydrolase (FAAH) and N-acylethanolamine-hydrolyzing acid amidase (NAAA) are key modulators of NAE levels. This study aims to investigate and compare the effect of NAAA inhibition, FAAH inhibition, and dual inhibition of both enzymes in a mouse model of MS, namely the experimental autoimmune encephalomyelitis (EAE). Our data show that NAAA inhibition strongly decreased the hallmarks of the pathology. Interestingly, FAAH inhibition was less efficient in decreasing inflammatory hallmarks despite the increased NAE levels. Moreover, the inhibition of both NAAA and FAAH, using a dual-inhibitor or the co-administration of NAAA and FAAH inhibitors, did not show an added value compared to NAAA inhibition. Furthermore, our data suggest an important role of decreased activation of astrocytes and microglia in the effects of NAAA inhibition on EAE, while NAAA inhibition did not affect T cell recall. This work highlights the beneficial effects of NAAA inhibition in the context of central nervous system inflammation and suggests that the simultaneous inhibition of NAAA and FAAH has no additional beneficial effect in EAE.


Assuntos
Amidoidrolases/antagonistas & inibidores , Encefalomielite Autoimune Experimental/enzimologia , Encefalomielite Autoimune Experimental/prevenção & controle , Inibidores Enzimáticos/uso terapêutico , Amidoidrolases/metabolismo , Animais , Técnicas de Cocultura , Inibidores Enzimáticos/farmacologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico
9.
FASEB J ; 35(4): e21411, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33749884

RESUMO

Pain is one of the cardinal signs accompanying inflammation. The prostaglandins (PGs), synthetized from arachidonic acid by cyclooxygenase (COX)-2, are major bioactive lipids implicated in inflammation and pain. However, COX-2 is also able to metabolize other lipids, including the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA), to give glycerol ester (PG-G) and ethanolamide (PG-EA) derivatives of the PGs. Consequently, COX-2 can be considered as a hub not only controlling PG synthesis, but also PG-G and PG-EA synthesis. As they were more recently characterized, these endocannabinoid metabolites are less studied in nociception compared to PGs. Interestingly R-profens, previously considered as inactive enantiomers of nonsteroidal anti-inflammatory drugs (NSAIDs), are substrate-selective COX inhibitors. Indeed, R-flurbiprofen can selectively block PG-G and PG-EA production, without affecting PG synthesis from COX-2. Therefore, we compared the effect of R-flurbiprofen and S-flurbiprofen in models of inflammatory pain triggered by local administration of lipopolysaccharides (LPS) and carrageenan in mice. Remarkably, the effects of flurbiprofen enantiomers on mechanical hyperalgesia seem to depend on (i) the inflammatory stimuli, (ii) the route of administration, and (iii) the timing of administration. We also assessed the effect of administration of the PG-Gs, PG-EAs, and PGs on LPS-induced mechanical hyperalgesia. Our data support the interest of studying the nonhydrolytic endocannabinoid metabolism in the context of inflammatory pain.


Assuntos
Endocanabinoides/farmacologia , Flurbiprofeno/farmacologia , Inflamação/tratamento farmacológico , Dor/induzido quimicamente , Dor/tratamento farmacológico , Animais , Biomarcadores/sangue , Biomarcadores/metabolismo , Capsaicina/toxicidade , Carragenina/toxicidade , Endocanabinoides/química , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperalgesia , Inflamação/induzido quimicamente , Lipopolissacarídeos , Masculino , Camundongos
10.
FASEB J ; 35(4): e21514, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33734509

RESUMO

Inflammation is a critical component of many lung diseases including asthma and acute lung injury (ALI). Using high-performance liquid chromatography-mass spectrometry, we quantified the levels of oxysterols in two different murine models of lung diseases. These are lipid mediators derived from cholesterol and known to modulate immunity and inflammation. Interestingly, 25-hydroxycholesterol (25-OHC) was the only oxysterol with altered levels during lung inflammation, and its levels were differently affected according to the model. Therefore, we sought to assess how this oxysterol would affect lung inflammatory responses. In a model of lipopolysaccharide (LPS)-induced acute lung inflammation, 25-OHC levels were increased, and most of the hallmarks of the model (eg, leukocyte recruitment, mRNA expression, and secretion of inflammatory cytokines) were decreased following its intratracheal administration. We also found that, when administered in the lung, 25-OHC is metabolized locally into 25-hydroxycholesterol-3-sulfate and 7α,25-dihydroxycholesterol. Their administration in the lungs did not recapitulate all the effects of 25-OHC. Conversely, in a model of allergic asthma induced by intranasal administration of house dust mites (HDM), 25-OHC levels were decreased, and when intranasally administered, this oxysterol worsened the hallmarks of the model (eg, leukocyte recruitment, tissue remodeling [epithelium thickening and peribranchial fibrosis], and cytokine expression) and induced changes in leukotriene levels. Ex vivo, we found that 25-OHC decreases LPS-induced primary alveolar macrophage activation while having no effect on neutrophil activation. Its sulfated metabolite, 25-hydroxycholesterol-3-sulfate, decreased neutrophil, but not macrophage activation. Taken together, our data support a differential role of 25-OHC in ALI and allergic inflammation models.


Assuntos
Colesterol/metabolismo , Hidroxicolesteróis/metabolismo , Oxisteróis/metabolismo , Pneumonia/metabolismo , Animais , Citocinas/metabolismo , Lipopolissacarídeos/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Camundongos
11.
Elife ; 92020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32940597

RESUMO

Cortical lesions represent a hallmark of multiple sclerosis and are proposed as a predictor of disease severity. microRNAs are suggested to be important players in the disease pathogenesis and the experimental autoimmune encephalomyelitis animal model. We implemented a mouse model recapitulating more closely the human pathology as it is characterized by both an autoimmune heterogeneity and the presence of cortical lesions, two parameters missing in experimental autoimmune encephalomyelitis. In our model, mice clustered in two groups displaying high or low clinical scores. Upon cortical cytokine injection, lesions appeared with a specific topography while cortical miRNA profiles were altered. These two features differed according to disease severity. We evidenced changes in miRNA regulators and targets suggesting that miRNA alteration had functional repercussions that could explain the differences in cortical lesions. This model represents a crucial tool for the study of both miRNA involvement and cortical lesion formation in disease pathogenesis.


Assuntos
Córtex Cerebral/patologia , Encefalomielite Autoimune Experimental , MicroRNAs , Animais , Córtex Cerebral/efeitos dos fármacos , Citocinas/administração & dosagem , Citocinas/farmacologia , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/análise , MicroRNAs/genética , MicroRNAs/metabolismo , Transcriptoma/efeitos dos fármacos
12.
Trends Mol Med ; 25(10): 882-896, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31160168

RESUMO

Interfering with endocannabinoid (eCB) metabolism to increase their levels is a proven anti-nociception strategy. However, because the eCB and prostanoid systems are intertwined, interfering with eCB metabolism will affect the prostanoid system and inversely. Key to this connection is the production of the cyclooxygenase (COX) substrate arachidonic acid upon eCB hydrolysis as well as the ability of COX to metabolize the eCBs anandamide (AEA) and 2-arachidonoylglycerol (2-AG) into prostaglandin-ethanolamides (PG-EA) and prostaglandin-glycerol esters (PG-G), respectively. Recent studies shed light on the role of PG-Gs and PG-EAs in nociception and inflammation. Here, we discuss the role of these complex systems in nociception and new opportunities to alleviate pain by interacting with them.


Assuntos
Endocanabinoides/metabolismo , Dor/metabolismo , Prostaglandinas/metabolismo , Animais , Humanos , Prostaglandina-Endoperóxido Sintases/metabolismo
13.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1864(5): 609-618, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30684679

RESUMO

Pain is one of the cardinal signs of inflammation and is present in many inflammatory conditions. Therefore, anti-inflammatory drugs such as NSAIDs also have analgesic properties. We previously showed that prostaglandin D2-glycerol ester (PGD2-G), endogenously produced by cyclooxygenase-2 from the endocannabinoid 2-arachidonoylglycerol, has anti-inflammatory effects in vitro and in vivo that are partly mediated by DP1 receptor activation. In this work, we investigated its effect in a model of carrageenan-induced inflammatory pain. PGD2-G decreased hyperalgesia and edema, leading to a faster recovery. Moreover, PGD2-G decreased carrageenan-induced inflammatory markers in the paw as well as inflammatory cell recruitment. The effects of PGD2-G were independent from metabolite formation (PGD2 and 15d-PGJ2-G) or DP1 receptor activation in this model. Indeed PGD2 delayed recovery from hyperalgesia while 15d-PGJ2-G worsened the edema. However, while PGD2-G decreased hyperalgesia in this model of inflammatory pain, it had no effect when tested in the capsaicin-induced pain model. While the targets mediating the effects of this bioactive lipid in inflammatory pain remain to be elucidated, our findings further support the interest of anti-inflammatory lipid mediators in the management of inflammatory pain.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Hiperalgesia/tratamento farmacológico , Inflamação/tratamento farmacológico , Prostaglandina D2/uso terapêutico , Animais , Carragenina , Esterificação , Hiperalgesia/induzido quimicamente , Inflamação/induzido quimicamente , Masculino , Camundongos
14.
J Crohns Colitis ; 13(2): 218-229, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30295779

RESUMO

BACKGROUND AND AIMS: Inflammatory bowel diseases [IBD] represent a challenging health issue with a complex aetiology involving genetic and environmental parameters. Although our understanding of the pathophysiology of IBD has improved, much remains to be explored. In this context, bioactive lipids, more specifically oxysterols, i.e. oxygenated derivatives of cholesterol, represent an interesting avenue to investigate. Indeed, oxysterols or their receptors are involved in inflammation and immune regulation. Therefore, we set out to study the oxysterome in IBD. METHODS: We used both high-performance liquid chromatograph/mass spectroscopy and molecular biology tools to quantify oxysterol levels and the expression of their metabolic enzymes in several models of murine colitis [both acute and chronic], as well as in colon biopsies from patients with Crohn's disease and ulcerative colitis. RESULTS: We found that the oxysterome is altered in IBD, in both acute and chronic murine models as well as in human IBD. Two of the oxysterols quantified, 4ß-hydroxycholesterol and 25-hydroxycholesterol, were consistently altered in all our models and therefore could be of interest in this context. Hence, we administered them to mice with colitis. While 25-hydroxycholesterol had no effect, 4ß-hydroxycholesterol worsened colon inflammation. CONCLUSIONS: Our study addresses the potential involvement of oxysterols in colitis and clearly points towards an active role as well as a clinical relevance for these bioactive lipids.


Assuntos
Colite Ulcerativa/metabolismo , Colite/metabolismo , Colo/metabolismo , Doença de Crohn/metabolismo , Hidroxicolesteróis/farmacologia , Oxisteróis/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Colite Ulcerativa/patologia , Colo/química , Colo/efeitos dos fármacos , Colo/patologia , Doença de Crohn/patologia , Modelos Animais de Doenças , Humanos , Fígado/química , Masculino , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos C57BL , Oxisteróis/análise , Oxisteróis/sangue , Peroxidase/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Transcriptoma
15.
Brain Behav Immun ; 74: 96-105, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30071254

RESUMO

The prevalence of obesity has increased at an alarming rate during past decades. Obesity is associated with pathophysiological disorders that can evolve and increase the risk of heart disease, diabetes and hypertension. While the impact of diabetes on post-operative recovery is now known, the consequences of obesity on post-operative pain remain much less explored. Here, we show that obesity affects post-operative pain resolution and leads to a chronic pain state in mice. Several mechanisms were identified as implicated in the prolonged post-operative pain. Indeed, we found that following a hind paw incision, high fat diet prolonged glial cell activation in the spinal cord. It also altered the expression of neurotrophins and increased inflammatory and endoplasmic reticulum stress markers in both central and peripheral nervous systems. Moreover, we show that a dietary intervention, leading to weight reduction and decreased inflammation, was able to restore normal pain sensitivity in mice suffering from chronic pain for more than 10 weeks. In conclusion, our data demonstrate that obesity is responsible for pain chronicization. This is clearly of importance in a clinical post-operative setting.


Assuntos
Limiar da Dor/fisiologia , Dor Pós-Operatória/dietoterapia , Animais , Astrócitos/metabolismo , Dieta Hiperlipídica/efeitos adversos , Hiperalgesia/metabolismo , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Crescimento Neural/efeitos dos fármacos , Neuroglia/metabolismo , Obesidade/metabolismo , Obesidade/fisiopatologia , Dor Pós-Operatória/fisiopatologia , Medula Espinal/metabolismo
16.
FASEB J ; 32(9): 5000-5011, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29630407

RESUMO

Cyclooxygenase-2 (COX-2) has long been implicated in the pathogenesis of inflammatory bowel diseases (IBDs). COX-2 is mostly known for the production of prostaglandins (PGs) from arachidonic acid. However, it also metabolizes the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide into the less well-studied bioactive lipids PG-glycerol esters (PG-Gs) and PG-ethanolamides (PG-EAs or prostamides). We previously showed that PGD2-G, a product of 2-AG oxygenation by COX-2, has anti-inflammatory effects. Therefore, we used the dextran sulfate sodium (DSS)-induced model of colitis in mice to explore the role of PGD2-G in murine models of IBD. Colon inflammation was assessed using macroscopic and histologic scores, myeloperoxidase activity, and expression of inflammatory mediators by real-time quantitative PCR and ELISA. We also compared the effects of PGD2-G with those of PGD2 and PGD2-EA. Finally, we used receptor antagonists to gain mechanistic insight into the receptors responsible for the observed effects. PGD2-G reduced DSS-induced colitis, but PGD2 and PGD2-EA did not have the same effect. Furthermore, we showed that PGD2-G is an agonist of the PGD2 receptor 1 (DP1) and that some of the effects of PGD2-G were blocked by antagonism of peroxisome proliferator-activated receptor γ and DP1. Therefore, PGD2-G could be one of the products from the COX-2/prostaglandin D synthase axis to exert beneficial effects in colitis.-Alhouayek, M., Buisseret, B., Paquot, A., Guillemot-Legris, O., Muccioli, G. G. The endogenous bioactive lipid prostaglandin D2-glycerol ester reduces murine colitis via DP1 and PPARγ receptors.


Assuntos
Glicerol/metabolismo , Lipídeos , PPAR gama/metabolismo , Prostaglandina D2/metabolismo , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Animais , Ciclo-Oxigenase 2/metabolismo , Metabolismo dos Lipídeos , Masculino , Camundongos Endogâmicos C57BL , Oxirredução
17.
J Neuroinflammation ; 15(1): 74, 2018 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-29523207

RESUMO

BACKGROUND: Oxysterols are cholesterol derivatives that have been suggested to play a role in inflammatory diseases such as obesity, atherosclerosis, or neuroinflammatory diseases. However, the effect of neuroinflammation on oxysterol levels has only been partially studied so far. METHODS: We used an HPLC-MS method to quantify over ten oxysterols both in in vitro and in vivo models of neuroinflammation. In the same models, we used RT-qPCR to analyze the expression of the enzymes responsible for oxysterol metabolism. Using the BV2 microglial cell line, we explored the effect of lipopolysaccharide (LPS)-induced (M1-type) and IL-4-induced (M2-type) cell activation on oxysterol levels. We also used LPS-activated co-cultures of mouse primary microglia and astrocytes. In vivo, we induced a neuroinflammation by administering LPS to mice. Finally, we used a mouse model of multiple sclerosis, namely the experimental autoimmune encephalomyelitis (EAE) model, that is characterized by demyelination and neuroinflammation. RESULTS: In vitro, we found that LPS activation induces profound alterations in oxysterol levels. Interestingly, we could discriminate between control and LPS-activated cells based on the changes in oxysterol levels both in BV2 cells and in the primary co-culture of glial cells. In vivo, the changes in oxysterol levels were less marked than in vitro. However, we found in both models increased levels of the GPR183 agonist 7α,25-dihydroxycholesterol. Furthermore, we studied in vitro the effect of 14 oxysterols on the mRNA expression of inflammatory markers in LPS-activated co-culture of microglia and astrocytes. We found that several oxysterols decreased the LPS-induced expression of pro-inflammatory markers. CONCLUSIONS: These data demonstrate that inflammation profoundly affects oxysterol levels and that oxysterols can modulate glial cell activation. This further supports the interest of a large screening of oxysterol levels when studying the interplay between neuroinflammation and bioactive lipids.


Assuntos
Encefalite/metabolismo , Encefalite/patologia , Encefalomielite Autoimune Experimental/metabolismo , Metabolismo , Oxisteróis/metabolismo , Animais , Animais Recém-Nascidos , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Encéfalo/citologia , Células Cultivadas , Colestanotriol 26-Mono-Oxigenase/genética , Colestanotriol 26-Mono-Oxigenase/metabolismo , Técnicas de Cocultura , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalite/induzido quimicamente , Feminino , Regulação da Expressão Gênica/fisiologia , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo
18.
Trends Neurosci ; 40(4): 237-253, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28318543

RESUMO

Obesity is now a worldwide health issue. Far from being limited to weight gain, obesity is generally associated with low-grade inflammation and with a cluster of disorders collectively known as the 'metabolic syndrome'. When considering obesity and the subsequent neuroinflammation, the focus was long set on the hypothalamus. More recently, obesity-derived neuroinflammation has been shown to affect other brain structures such as the hippocampus, cortex, brainstem, or amygdala. Furthermore, obesity has been associated with increased occurrence of central disorders such as depression and impaired cognitive function. We discuss here the effects and mechanisms of obesity-derived neuroinflammation, with a specific emphasis on extra-hypothalamic structures, as well as the repercussions of neuroinflammation for some cerebral functions.


Assuntos
Encéfalo/imunologia , Inflamação/metabolismo , Obesidade/imunologia , Animais , Humanos
19.
Prog Lipid Res ; 64: 152-169, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27687912

RESUMO

Oxysterols are cholesterol metabolites that can be produced through enzymatic or radical processes. They constitute a large family of lipids (i.e. the oxysterome) involved in a plethora of physiological processes. They can act through GPCR (e.g. EBI2, SMO, CXCR2), nuclear receptors (LXR, ROR, ERα) and through transporters or regulatory proteins. Their physiological effects encompass cholesterol, lipid and glucose homeostasis. Additionally, they were shown to be involved in other processes such as immune regulatory functions and brain homeostasis. First studied as precursors of bile acids, they quickly emerged as interesting lipid mediators. Their levels are greatly altered in several pathologies and some oxysterols (e.g. 4ß-hydroxycholesterol or 7α-hydroxycholestenone) are used as biomarkers of specific pathologies. In this review, we discuss the complex metabolism and molecular targets (including binding properties) of these bioactive lipids in human and mice. We also discuss the genetic mouse models currently available to interrogate their effects in pathophysiological settings. We also summarize the levels of oxysterols reported in two key organs in oxysterol metabolism (liver and brain), plasma and cerebrospinal fluid. Finally, we consider future opportunities and directions in the oxysterol field in order to gain a better insight and understanding of the complex oxysterol system.


Assuntos
Oxisteróis/metabolismo , Animais , Colesterol/metabolismo , Humanos , Hidrolases/metabolismo , Modelos Animais , Oxirredutases/metabolismo , Oxisteróis/química , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transferases/metabolismo
20.
J Neuroinflammation ; 13(1): 206, 2016 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-27566530

RESUMO

BACKGROUND: Obesity and its associated disorders are becoming a major health issue in many countries. The resulting low-grade inflammation not only affects the periphery but also the central nervous system. We set out to study, in a time-dependent manner, the effects of a high-fat diet on different regions of the central nervous system with regard to the inflammatory tone. METHODS: We used a diet-induced obesity model and compared at several time-points (1, 2, 4, 6, 8, and 16 weeks) a group of mice fed a high-fat diet with its respective control group fed a standard diet. We also performed a large-scale analysis of lipids in the central nervous system using HPLC-MS, and we then tested the lipids of interest on a primary co-culture of astrocytes and microglial cells. RESULTS: We measured an increase in the inflammatory tone in the cerebellum at the different time-points. However, at week 16, we evidenced that the inflammatory tone displayed significant differences in two different regions of the central nervous system, specifically an increase in the cerebellum and no modification in the cortex for high-fat diet mice when compared with chow-fed mice. Our results clearly suggest region-dependent as well as time-dependent adaptations of the central nervous system to the high-fat diet. The differences in inflammatory tone between the two regions considered seem to involve astrocytes but not microglial cells. Furthermore, a large-scale lipid screening coupled to ex vivo testing enabled us to identify three classes of lipids-phosphatidylinositols, phosphatidylethanolamines, and lysophosphatidylcholines-as well as palmitoylethanolamide, as potentially responsible for the difference in inflammatory tone. CONCLUSIONS: This study demonstrates that the inflammatory tone induced by a high-fat diet does not similarly affect distinct regions of the central nervous system. Moreover, the lipids identified and tested ex vivo showed interesting anti-inflammatory properties and could be further studied to better characterize their activity and their role in controlling inflammation in the central nervous system.


Assuntos
Sistema Nervoso Central/metabolismo , Citocinas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Inflamação/patologia , Obesidade/etiologia , Animais , Animais Recém-Nascidos , Células Cultivadas , Sistema Nervoso Central/efeitos dos fármacos , Córtex Cerebral/citologia , Colesterol/metabolismo , Cultura , Citocinas/genética , Modelos Animais de Doenças , Inflamação/induzido quimicamente , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neuroglia/efeitos dos fármacos , Neuroglia/patologia , Fatores de Tempo
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