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1.
Proc Natl Acad Sci U S A ; 113(1): 26-33, 2016 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-26668358

RESUMEN

Diacylglycerol lipases (DAGLα and DAGLß) convert diacylglycerol to the endocannabinoid 2-arachidonoylglycerol. Our understanding of DAGL function has been hindered by a lack of chemical probes that can perturb these enzymes in vivo. Here, we report a set of centrally active DAGL inhibitors and a structurally related control probe and their use, in combination with chemical proteomics and lipidomics, to determine the impact of acute DAGL blockade on brain lipid networks in mice. Within 2 h, DAGL inhibition produced a striking reorganization of bioactive lipids, including elevations in DAGs and reductions in endocannabinoids and eicosanoids. We also found that DAGLα is a short half-life protein, and the inactivation of DAGLs disrupts cannabinoid receptor-dependent synaptic plasticity and impairs neuroinflammatory responses, including lipopolysaccharide-induced anapyrexia. These findings illuminate the highly interconnected and dynamic nature of lipid signaling pathways in the brain and the central role that DAGL enzymes play in regulating this network.


Asunto(s)
Ácidos Araquidónicos/metabolismo , Encéfalo/efectos de los fármacos , Diglicéridos/metabolismo , Endocannabinoides/metabolismo , Inhibidores Enzimáticos/farmacología , Glicéridos/metabolismo , Lipoproteína Lipasa/antagonistas & inhibidores , Plasticidad Neuronal/efectos de los fármacos , Animales , Encéfalo/enzimología , Encéfalo/metabolismo , Inhibidores Enzimáticos/química , Lipoproteína Lipasa/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Receptores de Cannabinoides/metabolismo , Transducción de Señal/efectos de los fármacos
2.
J Pharmacol Exp Ther ; 367(3): 494-508, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30305428

RESUMEN

Monoacylglycerol lipase (MGLL) is the primary degradative enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG). The first MGLL inhibitors have recently entered clinical development for the treatment of neurologic disorders. To support this clinical path, we report the pharmacological characterization of the highly potent and selective MGLL inhibitor ABD-1970 [1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-chlorobenzyl)piperazine-1-carboxylate]. We used ABD-1970 to confirm the role of MGLL in human systems and to define the relationship between MGLL target engagement, brain 2-AG concentrations, and efficacy. Because MGLL contributes to arachidonic acid metabolism in a subset of rodent tissues, we further used ABD-1970 to evaluate whether selective MGLL inhibition would affect prostanoid production in several human assays known to be sensitive to cyclooxygenase inhibitors. ABD-1970 robustly elevated brain 2-AG content and displayed antinociceptive and antipruritic activity in a battery of rodent models (ED50 values of 1-2 mg/kg). The antinociceptive effects of ABD-1970 were potentiated when combined with analgesic standards of care and occurred without overt cannabimimetic effects. ABD-1970 also blocked 2-AG hydrolysis in human brain tissue and elevated 2-AG content in human blood without affecting stimulated prostanoid production. These findings support the clinical development of MGLL inhibitors as a differentiated mechanism to treat pain and other neurologic disorders.


Asunto(s)
Endocannabinoides/metabolismo , Inhibidores Enzimáticos/farmacología , Monoacilglicerol Lipasas/antagonistas & inhibidores , Analgésicos/farmacología , Animales , Antipruriginosos/farmacología , Ácidos Araquidónicos/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Línea Celular Tumoral , Inhibidores de la Ciclooxigenasa/farmacología , Glicéridos/metabolismo , Humanos , Hidrólisis/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos ICR , Células PC-3 , Dolor/tratamiento farmacológico , Dolor/metabolismo , Piperidinas/farmacología , Prostaglandinas/farmacología , Ratas , Ratas Sprague-Dawley , Roedores
3.
Proc Natl Acad Sci U S A ; 111(41): 14924-9, 2014 Oct 14.
Artículo en Inglés | MEDLINE | ID: mdl-25267624

RESUMEN

Complex hereditary spastic paraplegia (HSP) is a genetic disorder that causes lower limb spasticity and weakness and intellectual disability. Deleterious mutations in the poorly characterized serine hydrolase DDHD2 are a causative basis for recessive complex HSP. DDHD2 exhibits phospholipase activity in vitro, but its endogenous substrates and biochemical functions remain unknown. Here, we report the development of DDHD2(-/-) mice and a selective, in vivo-active DDHD2 inhibitor and their use in combination with mass spectrometry-based lipidomics to discover that DDHD2 regulates brain triglycerides (triacylglycerols, or TAGs). DDHD2(-/-) mice show age-dependent TAG elevations in the central nervous system, but not in several peripheral tissues. Large lipid droplets accumulated in DDHD2(-/-) brains and were localized primarily to the intracellular compartments of neurons. These metabolic changes were accompanied by impairments in motor and cognitive function. Recombinant DDHD2 displays TAG hydrolase activity, and TAGs accumulated in the brains of wild-type mice treated subchronically with a selective DDHD2 inhibitor. These findings, taken together, indicate that the central nervous system possesses a specialized pathway for metabolizing TAGs, disruption of which leads to massive lipid accumulation in neurons and complex HSP syndrome.


Asunto(s)
Lipasa/metabolismo , Fosfolipasas A1/metabolismo , Paraplejía Espástica Hereditaria/enzimología , Animales , Encéfalo/metabolismo , Encéfalo/ultraestructura , Cognición , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Eliminación de Gen , Marcación de Gen , Células HEK293 , Humanos , Lipasa/antagonistas & inhibidores , Gotas Lipídicas/metabolismo , Gotas Lipídicas/ultraestructura , Locomoción , Ratones Endogámicos C57BL , Neuronas/metabolismo , Fosfolipasas , Fosfolipasas A1/antagonistas & inhibidores , Fosfolipasas A1/deficiencia , Reproducibilidad de los Resultados , Paraplejía Espástica Hereditaria/genética , Triglicéridos/metabolismo
4.
Proc Natl Acad Sci U S A ; 108(43): E952-61, 2011 Oct 25.
Artículo en Inglés | MEDLINE | ID: mdl-21949390

RESUMEN

The formation of myelin by Schwann cells (SCs) occurs via a series of orchestrated molecular events. We previously used global expression profiling to examine peripheral nerve myelination and identified the NAD(+)-dependent deacetylase Sir-two-homolog 2 (Sirt2) as a protein likely to be involved in myelination. Here, we show that Sirt2 expression in SCs is correlated with that of structural myelin components during both developmental myelination and remyelination after nerve injury. Transgenic mice lacking or overexpressing Sirt2 specifically in SCs show delays in myelin formation. In SCs, we found that Sirt2 deacetylates Par-3, a master regulator of cell polarity. The deacetylation of Par-3 by Sirt2 decreases the activity of the polarity complex signaling component aPKC, thereby regulating myelin formation. These results demonstrate that Sirt2 controls an essential polarity pathway in SCs during myelin assembly and provide insights into the association between intracellular metabolism and SC plasticity.


Asunto(s)
Moléculas de Adhesión Celular/metabolismo , Vaina de Mielina/fisiología , Proteína Quinasa C/metabolismo , Células de Schwann/fisiología , Transducción de Señal/fisiología , Sirtuina 2/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Animales , Western Blotting , Proteínas de Ciclo Celular , Cromatografía Liquida , Cartilla de ADN/genética , Genotipo , Inmunoprecipitación , Luciferasas , Ratones , Ratones Transgénicos , Plásmidos/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Sirtuina 2/genética , Espectrometría de Masas en Tándem
5.
BMC Genomics ; 14: 84, 2013 Feb 06.
Artículo en Inglés | MEDLINE | ID: mdl-23387820

RESUMEN

BACKGROUND: The regenerative response of Schwann cells after peripheral nerve injury is a critical process directly related to the pathophysiology of a number of neurodegenerative diseases. This SC injury response is dependent on an intricate gene regulatory program coordinated by a number of transcription factors and microRNAs, but the interactions among them remain largely unknown. Uncovering the transcriptional and post-transcriptional regulatory networks governing the Schwann cell injury response is a key step towards a better understanding of Schwann cell biology and may help develop novel therapies for related diseases. Performing such comprehensive network analysis requires systematic bioinformatics methods to integrate multiple genomic datasets. RESULTS: In this study we present a computational pipeline to infer transcription factor and microRNA regulatory networks. Our approach combined mRNA and microRNA expression profiling data, ChIP-Seq data of transcription factors, and computational transcription factor and microRNA target prediction. Using mRNA and microRNA expression data collected in a Schwann cell injury model, we constructed a regulatory network and studied regulatory pathways involved in Schwann cell response to injury. Furthermore, we analyzed network motifs and obtained insights on cooperative regulation of transcription factors and microRNAs in Schwann cell injury recovery. CONCLUSIONS: This work demonstrates a systematic method for gene regulatory network inference that may be used to gain new information on gene regulation by transcription factors and microRNAs.


Asunto(s)
Biología Computacional/métodos , Redes Reguladoras de Genes , MicroARNs/genética , MicroARNs/metabolismo , Traumatismos de los Nervios Periféricos/patología , Células de Schwann/metabolismo , Factores de Transcripción/metabolismo , Animales , Inmunoprecipitación de Cromatina , Proteína 2 de la Respuesta de Crecimiento Precoz/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Genómica , Humanos , Ratones , Vaina de Mielina/fisiología , Traumatismos de los Nervios Periféricos/genética , Traumatismos de los Nervios Periféricos/metabolismo , Traumatismos de los Nervios Periféricos/fisiopatología , ARN Mensajero/genética , ARN Mensajero/metabolismo
6.
Muscle Nerve ; 47(2): 213-23, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23169341

RESUMEN

INTRODUCTION: We sought to determine whether supplementation of acellular nerve allografts (ANAs) with Schwann cells overexpressing GDNF (G-SCs) would enhance functional recovery after peripheral nerve injury. METHODS: SCs expanded in vitro were infected with a lentiviral vector to induce GDNF overexpression. Wild-type SCs (WT-SCs) and G-SCs were seeded into ANAs used to repair a 14-mm nerve gap defect. Animals were harvested after 6 and 12 weeks for histomorphometric and muscle force analysis. RESULTS: At 6 weeks, histomorphometry revealed that ANAs supplemented with G-SCs promoted similar regeneration compared with isograft at midgraft. However, G-SCs failed to promote regeneration into the distal stump. At 12 weeks, ANAs with G-SCs had lower maximum and specific force production compared with controls. CONCLUSIONS: The combined results suggest that consistent overexpression of GDNF by G-SCs trapped axons in the graft and prevented functional regeneration.


Asunto(s)
Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Tejido Nervioso/trasplante , Traumatismos de los Nervios Periféricos/cirugía , Recuperación de la Función/fisiología , Células de Schwann/trasplante , Animales , Masculino , Regeneración Nerviosa/fisiología , Tejido Nervioso/metabolismo , Traumatismos de los Nervios Periféricos/metabolismo , Ratas , Ratas Endogámicas Lew , Ratas Sprague-Dawley , Células de Schwann/metabolismo
7.
J Neurosci ; 31(48): 17358-69, 2011 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-22131398

RESUMEN

In the peripheral nervous system, Schwann cells (SCs) surrounding damaged axons undergo an injury response that is driven by an intricate transcriptional program and is critical for nerve regeneration. To examine whether these injury-induced changes in SCs are also regulated posttranscriptionally by miRNAs, we performed miRNA expression profiling of mouse sciatic nerve distal segment after crush injury. We also characterized the SC injury response in mice containing SCs with disrupted miRNA processing due to loss of Dicer. We identified 87 miRNAs that were expressed in mouse adult peripheral nerve, 48 of which were dynamically regulated after nerve injury. Most of these injury-regulated SC miRNAs were computationally predicted to inhibit drivers of SC dedifferentiation/proliferation and thereby re-enforce the transcriptional program driving SC remyelination. SCs deficient in miRNAs manifested a delay in the transition between the distinct differentiation states required to support peripheral nerve regeneration. Among the miRNAs expressed in adult mouse SCs, miR-34a and miR-140 were identified as functional regulators of SC dedifferentiation/proliferation and remyelination, respectively. We found that miR-34a interacted with positive regulators of dedifferentiation and proliferation such as Notch1 and Ccnd1 to control cell cycle dynamics in SCs. miR-140 targeted the transcription factor Egr2, a master regulator of myelination, and modulated myelination in DRG/SC cocultures. Together, these results demonstrate that SC miRNAs are important modulators of the SC regenerative response after nerve damage.


Asunto(s)
Desdiferenciación Celular/genética , Silenciador del Gen , MicroARNs/metabolismo , Células de Schwann/metabolismo , Nervio Ciático/lesiones , Animales , Axones/metabolismo , Células Cultivadas , Regulación de la Expresión Génica , Ratones , MicroARNs/genética , Compresión Nerviosa , Regeneración Nerviosa/fisiología , Nervio Ciático/metabolismo
8.
J Neurosci ; 31(28): 10128-40, 2011 Jul 13.
Artículo en Inglés | MEDLINE | ID: mdl-21752989

RESUMEN

Mitochondrial dysfunction is a common cause of peripheral neuropathies. While the role of neuron and axonal mitochondria in peripheral nerve disease is well appreciated, whether Schwann cell (SC) mitochondrial deficits contribute to peripheral neuropathies is unclear. Here, we examine how SC mitochondrial dysfunction affects axonal survival and contributes to the decline of peripheral nerve function by generating mice with SC-specific mitochondrial deficits. These mice (Tfam-SCKOs) were produced through the tissue-specific deletion of the mitochondrial transcription factor A gene (Tfam), which is essential for mitochondrial DNA (mtDNA) transcription and maintenance. Tfam-SCKOs were viable, but as they aged, they developed a progressive peripheral neuropathy characterized by nerve conduction abnormalities as well as extensive muscle denervation. Morphological examination of Tfam-SCKO nerves revealed early preferential loss of small unmyelinated fibers followed by prominent demyelination and degeneration of larger-caliber axons. Tfam-SCKOs displayed sensory and motor deficits consistent with this pathology. Remarkably, the severe mtDNA depletion and respiratory chain abnormalities in Tfam-SCKO mice did not affect SC proliferation or survival. Mitochondrial function in SCs is therefore essential for maintenance of axonal survival and normal peripheral nerve function, suggesting that SC mitochondrial dysfunction contributes to human peripheral neuropathies.


Asunto(s)
Axones/metabolismo , Mitocondrias/metabolismo , Nervios Periféricos/metabolismo , Células de Schwann/metabolismo , Animales , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Proteínas del Grupo de Alta Movilidad/genética , Proteínas del Grupo de Alta Movilidad/metabolismo , Ratones , Mitocondrias/genética , Vaina de Mielina/metabolismo , Neuronas/metabolismo
9.
Sci Rep ; 11(1): 11861, 2021 06 04.
Artículo en Inglés | MEDLINE | ID: mdl-34088912

RESUMEN

Nonalcoholic steatohepatitis (NASH) is a complex metabolic disease of heterogeneous and multifactorial pathogenesis that may benefit from coordinated multitargeted interventions. Endogenous metabolic modulators (EMMs) encompass a broad set of molecular families, including amino acids and related metabolites and precursors. EMMs often serve as master regulators and signaling agents for metabolic pathways throughout the body and hold the potential to impact a complex metabolic disease like NASH by targeting a multitude of pathologically relevant biologies. Here, we describe a study of a novel EMM composition comprising five amino acids and an amino acid derivative (Leucine, Isoleucine, Valine, Arginine, Glutamine, and N-acetylcysteine [LIVRQNac]) and its systematic evaluation across multiple NASH-relevant primary human cell model systems, including hepatocytes, macrophages, and stellate cells. In these model systems, LIVRQNac consistently and simultaneously impacted biology associated with all three core pathophysiological features of NASH-metabolic, inflammatory, and fibrotic. Importantly, it was observed that while the individual constituent amino acids in LIVRQNac can impact specific NASH-related phenotypes in select cell systems, the complete combination was necessary to impact the range of disease-associated drivers examined. These findings highlight the potential of specific and potent multitargeted amino acid combinations for the treatment of NASH.


Asunto(s)
Técnicas de Cultivo de Célula , Fibrosis/metabolismo , Inflamación/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Alanina Transaminasa/metabolismo , Biomarcadores/metabolismo , Colágeno/química , Hepatocitos/metabolismo , Humanos , Técnicas In Vitro , Hígado/metabolismo , Cirrosis Hepática/patología , Hepatopatías/metabolismo , Macrófagos/metabolismo , Fenotipo , Transducción de Señal
10.
Sci Rep ; 6: 35829, 2016 10 24.
Artículo en Inglés | MEDLINE | ID: mdl-27775008

RESUMEN

The endocannabinoid 2-arachidonoylglycerol (2-AG) mediates retrograde synaptic depression including depolarization-induced suppression of excitation (DSE) and inhibition (DSI). 2-AG is degraded primarily by monoacylglycerol lipase (MAGL), which is expressed in neurons and astrocytes. Using knockout mice in which MAGL is deleted globally or selectively in neurons or astrocytes, we investigated the relative contribution of neuronal and astrocytic MAGL to the termination of DSE and DSI in Purkinje cells (PCs) in cerebellar slices. We report that neuronal MAGL plays a predominant role in terminating DSE at climbing fiber (CF) to PC synapses, while both neuronal and astrocytic MAGL significantly contributes to the termination of DSE at parallel fiber (PF) to PC synapses and DSI at putative Stellate cell to PC synapses. Thus, DSE and DSI at different synapses is not uniformly affected by global and cell type-specific knockout of MAGL. Additionally, MAGL global knockout, but not cell type-specific knockout, caused tonic activation and partial desensitization of the CB1 receptor at PF-PC synapses. This tonic CB1 activation is mediated by 2-AG since it was blocked by the diacylglycerol lipase inhibitor DO34. Together, these results suggest that both neuronal and astrocytic MAGL contribute to 2-AG clearance and prevent CB1 receptor over-stimulation in the cerebellum.


Asunto(s)
Cerebelo/metabolismo , Endocannabinoides/metabolismo , Monoacilglicerol Lipasas/metabolismo , Sinapsis/fisiología , Animales , Ácidos Araquidónicos/metabolismo , Astrocitos/fisiología , Benzodioxoles/farmacología , Benzoxazinas/farmacología , Cerebelo/citología , Inhibidores Enzimáticos/farmacología , Femenino , Glicéridos/metabolismo , Masculino , Ratones Noqueados , Monoacilglicerol Lipasas/antagonistas & inhibidores , Monoacilglicerol Lipasas/genética , Morfolinas/farmacología , Naftalenos/farmacología , Neuronas/fisiología , Técnicas de Placa-Clamp , Piperidinas/farmacología , Células de Purkinje/fisiología , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/metabolismo , Sinapsis/efectos de los fármacos
11.
Elife ; 5: e12345, 2016 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-26779719

RESUMEN

Metabolic specialization among major brain cell types is central to nervous system function and determined in large part by the cellular distribution of enzymes. Serine hydrolases are a diverse enzyme class that plays fundamental roles in CNS metabolism and signaling. Here, we perform an activity-based proteomic analysis of primary mouse neurons, astrocytes, and microglia to furnish a global portrait of the cellular anatomy of serine hydrolases in the brain. We uncover compelling evidence for the cellular compartmentalization of key chemical transmission pathways, including the functional segregation of endocannabinoid (eCB) biosynthetic enzymes diacylglycerol lipase-alpha (DAGLα) and -beta (DAGLß) to neurons and microglia, respectively. Disruption of DAGLß perturbed eCB-eicosanoid crosstalk specifically in microglia and suppressed neuroinflammatory events in vivo independently of broader effects on eCB content. Mapping the cellular distribution of metabolic enzymes thus identifies pathways for regulating specialized inflammatory responses in the brain while avoiding global alterations in CNS function.


Asunto(s)
Encéfalo/enzimología , Proteómica , Serina Endopeptidasas/análisis , Animales , Astrocitos/química , Lipoproteína Lipasa/análisis , Ratones , Microglía/química , Neuronas/química
12.
eNeuro ; 3(3)2016.
Artículo en Inglés | MEDLINE | ID: mdl-27182552

RESUMEN

Endocannabinoids are diffusible lipophilic molecules that may spread to neighboring synapses. Monoacylglycerol lipase (MAGL) is the principal enzyme that degrades the endocannabinoid 2-arachidonoylglycerol (2-AG). Using knock-out mice in which MAGL is deleted globally or selectively in neurons and astrocytes, we investigated the extent to which neuronal and astrocytic MAGL limit the spread of 2-AG-mediated retrograde synaptic depression in cerebellar slices. A brief tetanic stimulation of parallel fibers in the molecular layer induced synaptically evoked suppression of excitation (SSE) in Purkinje cells, and both neuronal and astrocytic MAGL contribute to the termination of this form of endocannabinoid-mediated synaptic depression. The spread of SSE among Purkinje cells occurred only after global knock-out of MAGL or pharmacological blockade of either MAGL or glutamate uptake, but no spread was detected following neuron- or astrocyte-specific deletion of MAGL. The spread of endocannabinoid signaling was also influenced by the spatial pattern of synaptic stimulation, because it did not occur at spatially dispersed parallel fiber synapses induced by stimulating the granular layer. The tetanic stimulation of parallel fibers did not induce endocannabinoid-mediated synaptic suppression in Golgi cells even after disruption of MAGL and glutamate uptake, suggesting that heightened release of 2-AG by Purkinje cells does not spread the retrograde signal to parallel fibers that innervate Golgi cells. These results suggest that both neuronal and astrocytic MAGL limit the spatial diffusion of 2-AG and confer synapse-specificity of endocannabinoid signaling.


Asunto(s)
Astrocitos/enzimología , Cerebelo/enzimología , Endocannabinoides/metabolismo , Monoacilglicerol Lipasas/metabolismo , Neuronas/enzimología , Transmisión Sináptica/fisiología , Sistema de Transporte de Aminoácidos X-AG/antagonistas & inhibidores , Sistema de Transporte de Aminoácidos X-AG/metabolismo , Animales , Ácidos Araquidónicos/farmacología , Astrocitos/efectos de los fármacos , Agonistas de Receptores de Cannabinoides/farmacología , Cerebelo/efectos de los fármacos , Endocannabinoides/farmacología , Ácido Glutámico/metabolismo , Glicéridos/farmacología , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Ratones Noqueados , Monoacilglicerol Lipasas/genética , Neuronas/efectos de los fármacos , Técnicas de Placa-Clamp , Transmisión Sináptica/efectos de los fármacos , Técnicas de Cultivo de Tejidos
13.
PLoS One ; 10(8): e0134437, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26287872

RESUMEN

Cyclooxygenase inhibitors such as ibuprofen have been used for decades to control fever through reducing the levels of the pyrogenic lipid transmitter prostaglandin E2 (PGE2). Historically, phospholipases have been considered to be the primary generator of the arachidonic acid (AA) precursor pool for generating PGE2 and other eicosanoids. However, recent studies have demonstrated that monoacyglycerol lipase (MAGL), through hydrolysis of the endocannabinoid 2-arachidonoylglycerol, provides a major source of AA for PGE2 synthesis in the mammalian brain under basal and neuroinflammatory states. We show here that either genetic or pharmacological ablation of MAGL leads to significantly reduced fever responses in both centrally or peripherally-administered lipopolysaccharide or interleukin-1ß-induced fever models in mice. We also show that a cannabinoid CB1 receptor antagonist does not attenuate these anti-pyrogenic effects of MAGL inhibitors. Thus, much like traditional nonsteroidal anti-inflammatory drugs, MAGL inhibitors can control fever, but appear to do so through restricted control over prostaglandin production in the nervous system.


Asunto(s)
Inhibidores Enzimáticos/uso terapéutico , Fiebre/tratamiento farmacológico , Fiebre/enzimología , Monoacilglicerol Lipasas/antagonistas & inhibidores , Monoacilglicerol Lipasas/metabolismo , Animales , Temperatura Corporal , Moduladores de Receptores de Cannabinoides/uso terapéutico , Fiebre/genética , Fiebre/metabolismo , Eliminación de Gen , Masculino , Ratones , Monoacilglicerol Lipasas/genética , Receptor Cannabinoide CB1/antagonistas & inhibidores
14.
Cell Rep ; 12(5): 798-808, 2015 Aug 04.
Artículo en Inglés | MEDLINE | ID: mdl-26212325

RESUMEN

The endocannabinoid 2-arachidonoylglycerol (2-AG) is a retrograde lipid messenger that modulates synaptic function, neurophysiology, and behavior. 2-AG signaling is terminated by enzymatic hydrolysis-a reaction that is principally performed by monoacylglycerol lipase (MAGL). MAGL is broadly expressed throughout the nervous system, and the contributions of different brain cell types to the regulation of 2-AG activity in vivo remain poorly understood. Here, we genetically dissect the cellular anatomy of MAGL-mediated 2-AG metabolism in the brain and show that neurons and astrocytes coordinately regulate 2-AG content and endocannabinoid-dependent forms of synaptic plasticity and behavior. We also find that astrocytic MAGL is mainly responsible for converting 2-AG to neuroinflammatory prostaglandins via a mechanism that may involve transcellular shuttling of lipid substrates. Astrocytic-neuronal interplay thus provides distributed oversight of 2-AG metabolism and function and, through doing so, protects the nervous system from excessive CB1 receptor activation and promotes endocannabinoid crosstalk with other lipid transmitter systems.


Asunto(s)
Ácidos Araquidónicos/metabolismo , Astrocitos/metabolismo , Comunicación Celular/fisiología , Endocannabinoides/metabolismo , Glicéridos/metabolismo , Neuronas/metabolismo , Animales , Ácidos Araquidónicos/genética , Astrocitos/citología , Endocannabinoides/genética , Glicéridos/genética , Ratones , Ratones Noqueados , Monoacilglicerol Lipasas/genética , Monoacilglicerol Lipasas/metabolismo , Neuronas/citología , Receptor Cannabinoide CB1/genética , Receptor Cannabinoide CB1/metabolismo
15.
Neuron ; 77(5): 886-98, 2013 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-23473319

RESUMEN

Mitochondrial dysfunction is a common cause of peripheral neuropathy. Much effort has been devoted to examining the role played by neuronal/axonal mitochondria, but how mitochondrial deficits in peripheral nerve glia (Schwann cells [SCs]) contribute to peripheral nerve diseases remains unclear. Here, we investigate a mouse model of peripheral neuropathy secondary to SC mitochondrial dysfunction (Tfam-SCKOs). We show that disruption of SC mitochondria activates a maladaptive integrated stress response (ISR) through the actions of heme-regulated inhibitor (HRI) kinase, and causes a shift in lipid metabolism away from fatty acid synthesis toward oxidation. These alterations in SC lipid metabolism result in depletion of important myelin lipid components as well as in accumulation of acylcarnitines (ACs), an intermediate of fatty acid ß-oxidation. Importantly, we show that ACs are released from SCs and induce axonal degeneration. A maladaptive ISR as well as altered SC lipid metabolism are thus underlying pathological mechanisms in mitochondria-related peripheral neuropathies.


Asunto(s)
Axones/patología , Metabolismo de los Lípidos/fisiología , Encefalomiopatías Mitocondriales/metabolismo , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/patología , Enfermedades del Sistema Nervioso Periférico/metabolismo , Enfermedades del Sistema Nervioso Periférico/patología , Células de Schwann/metabolismo , Compuestos de Anilina , Animales , Western Blotting , Carnitina/análogos & derivados , Carnitina/metabolismo , Células Cultivadas , Ácidos Grasos/metabolismo , Colorantes Fluorescentes , Ganglios Espinales/citología , Ratones , Ratones Noqueados , Ratones Transgénicos , Análisis por Micromatrices , Proteínas Serina-Treonina Quinasas/biosíntesis , Proteínas Serina-Treonina Quinasas/genética , Xantenos
16.
PLoS One ; 6(11): e27727, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-22110743

RESUMEN

Mitochondrial dysfunction is a central mediator of disease progression in diverse neurodegenerative diseases that often present with prominent gastrointestinal abnormalities. Gastrointestinal dysfunction in these disorders is related, at least in part, to defects in the enteric nervous system (ENS). The role of mitochondrial deficits in ENS neurodegeneration and their relative contribution to gastrointestinal dysfunction, however, are unclear. To better understand how mitochondrial abnormalities in the ENS influence enteric neurodegeneration and affect intestinal function, we generated mice (Tfam-ENSKOs) with impaired mitochondrial metabolism in enteric neurons and glia through the targeted deletion of the mitochondrial transcription factor A gene (Tfam). Tfam-ENSKO mice were initially viable but, at an early age, they developed severe gastrointestinal motility problems characterized by intestinal pseudo-obstruction resulting in premature death. This gastrointestinal dysfunction was caused by extensive, progressive neurodegeneration of the ENS involving both neurons and glia. Interestingly, mitochondrial defects differentially affected specific subpopulations of enteric neurons and regions of the gastrointestinal tract. Mitochondrial deficiency-related neuronal and glial loss was most prominent in the proximal small intestine, but the first affected neurons, nitrergic inhibitory neurons, had the greatest losses in the distal small intestine. This regional and subtype-specific variability in susceptibility to mitochondrial defects resulted in an imbalance of inhibitory and excitatory neurons that likely accounts for the observed phenotype in Tfam-ENSKO mice. Mitochondrial dysfunction, therefore, is likely to be an important driving force of neurodegeneration in the ENS and contribute to gastrointestinal symptoms in people with neurodegenerative disorders.


Asunto(s)
Sistema Nervioso Entérico/patología , Enfermedades Mitocondriales/patología , Neuronas/patología , Animales , Axones/metabolismo , Axones/patología , Recuento de Células , Replicación del ADN/genética , ADN Mitocondrial/biosíntesis , ADN Mitocondrial/genética , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Susceptibilidad a Enfermedades , Sistema Nervioso Entérico/metabolismo , Sistema Nervioso Entérico/fisiopatología , Motilidad Gastrointestinal/genética , Tracto Gastrointestinal/fisiopatología , Eliminación de Gen , Técnicas de Inactivación de Genes , Proteínas del Grupo de Alta Movilidad/deficiencia , Proteínas del Grupo de Alta Movilidad/genética , Ratones , Mitocondrias/metabolismo , Mitocondrias/patología , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/metabolismo , Enfermedades Mitocondriales/fisiopatología , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Enfermedades Neurodegenerativas/fisiopatología , Neuroglía/metabolismo , Neuroglía/patología , Neuronas/metabolismo , Neuronas Nitrérgicas/metabolismo , Neuronas Nitrérgicas/patología , Especificidad de Órganos , Transcripción Genética/genética
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