FAAH-mediated modulation of TLR3-induced neuroinflammation in the rat hippocampus

Henry, Rebecca J.; Kerr, Daniel M.; Finn, David P.; Roche, Michelle

doi:10.1016/j.jneuroim.2014.09.002

Cited by 32 publications

(48 citation statements)

References 79 publications

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“…In addition to COX and AA, other molecules involved in the AA signaling pathway may also be useful for imaging neuroinflammation. Fatty acid amide hydrolase (FAAH) is one such molecule that has been implicated in neuroinflammation and human FAAH tracers are available 72 .…”

Section: Imaging Resident Immunocompetent Cellsmentioning

confidence: 99%

In Vivo Imaging of Human Neuroinflammation

Albrecht¹,

Granziera

Hooker³

et al. 2016

ACS Chem. Neurosci.

181

146

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Neuroinflammation is implicated in the pathophysiology of a growing number of human disorders, including multiple sclerosis, chronic pain, traumatic brain injury, and amyotrophic lateral sclerosis. As a result, interest in the development of novel methods to investigate neuroinflammatory processes, for the purpose of diagnosis, development of new therapies, and treatment monitoring, has surged over the past 15 years. Neuroimaging offers a wide array of non- or minimally invasive techniques to characterize neuroinflammatory processes. The intent of this Review is to provide brief descriptions of currently available neuroimaging methods to image neuroinflammation in the human central nervous system (CNS) in vivo. Specifically, because of the relatively widespread accessibility of equipment for nuclear imaging (positron emission tomography [PET]; single photon emission computed tomography [SPECT]) and magnetic resonance imaging (MRI), we will focus on strategies utilizing these technologies. We first provide a working definition of “neuroinflammation” and then discuss available neuroimaging methods to study human neuroinflammatory processes. Specifically, we will focus on neuroimaging methods that target (1) the activation of CNS immunocompetent cells (e.g. imaging of glial activation with TSPO tracer [11C]PBR28), (2) compromised BBB (e.g. identification of MS lesions with gadolinium-enhanced MRI), (3) CNS-infiltration of circulating immune cells (e.g. tracking monocyte infiltration into brain parenchyma with iron oxide nanoparticles and MRI), and (4) pathological consequences of neuroinflammation (e.g. imaging apoptosis with [99mTc]Annexin V or iron accumulation with T2* relaxometry). This Review provides an overview of state-of-the-art techniques for imaging human neuroinflammation which have potential to impact patient care in the foreseeable future.

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Section: Imaging Resident Immunocompetent Cellsmentioning

confidence: 99%

In Vivo Imaging of Human Neuroinflammation

Albrecht¹,

Granziera

Hooker³

et al. 2016

ACS Chem. Neurosci.

181

146

View full text Add to dashboard Cite

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“…injection of poly I:C (3 mg/kg) or saline (sterile 0.89% NaCl) administered in an injection volume of 1.5 ml/kg. The dose of URB597 was determined on the basis of previous published work demonstrating that systemic administration of URB597 at this dose enhanced levels of AEA and the related N ‐acylethanolamines (Henry et al, ; Kerr et al, ). Animals were sacrificed by decapitation at 4 hr post poly I:C/saline administration, and then the spleen was rapidly removed and the hypothalamus excised, snap‐frozen on dry ice, and stored at −80°C until being assayed for levels of endocannabinoids and N ‐acylethanolamines and cytokine expression.…”

Section: Methodsmentioning

confidence: 99%

“…The potent synthetic cannabinoid (CB) agonist WIN55,212‐2 has been shown to augment IRF3 signaling and IFN‐β production while concurrently attenuating TLR3‐induced nuclear factor kappa B (NFκB) activation and subsequent increases in TNF‐α in astrocyte cultures (Downer et al, ). Recent in vivo work from our group has demonstrated that the systemic and central administration of the FAAH inhibitor URB597 was associated with the modulation of TLR3‐induced neuroinflammatory responses in the hippocampus (Henry et al, ). However, to date, there have been no studies examining whether increasing 2‐AG tone modulates TLR3‐induced inflammatory responses.…”

Section: Introductionmentioning

confidence: 99%

FAAH, but not MAGL, inhibition modulates acute TLR3‐induced neuroimmune signaling in the rat, independent of sex

Flannery

Henry

Kerr

et al. 2017

J of Neuroscience Research

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Toll-like receptor (TLR)3 is a key component of the innate immune response to viral infection. The present study firstly examined whether sex differences exist in TLR3-induced inflammatory, endocrine, and sickness responses. The data revealed that TLR3-induced expression of interferon- or NFkB-inducible genes (IFN-α/β, IP-10, or TNF-α), either peripherally (spleen) or centrally (hypothalamus), did not differ between male and female rats, with the exception of TLR3-induced IFN-α expression in the spleen of female, but not male, rats 8 hr post TLR3 activation. Furthermore, TLR3 activation increased plasma corticosterone levels, induced fever, and reduced locomotor activity and body weight - effects independent of sex. Thus, the acute-phase inflammatory, endocrine, and sickness responses to TLR3 activation exhibit minimal sex-related differences. A further aim of this study was to examine whether enhancing endocannabinoid tone - namely, 2-arachidonylglycerol (2-AG) or N-arachidonoylethanolamine (AEA), exhibited similar effects on TLR3-induced inflammatory responses in male versus female rats. Systemic administration of the monoacylglycerol lipase (MAGL) inhibitor MJN110 and subsequent increases in 2-AG levels did not alter the TLR3-induced increase in IP-10, IRF7, or TNF-α expression in the spleen or the hypothalamus of male or female rats. In contrast, the fatty acid amide hydrolase (FAAH) inhibitor URB597 increased levels of AEA and related N-acylethanolamines, an effect associated with the attenuation of TLR3-induced inflammatory responses in the hypothalamus, but not the spleen, of male and female rats. These data support a role for FAAH, but not MAGL, substrates in the modulation of TLR3-induced neuroinflammatory responses, effects independent of sex.

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“…Quantitation of endocannabinoids was essentially as described previously (Henry et al, 2014;Kerr et al, 2012;Kerr et al, 2013a;Kerr et al, 2013b). In brief, cell pellets (1.5 x 10 6 ) were homogenised for 2 sec in 400 µL 100% acetonitrile containing deuterated internal standards (0.014 nmol anandamide-d8 and 0.48 nmol 2-AG-d8).…”

Section: Quantitation Of Endocannabinoid Concentrations In Nscs Usingmentioning

confidence: 99%

Distinctive effects of eicosapentaenoic and docosahexaenoic acids in regulating neural stem cell fate are mediated via endocannabinoid signalling pathways

et al. 2016

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Running title: EPA, but not DHA induces proliferation in NSCs Abbreviations: AA, Arachidonic acid, AEA, anandamide, DHA. Docosahexaenoic acid; EPA, eicosapentaenoic acid, 2-AG, 2-arachidonylglycerol 2 Title: Distinctive effects of eicosapentaenoic and docosahexaenoic acids in regulating neural stem cell fate are mediated via endocannabinoid signalling pathways Emerging evidence suggests a complex interplay between the endocannabinoid system, omega-3 fatty acids and the immune system in the promotion of brain self-repair. However, it is unknown if all omega-3 fatty acids elicit similar effects on adult neurogenesis and if such effects are mediated or regulated by interactions with the endocannabinoid system. This study investigated the effects of DHA and EPA on neural stem cell (NSC) fate and the role of the endocannabinoid signalling pathways in these effects.EPA, but not DHA, significantly increased proliferation of NSCs compared to controls, an effect associated with enhanced levels of the endocannabinoid 2-arachidonylglycerol (2-AG) and p-p38 MAPK, effects attenuated by pre-treatment with CB1 (AM251) or CB2 (AM630) receptor antagonists. Furthermore, in NSCs derived from IL-1 deficient mice, EPA significantly decreased proliferation and p-p38 MAPK levels compared to controls, suggesting a key role for IL-1 signalling in the effects observed. Although DHA similarly increased 2-AG levels in wild-type NSCs, there was no concomitant increase in proliferation or p-p38 MAPK activity. In addition, in NSCs from IL-1 deficient mice, DHA significantly increased proliferation without effects on p-P38 MAPK, suggesting effects of DHA are mediated via alternative signalling pathways. These results provide crucial new insights into the divergent effects of EPA and DHA in regulating NSC proliferation and the pathways involved, and highlight the therapeutic potential of their interplay with endocannabinoid signalling in brain repair.

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FAAH-mediated modulation of TLR3-induced neuroinflammation in the rat hippocampus

Cited by 32 publications

References 79 publications

In Vivo Imaging of Human Neuroinflammation

In Vivo Imaging of Human Neuroinflammation

FAAH, but not MAGL, inhibition modulates acute TLR3‐induced neuroimmune signaling in the rat, independent of sex

Distinctive effects of eicosapentaenoic and docosahexaenoic acids in regulating neural stem cell fate are mediated via endocannabinoid signalling pathways

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