The fatty acid amide hydrolase inhibitor URB597 exerts anti-inflammatory effects in hippocampus of aged rats and restores an age-related deficit in long-term potentiation

Niamh Murphy, Thelma R. Cowley, Christoph W. Blau, Colin N. Dempsey, Janis Noonan, Aoife Gowran, Riffat Tanveer, Weredeselam M. Olango, David P. Finn, Veronica A. Campbell, Marina A. Lynch

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Background: Several factors contribute to the deterioration in synaptic plasticity which accompanies age and one of these is neuroinflammation. This is characterized by increased microglial activation associated with increased production of proinflammatory cytokines like interleukin-1β (IL-1β). In aged rats these neuroinflammatory changes are associated with a decreased ability of animals to sustain long-term potentiation (LTP) in the dentate gyrus. Importantly, treatment of aged rats with agents which possess anti-inflammatory properties to decrease microglial activation, improves LTP. It is known that endocannabinoids, such as anandamide (AEA), have anti-inflammatory properties and therefore have the potential to decrease the age-related microglial activation. However, endocannabinoids are extremely labile and are hydrolyzed quickly after production. Here we investigated the possibility that inhibiting the degradation of endocannabinoids with the fatty acid amide hydrolase (FAAH) inhibitor, URB597, could ameliorate age-related increases in microglial activation and the associated decrease in LTP.Methods: Young and aged rats received subcutaneous injections of the FAAH inhibitor URB597 every second day and controls which received subcutaneous injections of 30% DMSO-saline every second day for 28 days. Long-term potentiation was recorded on day 28 and the animals were sacrificed. Brain tissue was analyzed for markers of microglial activation by PCR and for levels of endocannabinoids by liquid chromatography coupled to tandem mass spectrometry.Results: The data indicate that expression of markers of microglial activation, MHCII, and CD68 mRNA, were increased in the hippocampus of aged, compared with young, rats and that these changes were associated with increased expression of the proinflammatory cytokines interleukin (IL)-1β and tumor necrosis factor-α (TNFα) which were attenuated by treatment with URB597. Coupled with these changes, we observed an age-related decrease in LTP in the dentate gyrus which was partially restored in URB597-treated aged rats. The data suggest that enhancement of levels of endocannabinoids in the brain by URB597 has beneficial effects on synaptic function, perhaps by modulating microglial activation.

Original languageEnglish
Article number79
JournalJournal of Neuroinflammation
Volume9
DOIs
Publication statusPublished - Apr 26 2012

Fingerprint

Endocannabinoids
Long-Term Potentiation
Hippocampus
Anti-Inflammatory Agents
Dentate Gyrus
Subcutaneous Injections
Interleukin-1
Cytokines
Neuronal Plasticity
Brain
Tandem Mass Spectrometry
Dimethyl Sulfoxide
Liquid Chromatography
Tumor Necrosis Factor-alpha
fatty-acid amide hydrolase
cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester
Polymerase Chain Reaction
Messenger RNA
Therapeutics

Keywords

  • Age
  • Anandamide microglial activation
  • Endocannabinoids
  • Fatty acid amide hydrolase (FAAH)
  • Hippocampus
  • Long-term potentiation (LTP)

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Neurology
  • Immunology
  • Neuroscience(all)

Cite this

The fatty acid amide hydrolase inhibitor URB597 exerts anti-inflammatory effects in hippocampus of aged rats and restores an age-related deficit in long-term potentiation. / Murphy, Niamh; Cowley, Thelma R.; Blau, Christoph W.; Dempsey, Colin N.; Noonan, Janis; Gowran, Aoife; Tanveer, Riffat; Olango, Weredeselam M.; Finn, David P.; Campbell, Veronica A.; Lynch, Marina A.

In: Journal of Neuroinflammation, Vol. 9, 79, 26.04.2012.

Research output: Contribution to journalArticle

Murphy, Niamh ; Cowley, Thelma R. ; Blau, Christoph W. ; Dempsey, Colin N. ; Noonan, Janis ; Gowran, Aoife ; Tanveer, Riffat ; Olango, Weredeselam M. ; Finn, David P. ; Campbell, Veronica A. ; Lynch, Marina A. / The fatty acid amide hydrolase inhibitor URB597 exerts anti-inflammatory effects in hippocampus of aged rats and restores an age-related deficit in long-term potentiation. In: Journal of Neuroinflammation. 2012 ; Vol. 9.
@article{058c181c7c724b90988d1e5cf1c9eaf7,
title = "The fatty acid amide hydrolase inhibitor URB597 exerts anti-inflammatory effects in hippocampus of aged rats and restores an age-related deficit in long-term potentiation",
abstract = "Background: Several factors contribute to the deterioration in synaptic plasticity which accompanies age and one of these is neuroinflammation. This is characterized by increased microglial activation associated with increased production of proinflammatory cytokines like interleukin-1β (IL-1β). In aged rats these neuroinflammatory changes are associated with a decreased ability of animals to sustain long-term potentiation (LTP) in the dentate gyrus. Importantly, treatment of aged rats with agents which possess anti-inflammatory properties to decrease microglial activation, improves LTP. It is known that endocannabinoids, such as anandamide (AEA), have anti-inflammatory properties and therefore have the potential to decrease the age-related microglial activation. However, endocannabinoids are extremely labile and are hydrolyzed quickly after production. Here we investigated the possibility that inhibiting the degradation of endocannabinoids with the fatty acid amide hydrolase (FAAH) inhibitor, URB597, could ameliorate age-related increases in microglial activation and the associated decrease in LTP.Methods: Young and aged rats received subcutaneous injections of the FAAH inhibitor URB597 every second day and controls which received subcutaneous injections of 30{\%} DMSO-saline every second day for 28 days. Long-term potentiation was recorded on day 28 and the animals were sacrificed. Brain tissue was analyzed for markers of microglial activation by PCR and for levels of endocannabinoids by liquid chromatography coupled to tandem mass spectrometry.Results: The data indicate that expression of markers of microglial activation, MHCII, and CD68 mRNA, were increased in the hippocampus of aged, compared with young, rats and that these changes were associated with increased expression of the proinflammatory cytokines interleukin (IL)-1β and tumor necrosis factor-α (TNFα) which were attenuated by treatment with URB597. Coupled with these changes, we observed an age-related decrease in LTP in the dentate gyrus which was partially restored in URB597-treated aged rats. The data suggest that enhancement of levels of endocannabinoids in the brain by URB597 has beneficial effects on synaptic function, perhaps by modulating microglial activation.",
keywords = "Age, Anandamide microglial activation, Endocannabinoids, Fatty acid amide hydrolase (FAAH), Hippocampus, Long-term potentiation (LTP)",
author = "Niamh Murphy and Cowley, {Thelma R.} and Blau, {Christoph W.} and Dempsey, {Colin N.} and Janis Noonan and Aoife Gowran and Riffat Tanveer and Olango, {Weredeselam M.} and Finn, {David P.} and Campbell, {Veronica A.} and Lynch, {Marina A.}",
year = "2012",
month = "4",
day = "26",
doi = "10.1186/1742-2094-9-79",
language = "English",
volume = "9",
journal = "Journal of Neuroinflammation",
issn = "1742-2094",
publisher = "NLM (Medline)",

}

TY - JOUR

T1 - The fatty acid amide hydrolase inhibitor URB597 exerts anti-inflammatory effects in hippocampus of aged rats and restores an age-related deficit in long-term potentiation

AU - Murphy, Niamh

AU - Cowley, Thelma R.

AU - Blau, Christoph W.

AU - Dempsey, Colin N.

AU - Noonan, Janis

AU - Gowran, Aoife

AU - Tanveer, Riffat

AU - Olango, Weredeselam M.

AU - Finn, David P.

AU - Campbell, Veronica A.

AU - Lynch, Marina A.

PY - 2012/4/26

Y1 - 2012/4/26

N2 - Background: Several factors contribute to the deterioration in synaptic plasticity which accompanies age and one of these is neuroinflammation. This is characterized by increased microglial activation associated with increased production of proinflammatory cytokines like interleukin-1β (IL-1β). In aged rats these neuroinflammatory changes are associated with a decreased ability of animals to sustain long-term potentiation (LTP) in the dentate gyrus. Importantly, treatment of aged rats with agents which possess anti-inflammatory properties to decrease microglial activation, improves LTP. It is known that endocannabinoids, such as anandamide (AEA), have anti-inflammatory properties and therefore have the potential to decrease the age-related microglial activation. However, endocannabinoids are extremely labile and are hydrolyzed quickly after production. Here we investigated the possibility that inhibiting the degradation of endocannabinoids with the fatty acid amide hydrolase (FAAH) inhibitor, URB597, could ameliorate age-related increases in microglial activation and the associated decrease in LTP.Methods: Young and aged rats received subcutaneous injections of the FAAH inhibitor URB597 every second day and controls which received subcutaneous injections of 30% DMSO-saline every second day for 28 days. Long-term potentiation was recorded on day 28 and the animals were sacrificed. Brain tissue was analyzed for markers of microglial activation by PCR and for levels of endocannabinoids by liquid chromatography coupled to tandem mass spectrometry.Results: The data indicate that expression of markers of microglial activation, MHCII, and CD68 mRNA, were increased in the hippocampus of aged, compared with young, rats and that these changes were associated with increased expression of the proinflammatory cytokines interleukin (IL)-1β and tumor necrosis factor-α (TNFα) which were attenuated by treatment with URB597. Coupled with these changes, we observed an age-related decrease in LTP in the dentate gyrus which was partially restored in URB597-treated aged rats. The data suggest that enhancement of levels of endocannabinoids in the brain by URB597 has beneficial effects on synaptic function, perhaps by modulating microglial activation.

AB - Background: Several factors contribute to the deterioration in synaptic plasticity which accompanies age and one of these is neuroinflammation. This is characterized by increased microglial activation associated with increased production of proinflammatory cytokines like interleukin-1β (IL-1β). In aged rats these neuroinflammatory changes are associated with a decreased ability of animals to sustain long-term potentiation (LTP) in the dentate gyrus. Importantly, treatment of aged rats with agents which possess anti-inflammatory properties to decrease microglial activation, improves LTP. It is known that endocannabinoids, such as anandamide (AEA), have anti-inflammatory properties and therefore have the potential to decrease the age-related microglial activation. However, endocannabinoids are extremely labile and are hydrolyzed quickly after production. Here we investigated the possibility that inhibiting the degradation of endocannabinoids with the fatty acid amide hydrolase (FAAH) inhibitor, URB597, could ameliorate age-related increases in microglial activation and the associated decrease in LTP.Methods: Young and aged rats received subcutaneous injections of the FAAH inhibitor URB597 every second day and controls which received subcutaneous injections of 30% DMSO-saline every second day for 28 days. Long-term potentiation was recorded on day 28 and the animals were sacrificed. Brain tissue was analyzed for markers of microglial activation by PCR and for levels of endocannabinoids by liquid chromatography coupled to tandem mass spectrometry.Results: The data indicate that expression of markers of microglial activation, MHCII, and CD68 mRNA, were increased in the hippocampus of aged, compared with young, rats and that these changes were associated with increased expression of the proinflammatory cytokines interleukin (IL)-1β and tumor necrosis factor-α (TNFα) which were attenuated by treatment with URB597. Coupled with these changes, we observed an age-related decrease in LTP in the dentate gyrus which was partially restored in URB597-treated aged rats. The data suggest that enhancement of levels of endocannabinoids in the brain by URB597 has beneficial effects on synaptic function, perhaps by modulating microglial activation.

KW - Age

KW - Anandamide microglial activation

KW - Endocannabinoids

KW - Fatty acid amide hydrolase (FAAH)

KW - Hippocampus

KW - Long-term potentiation (LTP)

UR - http://www.scopus.com/inward/record.url?scp=84862232411&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84862232411&partnerID=8YFLogxK

U2 - 10.1186/1742-2094-9-79

DO - 10.1186/1742-2094-9-79

M3 - Article

VL - 9

JO - Journal of Neuroinflammation

JF - Journal of Neuroinflammation

SN - 1742-2094

M1 - 79

ER -