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

BackgroundSeveral 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.MethodsYoung 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.ResultsThe 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.

Melatonin and oestrogen treatments were able to improve neuroinflammation and apoptotic processes in dentate gyrus of old ovariectomized female rats

“…The levels of pro-inflammatory cytokines and the gene expressions were increased in the dentate gyrus of old females as compared with young animals. These data confirm previous studies, which showed that ageing led to increases in IL1β, TNFα, IL6, MHCII, CD68, and CD11b mRNA in hippocampal tissue (Murphy et al 2012). As we had previously demonstrated, ageing by itself was able to induce alterations in hippocampus, but when females with long-term oestrogen deprivation were investigated, the damages observed were due to the combination of ovariectomy and ageing combined and could be regarded as a model for menopause.…”

The Endocannabinoid, Anandamide, Augments Notch-1 Signaling in Cultured Cortical Neurons Exposed to Amyloid-β and in the Cortex of Aged Rats

“…Importantly the long term potentiation deficits seem to result specifically from deficits in Notch signaling, and this can be rescued by application of Notch ligand like Jagged 1, which increases Notch signal. In a parallel study to ours, it was observed that the aged rat used in this study had deficits in long term potentiation, and this was restored when aged rats were chronically treated with URB 597 (56). Apart from the antiinflammatory properties exerted by AEA, augmentation of Notch-1 signaling may represent a possible explanation for the improvement in long term potentiation observed in aged rats treated with URB 597.…”

Protective Action of Anandamide and Its COX-2 Metabolite against L-Homocysteine-Induced NLRP3 Inflammasome Activation and Injury in Podocytes

“…Several laboratories have reported inhibitory effects on inflammation and associated diseases and pathologic phenomena by elevating endogenous AEA levels through different approaches, including fatty acid amide hydrolase gene KO (Naidu et al, 2010;Kinsey et al, 2011;Wang et al, 2015), fatty acid amide hydrolase inhibitors (Kinsey et al, 2011;Schuelert et al, 2011;Booker et al, 2012;Caprioli et al, 2012;Kerr et al, 2012;Murphy et al, 2012;Sasso et al, 2012;Krustev et al, 2014;Sałaga et al, 2014;Tchantchou et al, 2014), and AEA reuptake inhibitors (Mestre et al, 2005;D'Argenio et al, 2006). Further studies are needed to address whether such approaches are also protective in glomerular injury associated with hHcys.…”