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  • It is well known that TLR induced inflammation is

    2021-09-17

    It is well known that TLR4-induced inflammation is associated with behavioural alterations including fever, hypolocomotion, altered appetite, anxiety and anhedonia (Dantzer, 2006, Dantzer et al., 2008). The current data demonstrate that while PF3845 potently attenuates TLR4-induced cytokines in the brain, this does not alter the associated sickness behaviour (hypolocomotion, fever, reduced body weight and food intake). Similarly, recent data have demonstrated that systemic administration of PF3845 does not alter LPS-induced hypothermia in mice (Nass et al., 2015), although effects of FAAH inhibition on other sickness-related behaviours have not been reported prior to this study. However, the data presented herein also indicate that LPS reduces sucrose intake, an effect not observed in PF3845-treated rats. This effect is modest and although not repeated in the second behavioural study, a trend for a similar effect was observed. This lack of robust anhedonic effects following LPS is likely due to the low dose of LPS used herein compared with previous studies (Biesmans et al., 2016, Sayd et al., 2015) and the confounding effect of prior surgery and icv vehicle administration. Despite this, the data suggest that FAAH inhibition may modulate immune-mediated anhedonia, a core symptom of psychiatric disorders such as depression. A recent study has demonstrated that OEA, but not PEA, attenuates LPS-induced anhedonia, an effect associated with attenuation of cytokine and inflammatory mediators in the 2-Methoxyestradiol (Sayd et al., 2015). Thus, it remains to be determined if one or a combination of the FAAH substrates enhanced following administration of PF3845 is responsible for the anti-anhedonic effects observed here-in, or modulates other immune-related behavioural and physiological responses. An addition aim of the current study was to examine if FAAH substrates directly within the brain are responsible for the modulation of TLR4-induced neuroinflammation. The data here-in demonstrate that increasing AEA, OEA and PEA brain levels following central administration of PF3845 was association with an attenuation of TLR4-induced inflammatory mediators in both the frontal cortex and hippocampus. Furthermore, administration of the peripherally restricted FAAH inhibitor URB937 increased FAAH substrate levels peripherally, with slight increases in OEA and PEA, but not AEA, levels in the brain; this treatment regime did not alter TLR4-induced increases in the expression of pro-inflammatory cytokines. These data suggest that either high levels of FAAH substrates in the brain are required to modulate TLR4-induced neuroinflammatory responses or alternatively, that the increase in levels of AEA within the brain, rather than OEA or PEA, is primarily responsible for mediating the effects on TLR-induced neuroinflammatory responses. Thus, taken together the data indicate that FAAH substrates act to modulate TLR4-, in addition to TLR3- (Henry et al., 2014), induced neuroinflammatory responses directly within the brain, rather than via modulation of peripheral immune responses. An important aim of this work was to attempt to uncover the mechanisms underlying FAAH substrate-induced modulation of neuroinflammation following TLR4 activation. AEA has been proposed to mediate some of its anti-inflammatory activity by increasing glial production of the anti-inflammatory cytokine IL-10 (Correa et al., 2010, Krishnan and Chatterjee, 2012). Furthermore, chronic administration of PF3845 was associated with a shift in M1 to an M2 microglia activation phenotype, a primary source of IL-10, an effect associated with a reversal of TBI-induced impairments in functional outcomes and neurodegenerative processes (Tchantchou et al., 2014). However, the current data do not support this as a mechanism of action of PF3845 on TLR4-induced neuroinflammation given a lack of effect on the expression of the M2 microglial marker MRC2 and the attenuation of TLR4-induced IL-10. Similarly, previous work from our lab has demonstrated that systemic administration of an alternative FAAH inhibitor URB597 and subsequent increases in AEA, OEA and PEA, also attenuated TLR4-induced increases in hypothalamic expression of IL-10 (Kerr et al., 2012). In addition, our findings demonstrated that FAAH substrate-mediated effects on TLR4-induced neuroinflammation are not likely mediated via increases in the IL-1β receptor antagonist, IL-1ra or the negative regulator of IL-6, SOCS3. Thus, a likely explanation for the current findings is that increasing FAAH substrates in the brain prevents or delays inflammation-induced microglial activation, consequently reduces activation of NF-κB, and downstream transcription of pro- and anti-inflammatory genes. Further support for this hypothesis comes from the finding that PF3845 attenuated the TLR4-induced expression of the markers of astrocyte and microglial activation, GFAP and CD11b, and IκBα, often used as an indirect measure of NF-κB activation (Read et al., 1994). Thus, FAAH substrates may act to down-regulate or delay glial activation under TLR4-induced neuroinflammatory conditions.