Abstract
Increasing evidence suggests that SARS-CoV-2, the virus responsible for the COVID-19 pandemic, is associated with increased risk of developing neurological or psychiatric conditions such as depression, anxiety or dementia. While the precise mechanism underlying this association is unknown, aberrant activation of toll-like receptor (TLR)3, a viral recognizing pattern recognition receptor, may play a key role. Synthetic cannabinoids and enhancing cannabinoid tone via inhibition of fatty acid amide hydrolase (FAAH) has been demonstrated to modulate TLR3-induced neuroimmune responses and associated sickness behaviour. However, the role of individual FAAH substrates, and the receptor mechanisms mediating these effects, are unknown. The present study examined the effects of intracerebral or systemic administration of the FAAH substrates N-oleoylethanolamide (OEA), N-palmitoylethanolamide (PEA) or the anandamide (AEA) analogue meth-AEA on hyperthermia and hypothalamic inflammatory gene expression following administration of the TLR3 agonist, and viral mimetic, poly I:C. The data demonstrate that meth-AEA does not alter TLR3-induced hyperthermia or hypothalamic inflammatory gene expression. In comparison, OEA and PEA attenuated the TLR3-induced hyperthermia, although only OEA attenuated the expression of hyperthermia-related genes (IL-1β, iNOS, COX2 and m-PGES) in the hypothalamus. OEA, but not PEA, attenuated TLR3-induced increases in the expression of all IRF- and NFκB-related genes examined in the hypothalamus, but not in the spleen. Antagonism of PPARα prevented the OEA-induced attenuation of IRF- and NFκB-related genes in the hypothalamus following TLR3 activation but did not significantly alter temperature. PPARα agonism did not alter TLR3-induced hyperthermia or hypothalamic inflammatory gene expression. These data indicate that OEA may be the primary FAAH substrate that modulates TLR3-induced neuroinflammation and hyperthermia, effects partially mediated by PPARα.
Highlights
Uncontrolled immune responses to viral infection have been pro posed to underlie the pathophysiology and exacerbation of a host of neurological and psychiatric conditions
The present study demonstrated that OEA and PEA, but not AEA, attenuate TLR3-induced hyperthermia and OEA attenuates the expression of interferon regulatory factor (IRF)- and Nuclear factor kappa B (NFκB)-related genes in the hypothalamus, including hyperthermic related genes (IL-1β, iNOS, COX2 and m-PGES)
Antagonism of PPARα prevented the OEA-induced attenuation of IRF- and NFκB-related genes in the hypothalamus following TLR3 activation, without altering temperature
Summary
Uncontrolled immune responses to viral infection have been pro posed to underlie the pathophysiology and exacerbation of a host of neurological and psychiatric conditions. Viral an tigens mediate immune responses by activating pattern recognition re ceptors such as toll-like receptor (TLR), resulting in induction of type 1 interferon (IFN-α and IFN-β) and NFĸB-inducible (e.g. IL-1β, IL-6 and TNF-α) inflammatory cascades responsible for host defences, homeo stasis and response to injury. Activation of TLR3 has been shown to impair contextual and working memory (Baghel et al, 2018; Galic et al, 2009), elicit anxiety- and depressive-like behaviour (Gibney et al, 2013), increase neuronal excitability and seizure susceptibility (Costello and Lynch, 2013; Galic et al, 2009) and exacerbate underlying neurodegenerative processes (Deleidi et al, 2010; Field et al, 2010). Modulating the neuroinflammatory, and conse quently neurological, effects of TLR3 activation is of critical physio logical and therapeutic importance
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