Anti‐inflammatory effects of cannabidiol against lipopolysaccharides in cardiac sodium channels

Abstract

Background Sepsis, caused by a dysregulated response to infections, can lead to cardiac arrhythmias. However, the mechanisms underlying sepsis‐induced inflammation, and how inflammation provokes cardiac arrhythmias, are not well understood. We hypothesized that cannabidiol (CBD) may ameliorate lipopolysaccharide (LPS)‐induced cardiotoxicity, via Toll‐like receptors (TLR4) and cardiac sodium channels (NaV1.5). Methods and results We incubated human immune cells (THP‐1 macrophages) with LPS for 24 h, then extracted the THP‐1 incubation media. ELISA assays showed that LPS (1 or 5 μg·ml−1), in a concentration‐dependent manner, or MPLA (TLR4 agonist, 5 μg·ml−1) stimulated the THP‐1 cells to release inflammatory cytokines (TNF‐α and IL‐6). Prior incubation (4 h) with CBD (5 μM) or C34 (TLR4 antagonist: 5 μg·ml−1) inhibited LPS and MPLA‐induced release of both IL‐6 and TNF‐α. Human‐induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CM) were subsequently incubated for 24 h in the media extracted from THP‐1 cells incubated with LPS, MPLA alone, or in combination with CBD or C34. Voltage‐clamp experiments showed a right shift in the voltage dependence of NaV1.5 activation, steady state fast inactivation (SSFI), increased persistent current and prolonged in silico action potential duration in hiSPC‐CMs incubated in the LPS or MPLA‐THP‐1 media. Co‐incubation with CBD or C34 rescued the biophysical dysfunction caused by LPS and MPLA. Conclusion Our results suggest that CBD may protect against sepsis‐induced inflammation and subsequent arrhythmias through (i) inhibition of the release of inflammatory cytokines, antioxidant and anti‐apoptotic effects and/or (ii) a direct effect on NaV1.5.

The dual role of cannabidiol on monocyte-derived dendritic cell differentiation and maturation

“…CBD has recently been shown to have a similar effect on B cells, since T cell-independent activation of B cells in the presence of CBD resulted in decreased IL-10 production; however, in the case of T cell-dependent activation, it was increased ( 71 ). We saw opposite effects to what we described in THP-1 macrophages treated with CBD (5 μM), since LPS-induced inflammatory cytokine (e.g., IL-6 and TNF-α) production was decreased ( 72 ), as was IL-1β secretion in the case of LPS-nigericin-induced activation ( 73 ). In PBMC-derived monocytes CBD once again decreased the secretion of IL-1β and IL-6 induced by activation of most TLRs (i.e., TLR1-9, with the exception of TLR3 and -8 for IL-1β and TLR1 and -3 for IL-6) ( 61 ).…”

Molecular and Cellular Mechanisms of Action of Cannabidiol

“…CBD treatment significantly reduces the expression of M1 macrophage-related genes (TNFα and MCP-1), suggesting that inhibition of M1 polarization could contribute to the anti-inflammatory effects of CBD [ 104 , 105 , 106 , 107 ]. Suppression of TNF-α expression and effects may be a direct effect of CBD inhibition of NF-κB signaling.…”

Chronic exposure to a synthetic cannabinoid alters cerebral brain metabolism and causes long-lasting behavioral deficits in adult mice

“…Natural and synthetic cannabinoids possess anti-inflammatory, anti-proliferative, and anti-analgesic properties (Fouda et al 2022;Kis et al 2019;McDougall and McKenna 2022;Nagarkatti et al 2009). Therefore, there has been growing interest in cannabis as a potential therapeutic agent (Henderson et al 2021;Haddad et al 2022;Khalsa et al 2022;Laws and Smid 2022;Pagano et al 2022;Bergamaschi et al 2011).…”