α7 Nicotinic acetylcholine receptor potentiation downregulates chemotherapy-induced inflammatory overactivation by overlapping intracellular mechanisms

There is mounting experimental evidence supporting the notion that α7 nicotinic acetylcholine receptors (nAChRs) expressed in the central and peripheral nervous systems, including neurons, glial and other immunocompetent cells, are potential targets for pain- and inflammatory-related conditions (reviewed in Toma et al., 2020; Hone and McIntosh, 2018). Based on results showing that structurally different positive allosteric modulators of α7 nAChRs (α7-PAMs) were able to decrease pain and inflammation mediated by drugs or surgical procedures that induce neuropathic pain in rodents (Freitas et al., 2013, Arias et al., 2020, Bagdas et al., 2015, Bagdas et al., 2021, Abbas et al., 2019, Abbas et al., 2021, Alzarea and Rahman, 2019), α7 nAChR potentiation has been proposed as a novel mechanism to alleviate neuropathic pain.

Considering the contribution of glial cells, including astrocytes and microglia, to sensory and non-sensory aspects of neuropathic pain (Egea et al., 2015; Revathikumar et al., 2016; Matejuk and Ransohoff, 2020), these non-neuronal cells are viable targets for pain-related therapies. More specifically, α7 nAChRs expressed in glial cells play important roles in the modulation of inflammatory processes. The activation of glial α7 nAChRs by nicotine or other agonists exerts protective effects by indirectly activating the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway (Egea et al., 2015, Patel et al., 2017, Piovesana et al., 2021, Báez-Pagán et al., 2015), which negatively regulates the nuclear factor kappa B (NF-κB) pathway.

α7-PAMs were found to potentiate α7 nAChRs in microglia and astrocytes (Shen and Yakel, 2012), which is likely related to the observed decrease in pro-inflammatory markers in these cells, and the concomitant reduction of pain in animal models (Alzarea and Rahman, 2019, Abbas et al., 2019, Abbas et al., 2021). α7-PAMs also decreased the expression of brain-derived neurotrophic factor (BDNF) in a mouse model of inflammatory pain (Abbas et al., 2021). Our previous works demonstrated that PAM-2 [(E)− 3-furan-2-yl-N-p-tolyl-acrylamide] inhibits inflammation and neuropathic pain in a variety of animal models by mechanisms involving α7 nAChR potentiation (Arias et al., 2020, Bagdas et al., 2015), and activates mammalian target of rapamycin (mTOR) and Ras-dependent extracellular signal-regulated kinase 1 and 2 (ERK1/2) in the hippocampus and cortex of chronically treated mice (Targowska-Duda et al., 2016, Targowska-Duda et al., 2021). However, a comprehensive mechanism explaining the relationship between α7 nAChR potentiation and the downregulation of intracellular pathways involved in inflammation processes is lacking. Thus, we studied, in the current work, the cellular and molecular mechanisms by which PAM-2 reduces the pro-inflammatory activity mediated by oxaliplatin (OXA; trans-R,R-cyclohexane-1,2-diamineoxalatoplatinum Ⅱ), a chemotherapeutic agent that activates glial cells leading to neuropathic pain in animals and cancer patients (Di Cesare Mannelli et al., 2014, Branca et al., 2021) in combination with interleukin-1β (IL-1β), a cytokine with recognized pro-inflammatory effects (Davis et al., 2018).

Our study showed that PAM-2 reduces the OXA/IL-1β-induced inflammatory process by a series of different, overlapping intracellular mechanisms. These findings are expected to advance the therapeutic potential of α7-PAMs in the treatment/prevention of chemotherapy-induced neuroinflammation and neuropathic pain in general.

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