PAM-2 downregulates activated human microglia and astrocytes by modulating α7 nicotinic acetylcholine receptors

Ilias Marmouzi, Randall L. Davis, Daniel J. Buck, Hugo Arias

Research output: Contribution to conferencePosterpeer-review

Abstract

Chronic pain (e.g., neuropathic pain) is a major health problem with high economic burden. Add to that the widespread opioid epidemic crisis consuming lives and devastating the health system. In that focus, developing an effective and adequate medication that acts on central and peripheral pain targets without inducing tolerance or addictive behaviors is an urgent need. Glial cells are viable targets for pain therapy; considering their contribution to sensory and/or non-sensory aspects of neuropathic pain. In fact, targeting glial cells may attenuate upregulation of inflammatory mediators in the spinal cord and brain, and reverse nociceptive behaviors. α7 nicotinic acetylcholine receptors (AChRs) are expressed in glial cells, and α7-selective positive allosteric modulators (α7-PAMs) decrease pain in animal models. Our group is particularly interested in identifying novel agents that target the cholinergic inflammatory pathway, particularly in microglia and astrocytes, as a potential therapeutic strategy.

To assess whether the anti-nociceptive activity elicited by PAM-2, an α7-PAM, is related to an antiinflammatory effect, the levels of inflammatory chemokine/cytokines (e.g., IL-6, CCL2, CXCL10) were measured in activated human microglia (C20) and astrocytes (NHA) using the enzyme-linked immunosorbent assay (ELISA). The modulating activity of PAM-2 (0-2.5 µM) was determined in the absence and presence of (-)-nicotine (5 µM). C20 or NHA cells were exposed to interleukin-1β (IL-1β; 25 pg/µL or 1 ng/µL, respectively), to stimulate the release of inflammatory mediators. IL-1β-induced expression of inflammatory mediators was minimally inhibited by (-)–nicotine (0-100 µM) or PAM-2 (0-5 µM), whereas PAM-2 potentiated the inhibitory effect of (-)-nicotine. The most pronounced effect was on CCL2 and IL-6 in microglia and on IL-6 in astrocytes. Interestingly, methyllycaconitine (MLA; α7- selective antagonist) inhibited the observed activity of PAM-2/(-)-nicotine, supporting a mechanism involving α7 AChRs. The current work supports a role for α7 AChRs in the regulation of glial cells as a therapeutic strategy for alleviating neuropathic pain.
Original languageAmerican English
Pages65
StatePublished - 22 Feb 2021
EventOklahoma State University Center for Health Sciences Research Days 2021: Poster presentation - Oklahoma State University Center for Health Sciences Campus, Tulsa, United States
Duration: 22 Feb 202126 Feb 2021

Conference

ConferenceOklahoma State University Center for Health Sciences Research Days 2021
Country/TerritoryUnited States
CityTulsa
Period22/02/2126/02/21

Keywords

  • Astrocytes
  • Microglia
  • PAMs
  • Nicotine
  • Pain
  • Human

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