Inhibition of neuroinflammation and neuronal damage by the selective non-steroidal ERβ agonist AC-186.
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Date
2024
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Abstract
Background: AC-186 (4-[4-4-Difuoro-1-(2-fuorophenyl) cyclohexyl] phenol) is a neuroprotective non-steroidal selective
oestrogen receptor modulator. This study investigated whether inhibition of neuroinfammation contributed to neuroprotec tive activity of this compound.
Methods: BV-2 microglia were treated with AC-186 (0.65–5 μM) prior to stimulation with LPS (100 ng/mL). Levels of
pro-infammatory mediators and proteins were then evaluated.
Results: Treatment of LPS-activated BV-2 microglia with AC-186 resulted in signifcant (p<0.05) reduction in TNFα,
IL-6, NO, PGE2, iNOS and COX-2. Further investigations showed that AC-186 decreased LPS-induced elevated levels of
phospho-p65, phospho-IκBα and acetyl-p65 proteins, while blocking DNA binding and luciferase activity of NF-κB. AC-186
induced signifcant (p<0.05) increase in protein expression of ERβ, while enhancing ERE luciferase activity in BV-2 cells.
Efects of the compound on oestrogen signalling in the microglia was confrmed in knockdown experiments which revealed
a loss of anti-infammatory activity following transfection with ERβ siRNA. In vitro neuroprotective activity of AC-186 was
demonstrated by inhibition of activated microglia-mediated damage to HT-22 neurons.
Conclusions: This study established that AC-186 produces NF-κB-mediated anti-infammatory activity, which is proposed
as a contributory mechanism involved in its neuroprotective actions. It is suggested that the anti-infammatory activity of
this compound is linked to its agonist efect on ERβ
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Keywords
AC-186, Anti-infammatory, Neuroprotective, NF-κB · ERβ
Citation
Katola, F. O., Adana, M. Y. & Olajide, O. A. (2024). Inhibition of neuroinflammation and neuronal damage by the selective non-steroidal ERβ agonist AC-186. Inflammation Research, 73(12), 2109–2121. Published by Springer Science+Business Media. Available online at https://link.springer.com/journal/11/volumes-and-issues/73-12. Scopus link: https://link.springer.com/article/10.1007/s00011-024-01952-y (Scopus indexed, Q1)