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Objective <p>To determine whether the α7nAChR agonist PNU-282,987 mitigates sevoflurane-induced cognitive impairment by suppressing NLRP3-mediated pyroptosis.</p> Methods <p>Adult Wistar rats were randomized to control (air), model (2.5% sevoflurane, 6&#xa0;h), or treatment (sevoflurane plus PNU-282987, 0.3&#xa0;mg/kg, i.p.). Cognitive performance was assessed using the Morris Water Maze (MWM) and Novel Object Recognition (NOR). Hippocampal pyroptosis signaling was quantified by qRT-PCR and Western blot for IL-1β, IL-18, caspase-1, and NLRP3, and by immunohistochemistry (IHC) for ASC, caspase-1, and IL-1β. One-way or repeated-measures ANOVA was applied (<i>p</i> &lt; 0.05).</p> Results <p>Sevoflurane impaired spatial learning and memory versus control (MWM escape latency: 35.7 ± 5.3&#xa0;s vs. 20.1 ± 4.2&#xa0;s; target-quadrant time: 22.6 ± 7.4% vs. 40.2 ± 8.1%) and reduced recognition memory (NOR index ≈ 37.5% vs. ≈ 60%). PNU-282,987 improved behavior toward control (escape latency 25.3 ± 4.6&#xa0;s; target-quadrant time 35.7 ± 7.8%; NOR index ≈ 56.7%). Molecular analyses showed sevoflurane upregulated IL-1β, IL-18, caspase-1, and NLRP3 at mRNA and protein levels, consistent with NLRP3 inflammasome activation. PNU-282,987 reduced these transcripts by 54.5% (IL-1β), 52.0% (IL-18), 56.7% (caspase-1), and 56.4% (NLRP3) relative to model, with concordant protein decreases. IHC revealed strong ASC, caspase-1, and IL-1β staining in model that was markedly attenuated by PNU-282,987.</p> Conclusion <p>Pharmacologic activation of α7nAChR with PNU-282,987 disrupts the NLRP3–ASC–caspase-1 axis and limits downstream IL-1β/IL-18 maturation, preserving hippocampal-dependent cognition after sevoflurane exposure. α7nAChR agonism represents a targeted strategy for perioperative neuroprotection.</p>

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Neuroprotective Effects of PNU-282,987, an α7-Nicotinic Receptor Agonist, on Sevoflurane-Induced Pyroptosis and Cognitive Impairment in Rats

  • 期刊论文

  • 发表日期：

    2026年4月16日

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  • Jun Xu,
  • Xufang Sun,
  • Dedong Xu,
  • Yuan Ge,
  • Lei Ming

摘要

Objective

To determine whether the α7nAChR agonist PNU-282,987 mitigates sevoflurane-induced cognitive impairment by suppressing NLRP3-mediated pyroptosis.

Methods

Adult Wistar rats were randomized to control (air), model (2.5% sevoflurane, 6 h), or treatment (sevoflurane plus PNU-282987, 0.3 mg/kg, i.p.). Cognitive performance was assessed using the Morris Water Maze (MWM) and Novel Object Recognition (NOR). Hippocampal pyroptosis signaling was quantified by qRT-PCR and Western blot for IL-1β, IL-18, caspase-1, and NLRP3, and by immunohistochemistry (IHC) for ASC, caspase-1, and IL-1β. One-way or repeated-measures ANOVA was applied (p < 0.05).

Results

Sevoflurane impaired spatial learning and memory versus control (MWM escape latency: 35.7 ± 5.3 s vs. 20.1 ± 4.2 s; target-quadrant time: 22.6 ± 7.4% vs. 40.2 ± 8.1%) and reduced recognition memory (NOR index ≈ 37.5% vs. ≈ 60%). PNU-282,987 improved behavior toward control (escape latency 25.3 ± 4.6 s; target-quadrant time 35.7 ± 7.8%; NOR index ≈ 56.7%). Molecular analyses showed sevoflurane upregulated IL-1β, IL-18, caspase-1, and NLRP3 at mRNA and protein levels, consistent with NLRP3 inflammasome activation. PNU-282,987 reduced these transcripts by 54.5% (IL-1β), 52.0% (IL-18), 56.7% (caspase-1), and 56.4% (NLRP3) relative to model, with concordant protein decreases. IHC revealed strong ASC, caspase-1, and IL-1β staining in model that was markedly attenuated by PNU-282,987.

Conclusion

Pharmacologic activation of α7nAChR with PNU-282,987 disrupts the NLRP3–ASC–caspase-1 axis and limits downstream IL-1β/IL-18 maturation, preserving hippocampal-dependent cognition after sevoflurane exposure. α7nAChR agonism represents a targeted strategy for perioperative neuroprotection.