Adiphenine Alleviates Impulsive-Like Behaviors in Aged Mice by Inhibiting Nicotinic Acetylcholine Receptors

Postoperative neurocognitive disorders (PND) are prevalent complications in the elderly following surgical interventions and anesthesia, with the underlying protective and damaging mechanisms remaining largely elusive. Impulsive-like behaviors and a decline in cognitive function were observed in the mouse model of PND established through tibial fracture surgery, accompanied by increased activity of astrocytes in the hippocampal CA1 region. Additionally, transcriptome Sequencing revealed increased expression of nicotinic acetylcholine receptors (nAChRs) in PND. In this study, we aimed to investigate the role of nAChRs in the pathogenesis of PND in aging mice. In 18-month-old male C57BL/6 mice, a PND model was established by tibial fracture surgery, and brain tissues were collected for transcriptomic Sequencing 24 h post-surgery. Behavioral assessments of PND mice were conducted using open field, light-dark box, and fear conditioning tests. An nAChRs inhibitor, Adiphenine (125 nM per day), was administered daily for 7 days via intracerebroventricular microinfusion. Pathological changes were observed using immunofluorescence staining and Western blotting, and hippocampal CA1 spikes activity and local field potentials (LFP) were monitored with a microelectrode array. Transcriptomic Sequencing of the brains of PND mice revealed upregulation of Cholinergic Receptor Nicotinic Beta 2 Subunit (Chrnb2) and Cholinergic Receptor Nicotinic Beta 4 Subunit (Chrnb4). Additionally, there was an increase in neuronal spikes and enhanced LFP power in the hippocampal CA1 region, along with an increase in the number and morphological changes of astrocytes. Adiphenine was able to inhibit tibial surgery-induced impulsive-like behaviors, but it showed no significant improvement in cognitive function. It also reduced spikes firing and LFP power in the CA1 region. Our study revealed that anesthesia and surgery-induced PND models exhibit impulsive-like behaviors and cognitive impairment. Astrocyte activation and elevated Vglut1 expression may be contributing factors, with nAChRs likely playing an initiating role in this process. Adiphenine can improve impulsive-like behaviors by inhibiting nAChRs.

PND; astrocyte activation; impulsive‐like behaviors; nAChRs inhibitors; neuroexcitatory toxicity.