Aucubin exerts neuroprotective effects against ADHD-like behaviors by suppressing astrocytic NLRP3 inflammasome activation.

ETHNOPHARMACOLOGICAL RELEVANCE: Aucubin is one of the major bioactive iridoid glycosides present in Rehmanniae radix preparata, a traditional Chinese medicinal herb that has long been used to nourish the kidney, benefit the brain, and calm the mind, and is widely applied in the treatment of neurological and neuropsychiatric disorders. Modern pharmacological studies have demonstrated that aucubin exerts prominent anti-inflammatory and neuroprotective effects. Aucubin has been shown to ameliorate attention deficit hyperactivity disorder (ADHD)-like behaviors; however, the underlying mechanisms remain largely unknown.

AIM OF THE STUDY: This study aimed to investigate the neuroprotective effects of aucubin against ADHD-like behaviors and to elucidate the underlying molecular mechanisms.

METHODS

To elucidate the protective effects of Aucubin against ADHD through network pharmacology, molecular docking analysis, and experimental validation. An ADHD-like phenotype in offspring mice was established through intraperitoneal administration of S-ketamine in the middle and late trimesters of gestation. Aucubin (40 mg/kg) was intraperitoneally injected into offspring mice 14 days after birth, once daily for seven consecutive days. To assess behavioral, electrophysiological, and pathological changes in mice, several tests were employed, including the open field test (OFT), novel object recognition (NOR) test, elevated plus-maze (EPM) test, fear conditioning (FC), local field potential recording, and immunofluorescence assays. Furthermore, results in vitro have investigated the impact of aucubin on S-ketamine-induced astrocytic damage.

RESULTS

Aucubin administration significantly reversed S-ketamine-induced ADHD-like behaviors, including decreased total distance in the OFT, increased recognition index in the NOR, reduced proportion of EPM's open-arm timing, and increased freezing time in the FC. Additionally, it decreased the glial fibrillary acidic protein intensity and theta (θ) oscillation power during NOR. In vitro studies demonstrated the neuroprotective effects of aucubin. Furthermore, NLRP3 activator Nigericin inhibited the neuroprotective effects of aucubin.

CONCLUSIONS

Aucubin significantly improved ADHD-like behavior in mice by inhibiting NLRP3 activity in astrocytes.