Urolithin A supplementation improves chronic sleep deprivation-induced cognitive impairments and anxiety in mice by suppressing hippocampal ferroptosis via the Nrf2 signaling

Key Findings

Sleep deprivation (SD) is now a widespread issue affecting people globally. It adversely impacts individuals of all ages, contributing to cognitive deficits and increased anxiety. Urolithin A (UA) has been found to address numerous health concerns, including the preservation of brain function. Nonetheless, the exact mechanisms by which UA counters cognitive deficits and anxiety resulting from SD are not well understood. To investigate the specific molecular mechanisms involving the Nrf2-ferroptosis axis through which UA ameliorates cognitive impairments and anxiety-like behaviors resulting from prolonged SD. A murine model of chronic SD was generated by implementing sleep restriction for a duration of 14 consecutive days (n=15 per group). Behavioral experiments were used to assess the success of the SD model and the therapeutic impact of UA. We explored the mechanisms using spatial metabolites and biological functional module network analysis. Furthermore, erastin was utilized to induce ferroptosis in HT-22 cells, creating a model to assess the ferroptosis inhibition effects of UA. UA treatment (100 mg/kg, i.g.) significantly mitigated behavioral abnormalities caused by chronic SD. UA prevented both histopathological alterations and structural injury to hippocampal neurons (P < 0.05, P < 0.01). Further analyses revealed that UA not only attenuated excessive neuroinflammation but also increased dendritic spine density and the protein levels of neurotrophic factors in the hippocampus of chronic SD mice. Mechanistically, spatial metabolomics and target prediction analyses further revealed that the effects of UA were closely associated with the Nrf2 signaling pathway and ferroptosis suppression. UA treatment significantly decreased total iron and Fe2+ levels (P < 0.05, P < 0.01), increased Nrf2, SLC7A11, GPX4, and HMOX1 protein levels (P < 0.01), and decreased ACSL4 expression (P < 0.01) in the hippocampus. In vitro, UA protected HT-22 cells against erastin-induced ferroptosis in a dose-dependent manner (2.5, 5, 10 µM), an effect abolished by the Nrf2 inhibitor ML385. Overall, supplementation with UA proved beneficial in counteracting chronic SD-induced cognitive deterioration and anxiety-like behaviors by attenuating hippocampal ferroptosis through the Nrf2 pathway. These results suggested that UA represents a potential candidate for future translational studies addressing cognitive impairments and anxiety related to insufficient sleep.

Why This Matters for Body-Mind Practice

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Source

• Urolithin A supplementation improves chronic sleep deprivation-induced cognitive impairments and anxiety in mice by suppressing hippocampal ferroptosis via the Nrf2 signaling. — Phytomedicine : international journal of phytotherapy and phytopharmacology