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Sleep deprivation (SD) has reached epidemic proportions worldwide and negatively affects people of all ages. Cognitive impairment induced by SD involves neuroinflammation and mitochondrial dysfunction, but the underlying mechanisms are largely unknown. Urolithin A (UA) is a natural compound that can reduce neuroinflammation and improve mitochondrial health, but its therapeutic effects in a SD model have not yet been studied. Young (3-months old) and aged (12-months old) mice were sleep deprived for 24 h, and UA (2.5 mg/kg or 10 mg/kg) was injected intraperitoneally for 7 consecutive days before the SD period. Immunofluorescent staining, western blotting, and RT-PCR were employed to evaluate levels of proteins involved in neuroinflammation and mitochondrial function. Transmission electron microscope and Golgi-Cox staining were used to evaluate mitochondrial and neuronal morphology, respectively. Finally, contextual fear conditioning and the Morris water maze test were conducted to assess hippocampal learning and memory. In the hippocampus of young (3 months-old) and aged (12 months-old) mice subjected to 24 h SD, pretreatment with UA prevented the activation of microglia and astrocytes, NF-κB-NLRP3 signaling and IL-1β, IL6, TNF-α cytokine production, thus ameliorating neuroinflammation. Furthermore, UA also attenuated SD-induced mitochondrial dysfunction, normalized autophagy and mitophagy and protected hippocampal neuronal morphology. Finally, UA prevented SD-induced hippocampal memory impairment. Cumulatively, the results show that UA imparts cognitive protection by reducing neuroinflammation and enhancing mitochondrial function in SD mice. This suggests that UA shows promise as a therapeutic for the treatment of SD-induced neurological disorders., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Environmental challenges, specifically chronic stress, have long been associated with neuropsychiatric disorders, including anxiety and depression. Sirtuin-1 (SIRT1) is a NAD + -dependent deacetylase that is widely distributed in the cortex and is involved in stress responses and neuropsychiatric disorders. Nevertheless, how chronic stress modulates the SIRT1 pathway and associated signaling remains unclear. In this study, we first explored the impact of chronic unpredictable mild stress (CUMS) on the SIRT1/PGC1α/SIRT3 pathway, on GABAergic mechanisms, and on mitophagy, autophagy and apoptosis in mice. We also asked whether activation of SIRT1 by resveratrol (RSV) can attenuate CUMS-induced molecular and behavioral alterations. Two-month-old C57/BL6J mice were subjected to three weeks of CUMS and one week of RSV treatment (30 mg/kg; i.p.) during the third week of CUMS. CUMS caused downregulation of the SIRT1/PGC1α/SIRT3 pathway leading to impaired mitochondrial morphology and function. CUMS also resulted in a reduction in numbers of parvalbumin-positive interneurons and increased oxidative stress leading to reduced expression of autophagy- and mitophagy-related proteins. Strikingly, activation of SIRT1 by RSV ameliorated expression of SIRT1/PGC1α/SIRT3, and also improved mitochondrial function, GABAergic mechanisms, mitophagy, autophagy and apoptosis. RSV also rescued CUMS-induced anxiety-like and depressive-like behavior in mice. Our results raise the compelling possibility that RSV treatment might be a viable therapeutic method of blocking stress-induced behavioral alterations., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)