Urolithin A Prevents Sleep-deprivation-induced Neuroinflammation and Mitochondrial Dysfunction in Young and Aged Mice

• Published in: Molecular neurobiology Vol. 61; no. 3; pp. 1448 - 1466
• Main Authors: Misrani, Afzal, Tabassum, Sidra, Zhang, Zai-yong, Tan, Shao-hua, Long, Cheng
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.03.2024; Springer Nature B.V
• Subjects: Astrocytes; Autophagy; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cognitive ability; Fear conditioning; Hippocampus; Inflammation; Memory; Microglia; Mitochondria; Mitophagy; Morphology; Neurobiology; Neurological diseases; Neurology; Neurosciences; NF-κB protein; Sleep deprivation; Tumor necrosis factor-α; Western blotting; Memory impairment; Neuroinflammation; Urolithin A; Mitochondrial dysfunction; Sleep deprivation; Hippocampus
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-023-03651-x

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.