Phloretin alleviates sleep deprivation-induced cognitive impairment by reducing inflammation through PPARγ/NF-κB signaling pathway

Sleep loss leads to significant pathophysiological consequences, including cognitive impairment. The neuroinflammation are pivotal factors in the pathogenesis of cognitive impairment induced by sleep loss. The phloretin (PHL), derived from peel of juicy fruits, has demonstrated potent anti-inflammatory properties. However, the precise influence of PHL on the cognitive impairment triggered by sleep loss and its underlying mechanism remain uncertain. In the present study, mice were subjected to sleep deprivation (SD) paradigm. Cognitive impairment induced by SD were significantly relieved by administration of PHL in a dose-dependent manner. Furthermore, PHL not only mitigated the synaptic losses but also enhanced dendritic spine density and neuronal activity within mice hippocampus following exposure to SD. Moreover, PHL treatment decreased the microglial numbers and altered microglial morphology in the hippocampus to restore the M1/M2 balances; these effects were accompanied by regulation of pro-/anti-inflammatory cytokine production and secretion in SD-exposed mice. Additionally, in vivo and in vitro studies showed PHL might attenuate the inflammation through the PPARγ/NF-κB pathway. Our findings suggest that PHL exerts inhibitory effects on microglia-mediated neuroinflammation, thereby providing protection against cognitive impairment induced by SD through a PPAR-γ dependent mechanism. The results indicate PHL is expected to provide a valuable candidate for new drug development for SD-induced cognitive impairment in the future.