Fisetin ameliorates cognitive impairment by activating mitophagy and suppressing neuroinflammation in rats with sepsis‐associated encephalopathy

Abstract

Background Fisetin, the effective ingredient of the traditional Chinese medicine named Cotinus coggygria, is recommended to be active therapeutic in many disorders. However, its role in sepsis‐associated encephalopathy (SAE) remains unclarified. Methods Cecal ligation and puncture (CLP) operation was performed to establish a rat model of SAE. Rats were grouped according to the surgery operation and fisetin administration. Cognitive impairment was assessed by Morris water maze test. Disruption of blood‐brain barrier (BBB) integrity was detected by Evan's blue staining. The mitophagy, reactive oxygen species (ROS) generation, NLRP3 inflammasome activation, and pro‐inflammatory cytokines levels were measured through western blot and double immunofluorescence labeling. A transmission electron microscope was applied for the observation of mitochondrial autophagosomes. Results Rats in the CLP group presented increased expression of IL‐1R1, pNF‐κB, TNF‐α, and iNOS in microglial cells, indicating severe inflammation in the central nervous system (CNS). Nevertheless, there was no increase in BBB permeability. Meanwhile, NLRP3 inflammasome was activated in cerebral microvascular endothelial cells (CMECs), presented with an elevation of caspase‐1 expression and IL‐1β secretion into CNS. In addition, we found fisetin significantly improved cognitive dysfunction in rats with SAE. Neuroprotective effects of fisetin might be associated with inhibition of neuroinflammation, represented with decreased expression of IL‐1R1, pNF‐κB, TNF‐α, and iNOS in microglia. Furthermore, fisetin induced mitophagy, scavenged ROS, blocked NLRP3 inflammasome activation of CMECs, as evidenced by decreased expression of caspase‐1 and reduced release of IL‐1β into CNS. Conclusion Collectively, fisetin‐blocked NLRP3 inflammasome activation via promoting mitophagy in CMECs may suppress the secretion of IL‐1β into CNS, reduce neuroinflammation, and contribute to the amelioration of cognitive impairment.

Fisetin Attenuated Oxidative Stress-Induced Cellular Damage in ARPE-19 Human Retinal Pigment Epithelial Cells Through Nrf2-Mediated Activation of Heme Oxygenase-1

“…Therefore, we investigated the ROS scavenging activity of fisetin and found that fisetin significantly repressed H 2 O 2 -induced ROS generation. This is in good agreement with the results of previous studies ( Zhao et al, 2019 ; Rodius et al, 2020 ; Molagoda et al, 2021 ; Ding et al, 2022 ) and suggests that fisetin may act as an oxidative stress blocker. Several previous studies have proven that oxidative stress-induced apoptosis by H 2 O 2 treatment in ARPE-19 cells is directly correlated with mitochondrial impairment ( Zhao et al, 2020 ; Hong et al, 2021b ; Kim et al, 2021b ).…”

“…Many studies have demonstrated that fisetin has multiple pharmacological activities such as neuroprotective, anti-inflammatory, chemopreventive, anti-angiogenic, anti-tumorigenic, anti-cancer activities without showing any appreciable toxicity ( Zhu et al, 2017 ; Mehta et al, 2018 ; Liang et al, 2020 ; Maher, 2021 ; Ravula et al, 2021 ). More interestingly, although excessive accumulation of ROS may be a major factor in fisetin-induced apoptosis of cancer cells ( Su et al, 2017 ; Tsai et al, 2019 ; Imran et al, 2021 ), the protective effects of fisetin against cell damage to various stimuli are associated with potent antioxidant activity by acting as a potent ROS scavenger ( Zhao et al, 2019 ; Rodius et al, 2020 ; Molagoda et al, 2021 ; Ding et al, 2022 ). Moreover, several previous studies have demonstrated that this compound can modulate the Nrf2/antioxidant response elements (AREs) pathway to exert antioxidant activity ( Sim et al, 2020 ; Jiang et al, 2021 ; Li et al, 2022 ).…”

Hippocampus‐prefrontal cortex inputs modulate spatial learning and memory in a mouse model of sepsis induced by cecal ligation puncture

“…Numerous drugs or chemical components have been used to ameliorate sepsis‐induced cognitive dysfunction and neuroinflammation in mice. These include traditional Chinese medicine, 26 acetylcholinesterase inhibitors, 27 angiotensin‐converting enzyme (ACE) inhibitors, 28 the benzodiazepine agonist MRK‐016, 29 the NMDA antagonist MK‐801, 30 ketamine, 31 morphine, 32 morin, 33 and others. Among these strategies, SAE prevention and treatment is achieved mainly via anti‐inflammatory and antioxidative interventions which indicates the importance of inflammatory pathways and oxidative stress in SAE pathogenesis.…”

Discovering the Effects of Fisetin on NF-κB/NLRP-3/NRF-2 Molecular Pathways in a Mouse Model of Vascular Dementia Induced by Repeated Bilateral Carotid Occlusion

“…It was well known that the antioxidant effects of fisetin could be attributable to the activation of Nrf2/HO-1 [ 22 ]. However, Fisetin also blocked NLRP3 inflammasome activation and inhibited the release of IL-1β into the CNS in rats with encephalopathy [ 23 ]. Therefore, this study was planned to explore the protective effect of fisetin on VaD, pointing to the contribution of NF-κB/NLRP3 inflammasome and NRF2/HO-1 signaling pathways.…”