Caffeic Acid Phenethyl Ester Suppresses Oxidative Stress and Regulates M1/M2 Microglia Polarization via Sirt6/Nrf2 Pathway to Mitigate Cognitive Impairment in Aged Mice following Anesthesia and Surgery

Abstract

Postoperative cognitive dysfunction (POCD) is a severe neurological complication after anesthesia and surgery. However, there is still a lack of effective clinical pharmacotherapy due to its unclear pathogenesis. Caffeic acid phenethyl ester (CAPE), which is obtained from honeybee propolis and medicinal plants, shows powerful antioxidant, anti-inflammatory, and immunomodulating properties. In this study, we aimed to evaluate whether CAPE mitigated cognitive impairment following anesthesia and surgery and its potential underlying mechanisms in aged mice. Here, isoflurane anesthesia and tibial fracture surgery were used as the POCD model, and H2O2-induced BV2 cells were established as the microglial oxidative stress model. We revealed that CAPE pretreatment suppressed oxidative stress and promoted the switch of microglia from the M1 to the M2 type in the hippocampus, thereby ameliorating cognitive impairment caused by anesthesia and surgery. Further investigation indicated that CAPE pretreatment upregulated hippocampal Sirt6/Nrf2 expression after anesthesia and surgery. Moreover, mechanistic studies in BV2 cells demonstrated that the potent effects of CAPE pretreatment on reducing ROS generation and promoting protective polarization were attenuated by a specific Sirt6 inhibitor, OSS_128167. In summary, our findings opened a promising avenue for POCD prevention through CAPE pretreatment that enhanced the Sirt6/Nrf2 pathway to suppress oxidative stress as well as favor microglia protective polarization.

mtDNA-cGAS-STING axis-dependent NLRP3 inflammasome activation contributes to postoperative cognitive dysfunction induced by sevoflurane in mice

“…Neuroinflammation with excessively activated microglia has been associated with the pathogenesis and progression of neurodegenerative diseases 46 . Increased experimental evidence has established that microglia-mediated inflammation is essential in postoperative cognitive dysfunction 47 , 48 . In this study, we demonstrated that sevoflurane induced the activation of the cGAS-STING pathway, which triggered NLRP3 inflammasome-associated neuroinflammation in microglia during POCD.…”

Interactions Between the Ubiquitin–Proteasome System, Nrf2, and the Cannabinoidome as Protective Strategies to Combat Neurodegeneration: Review on Experimental Evidence

“…Additionally, in subarachnoid hemorrhage models, it was proven that the activation of the PPARγ/Nrf2 axis via netrin-1 reduced ferroptotic cell death through the enhancement of Gpx4 and coenzyme-Q10/ferroptosis suppressor protein-1 pathways (Chen et al 2023 ). Neuroprotective effects of the PPARγ/Nrf2/Gpx4 pathway against ferroptosis have also been described in an epilepsy model tested on rats (Wang et al 2023a , b , c ). Taken together, these results suggest that the PPARγ/Nrf2 axis might aid in targeting ferroptosis in several NDs.…”

“…For instance, Nrf2 raised the expression of the mitochondrial biogenesis-related protein PPARγ-coactivator 1α (PGC1α) in the hippocampus, prefrontal cortex, and amygdala (Khalifeh et al 2017 ). Several studies reported that Nrf2 activators enhance microglial polarization towards an M2 neuroprotective phenotype (He et al 2021a , b ; Tao et al 2021 ; Wang et al 2023a , b , c ). Nrf2 is also activated in astrocytes to counteract Fe 2+ -induced toxicity (Cui et al 2016 ).…”

“…Microglia is known to express CB2R receptors and CB2R activation is thought to regulate microglial reactivity, therefore preventing inflammatory damage in several models of NDs (Ashton and Glass 2007 ; Komorowska-Müller and Schmöle 2020 ; Young and Denovan-Wright 2022 ). Outstandingly, it appears that this process might be regulated via Nrf2 signaling, as CB2R agonist JWH133 proved to prevent 1-methyl-4-phenylpyridinium (MPP +)-stimulated microglia from differentiating into a M1 proinflammatory/neurotoxic phenotype, while enhancing their differentiation into a M2 anti-inflammatory/neuroprotective phenotype, an effect that was reverted by Nrf2 inhibition (Wang et al 2023a , b , c ). Additionally, a study in macrophages found similar results, as TRPV1-dependent ion fluxes resulted in an increased Nrf2 signaling and consequently a decreased macrophage differentiation into a M1 phenotype (Lv et al 2021 ).…”

Caffeic acid phenethyl ester inhibits neuro-inflammation and oxidative stress following spinal cord injury by mitigating mitochondrial dysfunction via the SIRT1/PGC1α/DRP1 signaling pathway

“…Studies have shown that CAPE inhibits amyloid β-peptide-induced neuro-inflammation and oxidative stress through modulation of the Nrf2/HO-1 pathway in Alzheimer’s disease patients [ 22 ]. Further, CAPE treatment promotes microglial M2 polarization and suppresses oxidative stress, producing a neuroprotective effect for postoperative cognitive dysfunction patients [ 23 ]. Although previous authors demonstrated CAPE to reduce inflammatory mediators after SCI [ 24 ], the regulatory effects and specific mechanisms of CAPE action on microglia-mediated neuro-inflammation and oxidative stress are unknown.…”