RTA‐408 protects against propofol‐induced cognitive impairment in neonatal mice via the activation of Nrf2 and the inhibition of NF‐κB p65 nuclear translocation

Abstract

Objective To explore the effect of RTA‐408 on the propofol‐induced cognitive impairment of neonatal mice via regulating Nrf2 and NF‐κB p65 nuclear translocation. Methods C57BL/6 neonatal mice were randomized into intralipid, propofol, vehicle + propofol, and RTA‐408 + propofol groups. The learning and memory ability was inspected by Morries water maze (MWM) test. TUNEL staining was performed to examine the apoptosis of neurons in hippocampus. The gene and protein expressions in hippocampus were detected by immunohistochemistry, qRT‐PCR, or Western blotting. The activities of glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) were tested by the corresponding kits. Results Propofol prolonged escape latency of mice, decreased the times of crossing the platform, and shortened the time of staying in the target quadrant, while RTA‐408 treatment improved the above‐mentioned situation. Besides, Nrf2 protein in hippocampus of mice induced by propofol was decreased with the increased NF‐κB p65 nuclear translocation, which was reversed by RTA‐408. Meanwhile, RTA‐408 decreased the apoptosis of neurons accompanying with the down‐regulation of Caspase‐3 and the up‐regulations of neuronal‐specific nuclear protein (NeuN), microtubule‐associated protein 2 (Map2), Ca2+/Calmodulin‐dependent Protein Kinase II (CaMKII), and parvalbumin (PV) immunostaining in hippocampus. Besides, propofol‐induced high levels of proinflammatory cytokines and antioxidase activities in hippocampus were reduced by RTA‐408. Conclusion RTA‐408 improved propofol‐induced cognitive impairment in neonatal mice via enhancing survival of neurons, reducing the apoptosis of hippocampal neurons, mitigating the inflammation and oxidative stress, which may be correlated with the activation of Nrf2 and the inhibition of NF‐κB p65 nuclear translocation.

Protective effect of Houttuynia cordata extract on propofol-induced injury of rat hippocampal neurons by regulating PI3K/Akt and Toll-like receptor 4/NF-κB signaling pathway

“…The model has been used in several studies. Previous study showed RTA-408 protected against propofol-induced cognitive impairment in neonatal mice [4]. Additionally, repeated propofol exposure could induce neuronal damage and cognitive impairment in aged rats [16].…”

“…Propofol, an intravenous general anesthetic, is a commonly used sedative for induction, maintenance and severe anesthesia in children [3]. Notably, there is growing evidence that propofol induces developmental neurotoxicity that can impair brain development in newborn rats and extend into adulthood [4]. Therefore, it is necessary to understand the mechanism of propofol inducing neuronal developmental toxicity in pediatric anesthesia, so as to provide ideas for developing prevention and treatment strategies.…”

Natural compounds protect against the pathogenesis of osteoarthritis by mediating the NRF2/ARE signaling

“…RTA408 has been demonstrated to inhibit radiation-induced oxidative stress by disrupting the interaction between Keap1 and NRF2 ( Goldman et al, 2015 ). RTA408 is also effective against inflammation by suppressing the NF-κB signaling pathway ( Zhang et al, 2021 ). RTA408 has been reported to promote chondrocyte proliferation, suppress inflammation and oxidative stress, inhibit chondrocyte apoptosis, and ameliorate ECM degradation by activating the NRF2/ARE signaling and inhibiting the NF-κB pathway in IL-1β-treated chondrocytes.…”

Role of Nrf2 in Synaptic Plasticity and Memory in Alzheimer’s Disease

“…Propofol decreases consciousness and memory and is used as a general anesthesia. RTA-408 protected against propofol-induced memory impairment assessed with the MWM and increased activation of Nrf2 and the inhibition of NF-κB p65 nuclear translocation [103]. Other studies have shown that RTA-408 increases Nrf2 and decreases NF-κB [104][105][106][107][108].…”