PPARα agonist relieves spinal cord injury in rats by activating Nrf2/HO-1 via the Raf-1/MEK/ERK pathway

Abstract

Objective: To observe the inhibitory effects of the peroxisome proliferator-activated receptor alpha (PPARα) agonist palmitoylethanolamide (PEA) on inflammatory responses and oxidative stress injury in rats with spinal cord injury (SCI). Methods: The SCI rat model was established using modified Allen's method and the changes in rats’ joint motion were observed by Basso, Beattie and Bresnahan locomotor rating scale (BBB scale) at 1, 3 and 7 days after modeling, HE Staining and Nissl Staining has been carried out to evaluate the pathological lesion of spinal cords in rats. Besides, Immunohistochemical (IHC) was performed to detect the reactive oxygen species (ROS), expression levels of acrylamide (ACR) and manganese superoxide dismutase (MnSOD) in rat spinal cords, and Western Blotting was applied to measure protein expression levels of nuclear factor-kappa B (NF-κB), B cell lymphoma-2 (Bcl-2), BCL-2 associated X (BAX), phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), phosphorylated (p)-Akt, HO-1, Nrf2, trithorax-1 (TRX-1), Raf-1, MEK, ERK, p-MEK and p-ERK. Results: The PPARα agonist PEA could alleviate SCI in rats, inhibit inflammatory responses, mitigate oxidative stress injury, reduce the apoptotic rate and promote SCI rats motor function recovery. In addition, the PPARα agonist PEA was able to activate the phosphorylation of MEK and ERK, stimulate Nrf-2 translocation into the nucleus and up-regulate the expressions of HO-1 and TRX-1. Conclusion: PPARα agonist PEA can relieve SCI in rats by inhibiting inflammatory responses and oxidative stress, which may involve a mechanism associated with the activation of Nrf2/HO-1 via the Raf-1/MEK/ERK pathway.

Mechanism of Fat Mass and Obesity‐Related Gene‐Mediated Heme Oxygenase‐1 m6A Modification in the Recovery of Neurological Function in Mice with Spinal Cord Injury

“…Consistent with our study, a prior study revealed that activation of the Nrf2/HO‐1 pathway suppresses neuronal apoptosis and alleviates oxidative stress in SCI rats, 42 facilitating functional recovery in mice with SCI 43 . Importantly, prior research highlights the synergistic effects of the HO‐1 pathway and PPARα agonists in enhancing motor function and mitigating SCI in SCI rats 44 …”

“…43 Importantly, prior research highlights the synergistic effects of the HO-1 pathway and PPARα agonists in enhancing motor function and mitigating SCI in SCI rats. 44 Limitations and Strengths However, a notable limitation is the minimal exploration of FTO's downstream targets and specific pathways of action, a focus for future research. Due to constraints in laboratory conditions and funding, electromyography data is currently unavailable.…”

Trehalose inhibits ferroptosis via NRF2/HO-1 pathway and promotes functional recovery in mice with spinal cord injury

“…During oxidative stress, the interaction between NRF2 and Keap1 in the cytoplasm is disrupted [ 48 ]. NRF2 translocates to the nucleus and interacts with ARE, leading to the transcriptional induction of some cell defense genes, such as phase II detoxification enzymes HO-1, NQO1, and direct ROS scavenging proteins (GPx, SOD, CAT) [ 49 , 50 ]. Many studies have confirmed that activation of NRF2 can prevent damage caused by ferroptosis [ 14 , 24 , 51 ].…”

Oroxin A reduces oxidative stress, apoptosis, and autophagy and improves the developmental competence of porcine embryos in vitro

“…Glycogen synthase kinase‐3β (GSK3β), a serine/threonine protein kinase, is a multifunctional regulator of mitochondrial function (Wang et al, 2021). Inhibition of GSK3β activity attenuates oxidative stress‐induced mitochondrial dysfunction and apoptosis (Gao et al, 2017; He et al, 2019; Huang et al, 2017; Mao et al, 2019; Potz et al, 2018; Wang et al, 2015; Zhang et al, 2021). When the intracellular oxidative system exceeds antioxidant capacity, reactive oxygen species accumulate (ROS) and oxidative stress increases (Hardy et al, 2021).…”