Higenamine Attenuates Neuropathic Pain by Inhibition of NOX2/ROS/TRP/P38 Mitogen-Activated Protein Kinase/NF-ĸB Signaling Pathway

Abstract

Oxidative stress damage is known as one of the important factors that induce neuropathic pain (NP). Using antioxidant therapy usually achieves an obvious curative effect and alleviates NP. Previous pharmacological studies have shown that higenamine (Hig) performs to be antioxidant and anti-inflammatory. However, the protective effect and mechanism of Hig on NP are still unclear. This study mainly evaluated the changes in reactive oxygen species (ROS) level, lipid peroxidation, and antioxidant system composed of superoxide dismutase (SOD) and glutathione (GSH) through chronic constrict injury (CCI) model rats and t-BHP-induced Schwann cell (SC) oxidative stress model. The expressions of two inflammatory factors, tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), were also assessed. The possible molecular mechanism of Hig in the treatment of NP was explored in conjunction with the expression of mitochondrial apoptosis pathway and NOX2/ROS/TRP/P38 mitogen-activated protein kinase (MAPK)/NF-ĸB pathway-related indicators. Hig showed substantial antioxidant and anti-inflammatory properties both in vivo and in vitro. Hig significantly reduced the upregulated levels of ROS, malondialdehyde (MDA), TNF-α, and IL-6 and increased the levels of SOD and GSH, which rebalanced the redox system and improved the survival rate of cells. In the animal behavioral test, it was also observed that Hig relieved the CCI-induced pain, indicating that Hig had a pain relief effect. Our research results suggested that Hig improved NP-induced oxidative stress injury, inflammation, and apoptosis, and this neuroprotective effect may be related to the NOX2/ROS/TRP/P38 MAPK/NF-ĸB signaling pathway.

Upregulation of TLR4/MyD88 pathway in alcohol-induced Wernicke’s encephalopathy: Findings in preclinical models and in a postmortem human case

“…CA exposure induced an increasing trend in the phosphorylation of NF-ĸB that did not reach significance using ANOVA (Figure 1C, overall effect F (1, 29) = 2.995, p = 0.0941). We report the results of the phosphorylated-NFkB protein normalized by the structural protein β-actin, as done with the rest of the markers, in accordance with other authors (Yang et al, 2021), since the increase of the phosphorylation in the p65 subunit is indicative of NF-κB activation to mediate inflammatory gene transcription. The levels of total NFkB were measured, with no changes (see Supplementary Section S2.3 and Figure 5).…”

“Upregulation of TLR4/MyD88 pathway in alcohol-induced Wernicke’s encephalopathy: findings in preclinical models and in a postmortem human case”

“…CA exposure induced an increasing trend in the phosphorylation of NF-ĸB that did not reach significance by the ANOVA (Figure 1C, overall effect F (1, 29) =2.995, p=0.0941). We report the results of the phosphorylated-NFkB protein normalized by the structural protein β-actin, as done with the rest of the markers, in accordance to other authors (Yang et al, 2021), since the increase of the phosphorylation in p65 subunit is indicative of NF-κB activation to mediate inflammatory gene transcription. The levels of total NFkB were measured, with no changes (see Supplementary Material, section 2.3, Figure 5).…”

Pharmacological effects of higenamine based on signalling pathways and mechanism of action

“…HG increases the phosphorylation of AKT and the expression of Ser9p/GSK-3β by promoting the phosphorylation of Ser9, which decreases GSK-3β kinase activity and inhibits apoptosis. In another study by Yang et al (2021) , HG decreased the upregulated levels of ROS, MDA, TNF-α and IL-6 in t-BHP-induced Schwann cells, increased the levels of SOD and glutathione (GSH), rebalanced the redox system and increased cell survival by downregulating the NOX2/ROS/TRP/P38 MAPK/NF-κB signalling pathway.…”