Obesity increases neuropathic pain via the AMPK-ERK-NOX4 pathway in rats

Fu, Changning; Wei, Hui; Gao, Wen-Shuang; Song, Shasha; Yue, Shouwei; Qu, Yu-Juan

doi:10.18632/aging.203305

Cited by 17 publications

(11 citation statements)

References 36 publications

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“…We further explored the molecular mechanism by which MFA alleviates pain. Studies have shown that Nox4 overexpression can increase the level of oxidative stress in the spinal cord and DRG and cause neuropathic pain [35]. In this study, Nox4 was expressed in large, medium, and small DRG neurons in the immuno uorescence double labeling experiment.…”

Section: Discussionmentioning

confidence: 53%

Methyl Ferulic Acid Alleviates Neuropathic Pain by Inhibiting Nox4-induced Ferroptosis in Dorsal Root Ganglia Neurons in Rats

Liu

Jia

et al. 2023

Mol Neurobiol

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Neuropathic pain is a disease that has become one of the major public health problems and a global burden. Nox4-induced oxidative stress can lead to ferroptosis and neuropathic pain. Methyl ferulic acid (MFA) can inhibit the Nox4-induced oxidative stress. This study aimed to estimate whether methyl ferulic acid alleviates neuropathic pain by inhibiting the expression of Nox4 and its induction of ferroptosis.Adult male Sprague-Dawley rats were subjected to spared nerve injury (SNI) model to induce neuropathic pain. After the establishment of the model, methyl ferulic acid was given 14 days by gavage.Nox4 overexpression was induced by microinjection of the AAV-Nox4 RNAi vector. All groups measured paw mechanical withdrawal threshold (PMWT), paw thermal withdrawal latency (PTWL), and paw withdrawal cold duration (PWCD). The expression of Nox4, ACSL4, GPX4, and ROS was investigated by Western blot and immuno uorescence staining. The changes in iron content were detected by a tissue iron kit. The morphological changes in mitochondria were observed by transmission electron microscopy.In the SNI group, the paw mechanical withdrawal threshold, the paw withdrawal cold duration decreased, the paw thermal withdrawal latency did not change, the Nox4, ACSL4, ROS, and iron content increased, the GPX4 decreased, and the number of abnormal mitochondria increased. Methyl ferulic acid can increase PMWT and PWCD but does not affect PTWL. Methyl ferulic acid decreased Nox4, ACSL4, and ROS levels, and iron content increased GPX4 expression and decreased the number of abnormal mitochondria. By overexpressing Nox4, the PMWT, PWCD, and ferroptosis of rats were more severe than those of the SNI group, but they could be reversed after treatment with methyl ferulic acid. Methyl ferulic acid can alleviate neuropathic pain, which is related to Nox4-induced ferroptosis.

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Section: Discussionmentioning

confidence: 53%

Methyl Ferulic Acid Alleviates Neuropathic Pain by Inhibiting Nox4-induced Ferroptosis in Dorsal Root Ganglia Neurons in Rats

Liu

Jia

et al. 2023

Mol Neurobiol

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“…The normal control group was fed with normal diet continuously, and the model group was fed with high-fat diet. The calculation formula of obesity degree [ 11 ]: obesity degree (%) = (actual weight of the obesity model group−actual weight of the normal diet control group)/actual weight of the normal diet control group x 100%. If the obesity degree is greater than 20%, mice in the model group are considered as obese, and the obesity model is established successfully.…”

Section: Methodsmentioning

confidence: 99%

“…The clinical recommended dose for adults with diabetes starts from 0.1 mg, and the effective dose in rats starts from 0.03 mg/kg. Many studies have confirmed the safety and effectiveness of PEX-168 in the treatment of T2DM patients [ 11 ], but the effect of PEX-168 on simple obesity has not been reported. This paper aims to study the effects of continuous administration of PEX-168 for 12 weeks on blood glucose and body weight in mice with nondiabetic simple obesity, so as to provide relevant basis for further research.…”

Section: Introductionmentioning

confidence: 99%

Polyethylene Glycol Loxenatide (PEX-168) Reduces Body Weight and Blood Glucose in Simple Obese Mice

Guo

Wang³

et al. 2021

International Journal of Endocrinology

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Background. At present, there is a lack of drug treatment for obese patients, so it is needed to find a drug that is effective and has few side effects to treat obesity. PEX-168 is a novel long-acting glucagon-like peptide-1 receptor agonist for T2DM. It improves blood glucose with fewer side effects. The aim of the present study was to investigate the effect of PEX-168 on blood glucose and body weight of mice with simple obesity. Methods. Thirty healthy and 6-week-old C57BL/6 male mice were randomly divided into a normal control group (NC, n = 6) and obesity model group (n = 24). The obesity model mice were randomly divided into a high-fat diet group (HF) and intervention groups with different doses of PEX-168 (0.03 mg/kg, 0.1 mg/kg, and 0.3 mg/kg). Each group includes 6 mice. Body weight, food intake, and fasting blood glucose (FBG) were evaluated after intraperitoneal injection, and the intervention was performed weekly for 12 weeks. Fasting insulin (FINS) levels were measured at the 12th week. Results. Compared with HF, the food intake of mice in the intervention groups decreased transiently, but there was no difference between different doses ( P > 0.05 ). The body weight of mice in the middle and high dose of PEX-168 intervention groups decreased significantly, and the differences were statistically significant ( P < 0.05 ). The administration of PEX-168 can effectively improve the blood glucose of obese mice, the difference was statistically significant ( P < 0.05 ), but there was no difference between different doses ( P > 0.05 ). At the 10th week, the incidence of transient hypoglycemia was 67% and 50% in the middle- and high-dose groups, respectively. The levels of serum FINS in the intervention groups were significantly lower than those in the HF group, and the differences were statistically significant ( P < 0.05 ), but there was no difference between different doses ( P > 0.05 ). Conclusions. PEX-168 showed significant improvement in the FBG and FINS levels of simple obese mice. Middle and high doses of PEX-168 could reduce the weight of simple obese mice, but there was a certain risk of hypoglycemia.

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“…Furthermore, Nox4 signaling has been linked to pulmonary diseases as well as to various types of cancer [ 49 , 51 , 56 , 107 , 108 , 109 , 110 , 111 , 112 ]. Interestingly, in response to peripheral nerve injury or diabetic neuropathy, Nox4 expression is increased in the injured nerve, DRGs, and/or the spinal cord [ 75 , 113 ]. Notably, neuropathic pain behavior after peripheral nerve injury was attenuated in global Nox4 knockout mice [ 74 , 75 ], after temporal somatic knockdown of Nox4 in tamoxifen-inducible Nox4 knockout mice and in tissue-specific knockout mice lacking Nox4 in sensory neurons [ 27 , 74 ] ( Table 1 ).…”

Section: Nadph Oxidases Affect Pain Processing By Distinct Mechanismsmentioning

confidence: 99%

NADPH Oxidases in Pain Processing

2022

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Inflammation or injury to the somatosensory nervous system may result in chronic pain conditions, which affect millions of people and often cause major health problems. Emerging lines of evidence indicate that reactive oxygen species (ROS), such as superoxide anion or hydrogen peroxide, are produced in the nociceptive system during chronic inflammatory and neuropathic pain and act as specific signaling molecules in pain processing. Among potential ROS sources in the somatosensory system are NADPH oxidases, a group of electron-transporting transmembrane enzymes whose sole function seems to be the generation of ROS. Interestingly, the expression and relevant function of the Nox family members Nox1, Nox2, and Nox4 in various cells of the nociceptive system have been demonstrated. Studies using knockout mice or specific knockdown of these isoforms indicate that Nox1, Nox2, and Nox4 specifically contribute to distinct signaling pathways in chronic inflammatory and/or neuropathic pain states. As selective Nox inhibitors are currently being developed and investigated in various physiological and pathophysiological settings, targeting Nox1, Nox2, and/or Nox4 could be a novel strategy for the treatment of chronic pain. Here, we summarize the distinct roles of Nox1, Nox2, and Nox4 in inflammatory and neuropathic processing and discuss the effectiveness of currently available Nox inhibitors in the treatment of chronic pain conditions.

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Obesity increases neuropathic pain via the AMPK-ERK-NOX4 pathway in rats

Cited by 17 publications

References 36 publications

Methyl Ferulic Acid Alleviates Neuropathic Pain by Inhibiting Nox4-induced Ferroptosis in Dorsal Root Ganglia Neurons in Rats

Methyl Ferulic Acid Alleviates Neuropathic Pain by Inhibiting Nox4-induced Ferroptosis in Dorsal Root Ganglia Neurons in Rats

Polyethylene Glycol Loxenatide (PEX-168) Reduces Body Weight and Blood Glucose in Simple Obese Mice

NADPH Oxidases in Pain Processing

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