MAPK-ERK-CREB signaling pathway upregulates Nav1.6 in oxaliplatin-induced neuropathic pain in the rat

Yu, Wenli; Wei, Wei; Wang, Suifeng; Zheng, Zhenli; Li, Lei; Sun, Yanyan; Zhang, Jingjing; Li, Zhihua; Ren, Xiuhua; Zang, Weidong; Cao, Jing

doi:10.1016/j.toxlet.2023.07.010

Cited by 6 publications

(4 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, it was recently demonstrated that MAPK/ERK activation in dorsal root ganglia promotes the expression and activation of CREB, which binds directly to the promoter region of Scn8a, leading to an increase in Scn8a transcription. The increased expression of Na V 1.6 protein enhances neuronal excitability [ 92 ], thus providing a direct link between CREB signaling and Na V 1.6-related neuronal hyperexcitability and forming a positive feedback loop that could lead to weakening resilience in D/+ males ( Figure 6 , #5).…”

Section: Discussionmentioning

confidence: 99%

Sex differences in physiological response to increased neuronal excitability in a knockin mouse model of pediatric epilepsy

Hammer,

Krzyzaniak,

Bahramnejad

et al. 2024

Clinical Science

View full text Add to dashboard Cite

Epilepsy is a common neurological disease; however, few if any of the currently marketed antiseizure medications prevent or cure epilepsy. Discovery of pathological processes in the early stages of epileptogenesis has been challenging given the common use of preclinical models that induce seizures in physiologically normal animals. Moreover, despite known sex dimorphism in neurological diseases, females are rarely included in preclinical epilepsy models. We characterized sex differences in mice carrying a pathogenic knockin variant (p.N1768D) in the Scn8a gene that causes spontaneous tonic-clonic seizures (TCs) at ~3 months of age and found that heterozygous females are more resilient than males in mortality and morbidity. To investigate the cellular mechanisms that underlie female resilience, we utilized blood-brain barrier (BBB) and hippocampal transcriptomic analyses in heterozygous mice before seizure onset (pre-TC) and in mice that experienced ~20 TCs (post-TC). In the pre-TC latent phase, both sexes exhibited leaky BBB; however, patterns of gene expression were sexually dimorphic. Females exhibited enhanced oxidative phosphorylation and protein biogenesis, while males activated gliosis and CREB signaling. After seizure onset (chronic phase), females exhibited a metabolic switch to lipid metabolism, while males exhibited increased gliosis and BBB dysfunction and a strong activation of neuroinflammatory pathways. The results underscore the central role of oxidative stress and BBB permeability in the early stages of epileptogenesis, as well as sex dimorphism in response to increasing neuronal hyperexcitability. Our results also highlight the need to include both sexes in preclinical studies to effectively translate results of drug efficacy studies.

show abstract

Section: Discussionmentioning

confidence: 99%

Sex differences in physiological response to increased neuronal excitability in a knockin mouse model of pediatric epilepsy

Hammer,

Krzyzaniak,

Bahramnejad

et al. 2024

Clinical Science

View full text Add to dashboard Cite

show abstract

“…Moreover, PD98059 delays morphine tolerance development in rats [30]. Interestingly, it was recently shown, using an oxaliplatin-induced neuropathic pain model, that the activation of ERK1/2 kinases promotes the expression and activation of CREB, which leads to an increase in Nav1.6 protein expression, enhancing neuronal excitability and evoking pain [61]. The results of numerous studies clearly indicate the important role of the MEK/ERK signaling pathway in neuropathic pain.…”

Section: Mapks and Neuropathic Painmentioning

confidence: 98%

“…opioid treatment after combined administration with fisetin, demonstrated in experimental studies, opens new possibilities for combined therapy. inhibition of MAP kinases by fisetin, which in turn indirectly inhibits NF-κB, and, as a consequence, the production of pronociceptive cytokines, such as IL-6, IL-1β and TNFα [100], is lowered; influence on NF-κB activation, which causes a decrease in the synthesis of pronociceptive factors [97]; inhibition of PI3K/AKT, which in turn influence the cAMP-response element binding protein (CREB) that impacts the expression of Nav1.6 sodium channels, which reduces hypersensitivity but also decreases the production of ROS, which are confirmed to be responsible for the maintenance of neuropathic pain [61,96,233]. (B) The influence of fisetin on the activation of cells important for neuropathic pain development as proposed by in vitro studies [94,234]; and (C) the influence of fisetin on opioid effectiveness in neuropathic pain model [90].…”

Section: Fisetin-a Mapk Nf-κb and Pi3k Modulator In Neuropathic Painmentioning

confidence: 99%

Advances in Neuropathic Pain Research: Selected Intracellular Factors as Potential Targets for Multidirectional Analgesics

Ciapała,

Mika

2023

Pharmaceuticals

View full text Add to dashboard Cite

Neuropathic pain is a complex and debilitating condition that affects millions of people worldwide. Unlike acute pain, which is short-term and starts suddenly in response to an injury, neuropathic pain arises from somatosensory nervous system damage or disease, is usually chronic, and makes every day functioning difficult, substantially reducing quality of life. The main reason for the lack of effective pharmacotherapies for neuropathic pain is its diverse etiology and the complex, still poorly understood, pathophysiological mechanism of its progression. Numerous experimental studies, including ours, conducted over the last several decades have shown that the development of neuropathic pain is based on disturbances in cell activity, imbalances in the production of pronociceptive factors, and changes in signaling pathways such as p38MAPK, ERK, JNK, NF-κB, PI3K, and NRF2, which could become important targets for pharmacotherapy in the future. Despite the availability of many different analgesics, relieving neuropathic pain is still extremely difficult and requires a multidirectional, individual approach. We would like to point out that an increasing amount of data indicates that nonselective compounds directed at more than one molecular target exert promising analgesic effects. In our review, we characterize four substances (minocycline, astaxanthin, fisetin, and peimine) with analgesic properties that result from a wide spectrum of actions, including the modulation of MAPKs and other factors. We would like to draw attention to these selected substances since, in preclinical studies, they show suitable analgesic properties in models of neuropathy of various etiologies, and, importantly, some are already used as dietary supplements; for example, astaxanthin and fisetin protect against oxidative stress and have anti-inflammatory properties. It is worth emphasizing that the results of behavioral tests also indicate their usefulness when combined with opioids, the effectiveness of which decreases when neuropathy develops. Moreover, these substances appear to have additional, beneficial properties for the treatment of diseases that frequently co-occur with neuropathic pain. Therefore, these substances provide hope for the development of modern pharmacological tools to not only treat symptoms but also restore the proper functioning of the human body.

show abstract

“… 348 MAPK-ERK-CREB signaling has also been found to increase Nav1.6 expression in the oxaliplatin-induced neuropathic pain model. 349 Therefore, MAPK signaling has a broad promotion effect on VGSCs, facilitate the formation of pain hypersensitivity. In addition to TNF-α, MAPK signaling is responsible for the pain-inducing effects of other secretory factors.…”

Section: Molecular Mechanisms Of Pain Modulationmentioning

confidence: 99%

Pathology of pain and its implications for therapeutic interventions

Cao,

Xu,

Shi

et al. 2024

Sig Transduct Target Ther

View full text Add to dashboard Cite

Pain is estimated to affect more than 20% of the global population, imposing incalculable health and economic burdens. Effective pain management is crucial for individuals suffering from pain. However, the current methods for pain assessment and treatment fall short of clinical needs. Benefiting from advances in neuroscience and biotechnology, the neuronal circuits and molecular mechanisms critically involved in pain modulation have been elucidated. These research achievements have incited progress in identifying new diagnostic and therapeutic targets. In this review, we first introduce fundamental knowledge about pain, setting the stage for the subsequent contents. The review next delves into the molecular mechanisms underlying pain disorders, including gene mutation, epigenetic modification, posttranslational modification, inflammasome, signaling pathways and microbiota. To better present a comprehensive view of pain research, two prominent issues, sexual dimorphism and pain comorbidities, are discussed in detail based on current findings. The status quo of pain evaluation and manipulation is summarized. A series of improved and innovative pain management strategies, such as gene therapy, monoclonal antibody, brain-computer interface and microbial intervention, are making strides towards clinical application. We highlight existing limitations and future directions for enhancing the quality of preclinical and clinical research. Efforts to decipher the complexities of pain pathology will be instrumental in translating scientific discoveries into clinical practice, thereby improving pain management from bench to bedside.

show abstract

MAPK-ERK-CREB signaling pathway upregulates Nav1.6 in oxaliplatin-induced neuropathic pain in the rat

Cited by 6 publications

References 37 publications

Sex differences in physiological response to increased neuronal excitability in a knockin mouse model of pediatric epilepsy

Sex differences in physiological response to increased neuronal excitability in a knockin mouse model of pediatric epilepsy

Advances in Neuropathic Pain Research: Selected Intracellular Factors as Potential Targets for Multidirectional Analgesics

Pathology of pain and its implications for therapeutic interventions

Contact Info

Product

Resources

About