Probucol attenuates NF-κB/NLRP3 signalling and augments Nrf-2 mediated antioxidant defence in nerve injury induced neuropathic pain

Derangula, Kalyani; Javalgekar, Mohit; Arruri, Vijay Kumar; Gundu, Chayanika; Kalvala, Anil Kumar; Kumar, Ashutosh

doi:10.1016/j.intimp.2021.108397

Cited by 28 publications

(16 citation statements)

References 51 publications

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“…In addition, tBHQ abated NLRP3 inflammasome activation by ROS via Nrf2/ARE signaling in oxygen-glucose deprivation/reoxygenation (OGDR) model BV2 microglial cells ( 161 ). Moreover, multiple drugs, namely Ezetimibe ( 162 ), Ibrutinib ( 163 ), Dexmedetomidine ( 164 , 165 ), Tranilast ( 166 ), Probucol ( 167 ) and various other synthetic compounds such as sodium butyrate ( 168 ), diphenyl diselenide ( 169 ), 5-(3,4-Difluorophenyl)-3-(6-methylpyridin-3-yl)-1,2,4-oxadiazole ( 170 ) and tert-butylhydroquinone ( 94 , 160 , 161 ), were investigated against NLRP3 inflammasome activation and Nrf2 upregulation in several in vivo and in vitro models.…”

Section: Preclinical Experience With Nrf2 Inducers Against Nlrp3 Infl...mentioning

confidence: 99%

Targeting NLRP3 Inflammasome With Nrf2 Inducers in Central Nervous System Disorders

2022

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The NLRP3 inflammasome is an intracellular multiprotein complex that plays an essential role in the innate immune system by identifying and eliminating a plethora of endogenous and exogenous threats to the host. Upon activation of the NLRP3 complex, pro-inflammatory cytokines are processed and released. Furthermore, activation of the NLRP3 inflammasome complex can induce pyroptotic cell death, thereby propagating the inflammatory response. The aberrant activity and detrimental effects of NLRP3 inflammasome activation have been associated with cardiovascular, neurodegenerative, metabolic, and inflammatory diseases. Therefore, clinical strategies targeting the inhibition of the self-propelled NLRP3 inflammasome activation are required. The transcription factor Nrf2 regulates cellular stress response, controlling the redox equilibrium, metabolic programming, and inflammation. The Nrf2 pathway participates in anti-oxidative, cytoprotective, and anti-inflammatory activities. This prominent regulator, through pharmacologic activation, could provide a therapeutic strategy for the diseases to the etiology and pathogenesis of which NLRP3 inflammasome contributes. In this review, current knowledge on NLRP3 inflammasome activation and Nrf2 pathways is presented; the relationship between NLRP3 inflammasome signaling and Nrf2 pathway, as well as the pre/clinical use of Nrf2 activators against NLRP3 inflammasome activation in disorders of the central nervous system, are thoroughly described. Cumulative evidence points out therapeutic use of Nrf2 activators against NLRP3 inflammasome activation or diseases that NLRP3 inflammasome contributes to would be advantageous to prevent inflammatory conditions; however, the side effects of these molecules should be kept in mind before applying them to clinical practice.

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Section: Preclinical Experience With Nrf2 Inducers Against Nlrp3 Infl...mentioning

confidence: 99%

Targeting NLRP3 Inflammasome With Nrf2 Inducers in Central Nervous System Disorders

2022

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“…In the cancer-induced bone pain model, IL-1β and IL-18 were detected predominantly in neurons (97). Suppressing NLRP3 inflammasome activation with different microRNAs, reduced NLRP3 inflammasome activation in the sciatic nerve, spinal astrocytes and microglia, while concurrently attenuating mechanical allodynia after chronic constriction injury in mice and rats (92)(93)(94)(95)(96) and rats (99). Treatment with a ROS scavenger decreased paclitaxel-induced mechanical allodynia and reduced NLRP3 expression in DRG macrophages and caspase 1/IL-1β activation in lumbar DRG and sciatic nerve (100).…”

Section: Mitochondrial Mediated Nlrp3 Inflammasome Activationmentioning

confidence: 99%

“…Pre-clinical studies show that targeting inflammasomerelated proteins has analgesic effects (92)(93)(94)(95)(96)(97)(98). In a clinical trial, oral treatment with Dapansutrile, a specific NLRP3 inflammasome inhibitor, reduced joint pain 56%-68% and reduced joint and systemic inflammation in gout flare patients (296).…”

Section: Nlrp3 Inflammasomementioning

confidence: 99%

Mitochondria and sensory processing in inflammatory and neuropathic pain

2022

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Rheumatic diseases, such as osteoarthritis and rheumatoid arthritis, affect over 750 million people worldwide and contribute to approximately 40% of chronic pain cases. Inflammation and tissue damage contribute to pain in rheumatic diseases, but pain often persists even when inflammation/damage is resolved. Mechanisms that cause this persistent pain are still unclear. Mitochondria are essential for a myriad of cellular processes and regulate neuronal functions. Mitochondrial dysfunction has been implicated in multiple neurological disorders, but its role in sensory processing and pain in rheumatic diseases is relatively unexplored. This review provides a comprehensive understanding of how mitochondrial dysfunction connects inflammation and damage-associated pathways to neuronal sensitization and persistent pain. To provide an overall framework on how mitochondria control pain, we explored recent evidence in inflammatory and neuropathic pain conditions. Mitochondria have intrinsic quality control mechanisms to prevent functional deficits and cellular damage. We will discuss the link between neuronal activity, mitochondrial dysfunction and chronic pain. Lastly, pharmacological strategies aimed at reestablishing mitochondrial functions or boosting mitochondrial dynamics as therapeutic interventions for chronic pain are discussed. The evidence presented in this review shows that mitochondria dysfunction may play a role in rheumatic pain. The dysfunction is not restricted to neuronal cells in the peripheral and central nervous system, but also includes blood cells and cells at the joint level that may affect pain pathways indirectly. Pre-clinical and clinical data suggest that modulation of mitochondrial functions can be used to attenuate or eliminate pain, which could be beneficial for multiple rheumatic diseases.

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“…Probucol is an anti-oxidative and lipid-lowering drug shown in preclinical and clinical studies to reduce serum low-density lipoprotein-cholesterol (LDL-C) [ 170 ]. In addition, probucol has been shown to counteract CCI-induced neuropathy via modulating NF-κB/NLRP3 signaling and augmenting transcription factor nuclear related factor (Nrf-2) activity [ 171 ]. Current evidence suggests that Nrf2 signaling contributes to antinociceptive activity by reducing inflammation, oxidative stress, and mitochondrial dysfunction [ 172 ].…”

Section: Novel Antioxidant Therapies For Chronic Pain In Hemophiliamentioning

confidence: 99%

Pain in Hemophilia: Unexplored Role of Oxidative Stress

2022

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Hemophilia is the most common X-linked bleeding diathesis caused by the genetic deficiency of coagulation factors VIII or IX. Despite treatment advances and improvements in clinical management to prevent bleeding, management of acute and chronic pain remains to be established. Repeated bleeding of the joints leads to arthropathy, causing pain in hemophilia. However, mechanisms underlying the pathogenesis of pain in hemophilia remain underexamined. Herein, we describe the novel perspectives on the role for oxidative stress in the periphery and the central nervous system that may contribute to pain in hemophilia. Specifically, we cross examine preclinical and clinical studies that address the contribution of oxidative stress in hemophilia and related diseases that affect synovial tissue to induce acute and potentially chronic pain. This understanding would help provide potential treatable targets using antioxidants to ameliorate pain in hemophilia.

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Probucol attenuates NF-κB/NLRP3 signalling and augments Nrf-2 mediated antioxidant defence in nerve injury induced neuropathic pain

Cited by 28 publications

References 51 publications

Targeting NLRP3 Inflammasome With Nrf2 Inducers in Central Nervous System Disorders

Targeting NLRP3 Inflammasome With Nrf2 Inducers in Central Nervous System Disorders

Mitochondria and sensory processing in inflammatory and neuropathic pain

Pain in Hemophilia: Unexplored Role of Oxidative Stress

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