Neuroinflammation, oxidative stress and their interplay in neuropathic pain: Focus on specialized pro-resolving mediators and NADPH oxidase inhibitors as potential therapeutic strategies

Teixeira-Santos, Luísa; Albino‐Teixeira, António; Pinho, Dora

doi:10.1016/j.phrs.2020.105280

Cited by 50 publications

(47 citation statements)

References 287 publications

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“…ROS and lipid peroxidation products as a result of oxidative stress contribute to chronic pain via multiple mechanisms, including direct activation of nociceptor TRPA1 in the periphery and activation of microglia in the spinal cord, affecting spinal synaptic plasticity or producing pain-inducing substances [32,[58][59][60]. ROS scavengers or NADPH oxidase inhibitors, which reduce oxidative stress and ROS production, ameliorate chronic pain [61][62][63][64]. The Nrf2 antioxidant signaling is an endogenous machinery to counteract oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Nrf2 Activation Mediates Antiallodynic Effect of Electroacupuncture on a Rat Model of Complex Regional Pain Syndrome Type-I through Reducing Local Oxidative Stress and Inflammation

Yin

et al. 2022

Oxidative Medicine and Cellular Longevity

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Complex regional pain syndrome type-I (CRPS-I) represents a type of neurovascular condition featured by severe pain in affected extremities. Few treatments have proven effective for CRPS-I. Electroacupuncture (EA) is an effective therapy for pain relief. We explored the mechanism through which EA ameliorates pain in a rat CRPS-I model. The chronic postischemic pain (CPIP) model was established using Sprague-Dawley rats to mimic CRPS-I. We found that oxidative stress-related biological process was among the predominant biological processes in affected hindpaw of CPIP rats. Oxidative stress occurred primarily in local hindpaw but not in the spinal cord or serum of model rats. Antioxidant N-acetyl cysteine (NAC) attenuated mechanical allodynia and spinal glia overactivation in CPIP model rats, whereas locally increasing oxidative stress is sufficient to induce chronic pain and spinal glia overactivation in naive rats. EA exerted remarkable antiallodynia on CPIP rats by reducing local oxidative stress via enhancing nuclear factor erythroid 2-related factor 2 (Nrf2) expression. Pharmacological blocking Nrf2 abolished antioxidative and antiallodynic effects of EA. EA reduced spinal glia overactivation, attenuated the upregulation of inflammatory cytokines, reduced the enhanced TRPA1 channel activity in dorsal root ganglion neurons innervating the hindpaws, and improved blood flow dysfunction in hindpaws of CPIP rats, all of which were mimicked by NAC treatment. Thus, we identified local oxidative injury as an important contributor to pathogenesis of animal CRPS-I model. EA targets local oxidative injury by enhancing endogenous Nrf2-mediated antioxidative mechanism to relieve pain and inflammation. Our study indicates EA can be an alternative option for CRPS-I management.

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Section: Discussionmentioning

confidence: 99%

Nrf2 Activation Mediates Antiallodynic Effect of Electroacupuncture on a Rat Model of Complex Regional Pain Syndrome Type-I through Reducing Local Oxidative Stress and Inflammation

Yin

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…Nox4 is highly expressed in proximal tubular cells of the kidney, endothelial cells, fibroblasts, and osteoclasts, and may exert damaging or protective effects in a cell-specific manner. 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 ].…”

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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“…The titer for LV-TREM2 was 4.35×10 9 transducing unit (TU)/ml, while the LV-control was 7.16×10 9 TU/ml. A week before STZ injection, LV-TREM2 or LV-control vectors (5×10 7 TU, 5 μl) were injected i.t. using a 5-μl Hamilton microsyringe.…”

Section: Intrathecal Administration Of Lentiviral Vectors and Neutralizing Antibodiesmentioning

confidence: 99%

“…Neuroin ammation in the spinal cord has been identi ed as an essential mechanism in neuropathic pain [7,8]. The hallmarks of neuroin ammation are the presence of activated microglia and reactive astrocytes that intensify the production of cytokines, chemokines, or neurotoxic compounds [9,10].…”

Section: Introductionmentioning

confidence: 99%

Contribution of TREM2 Signaling to the Development of Painful Diabetic Neuropathy by Mediating Microglial Polarization in Mice

Chen

Yue

Tang

et al. 2021

Preprint

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Background: Painful diabetic neuropathy (PDN) is a common and intractable complication of diabetes mellitus, with little effective treatment. PDN has been associated with spinal neuroinflammation characterized by microglial activation. Recently, the triggering receptor expressed on myeloid cells 2 (TREM2), specifically localized on microglia, has been identified as a vital factor in modulating neuroinflammation and microglial phenotypes in neural diseases. Therefore, we hypothesized that spinal TREM2 might contribute to PDN and neuroinflammation by regulating microglial activity and phenotypes.Methods：Type I diabetes mellitus was elicited by a single intraperitoneal administration of streptozotocin (STZ) in mice. The pain behaviors were reflected by paw mechanical withdrawal thresholds (PMWT) and thermal withdrawal latency (PTWL). Results：We demonstrated that up-regulation of microglial TREM2 and amplification of both microglial M1 and M2 response was along with the presence of diabetes-related mechanical allodynia and thermal hypersensitivity. Moreover, we found that overexpression of TREM2 in microglia aggravated the symptom of PDN, amplified microglia M1 response, and suppressed microglia M2 polarization in the lumbar spinal cord of diabetic mice. However, inhibition of TREM2 with anti-TREM2 neutralizing antibodies attenuated mechanical allodynia and thermal hyperalgesia in diabetic mice. Besides, we identified Galectin-3 (GLT-3) as the potential ligand of the TREM2 receptor in facilitating the progression of PDN.Conclusions: TREM2 could be a critical microglial membrane molecule that modulates microglial phenotypes pain hypersensitivity in PDN. GLT-3 might act as a specific ligand to trigger TREM2 signaling in PDN or other neuropathic pain.

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Neuroinflammation, oxidative stress and their interplay in neuropathic pain: Focus on specialized pro-resolving mediators and NADPH oxidase inhibitors as potential therapeutic strategies

Cited by 50 publications

References 287 publications

Nrf2 Activation Mediates Antiallodynic Effect of Electroacupuncture on a Rat Model of Complex Regional Pain Syndrome Type-I through Reducing Local Oxidative Stress and Inflammation

Nrf2 Activation Mediates Antiallodynic Effect of Electroacupuncture on a Rat Model of Complex Regional Pain Syndrome Type-I through Reducing Local Oxidative Stress and Inflammation

NADPH Oxidases in Pain Processing

Contribution of TREM2 Signaling to the Development of Painful Diabetic Neuropathy by Mediating Microglial Polarization in Mice

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