Fatty acid suppression of glial activation prevents central neuropathic pain after spinal cord injury

Georgieva, Marieta; Wei, Yinmao; Dumitrascuta, Maria; Pertwee, Roger Guy; Finnerup, Nanna Brix; Huang, Wenlong

doi:10.1097/j.pain.0000000000001670

Cited by 21 publications

(11 citation statements)

References 63 publications

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“…Paraffin-processed tissues were deparaffinized in xylene and rehydrated with a graded alcohol solution. The sections were placed in 0.01 M citrate buffer (pH 6.0) and heated in a microwave oven for hot repair antigen ( 43 , 44 ). These sections were incubated with goat serum at 37 °C for 20 min and then with a mixture of rabbit-anti-Iba-1 monoclonal antibody and mouse-anti-GFAP monoclonal antibody at 4 °C overnight.…”

Section: Manuscript Formattingmentioning

confidence: 99%

ACT001 Inhibits TLR4 Signaling by Targeting Co-Receptor MD2 and Attenuates Neuropathic Pain

Lin

Jiang

et al. 2022

Front. Immunol.

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Neuropathic pain is a common and challenging neurological disease, which renders an unmet need for safe and effective new therapies. Toll-like receptor 4 (TLR4) expressed on immune cells in the central nervous system arises as a novel target for treating neuropathic pain. In this study, ACT001, an orphan drug currently in clinical trials for the treatment of glioblastoma, was identified as a TLR4 antagonist. In vitro quenching titrations of intrinsic protein fluorescence and saturation transfer difference (STD)-NMR showed the direct binding of ACT001 to TLR4 co-receptor MD2. Cellular thermal shift assay (CETSA) showed that ACT001 binding affected the MD2 stability, which implies that MD2 is the endogenous target of ACT001. In silico simulations showed that ACT001 binding decreased the percentage of hydrophobic area in the buried solvent-accessible surface areas (SASA) of MD2 and rendered most regions of MD2 to be more flexible, which is consistent with experimental data that ACT001 binding decreased MD2 stability. In keeping with targeting MD2, ACT001 was found to restrain the formation of TLR4/MD2/MyD88 complex and the activation of TLR4 signaling axes of NF-κB and MAPKs, therefore blocking LPS-induced TLR4 signaling downstream pro-inflammatory factors NO, IL-6, TNF-α, and IL-1β. Furthermore, systemic administration of ACT001 attenuated allodynia induced by peripheral nerve injury and activation of microglia and astrocyte in vivo. Given the well-established role of neuroinflammation in neuropathic pain, these data imply that ACT001 could be a potential drug candidate for the treatment of chronic neuropathic pain.

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Section: Manuscript Formattingmentioning

confidence: 99%

ACT001 Inhibits TLR4 Signaling by Targeting Co-Receptor MD2 and Attenuates Neuropathic Pain

Lin

Jiang

et al. 2022

Front. Immunol.

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“…The modulation of electrical and synaptic neuronal activity by glial cells in pain states is well accepted, whereas the role of microglia and astrocytes in the mPFC is only starting to gain interest [99][100][101]. The majority but not all studies support an upregulation of microglia or microglial markers, that might at least in part be induced by interleukin 1 beta (IL-1β) [102][103][104][105][106][107][108][109][110][111][112]. Inhibition of microglial activation in neuropathic pain models alleviates mechanical allodynia in nerve ligated mice and affective components of pain-like behavior [103,107].…”

Section: Modulation By Glial Cellsmentioning

confidence: 99%

The Medial Prefrontal Cortex as a Central Hub for Mental Comorbidities Associated with Chronic Pain

Kummer

Mitrić

Kalpachidou

et al. 2020

IJMS

108

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Chronic pain patients frequently develop and suffer from mental comorbidities such as depressive mood, impaired cognition, and other significant constraints of daily life, which can only insufficiently be overcome by medication. The emotional and cognitive components of pain are processed by the medial prefrontal cortex, which comprises the anterior cingulate cortex, the prelimbic, and the infralimbic cortex. All three subregions are significantly affected by chronic pain: magnetic resonance imaging has revealed gray matter loss in all these areas in chronic pain conditions. While the anterior cingulate cortex appears hyperactive, prelimbic, and infralimbic regions show reduced activity. The medial prefrontal cortex receives ascending, nociceptive input, but also exerts important top-down control of pain sensation: its projections are the main cortical input of the periaqueductal gray, which is part of the descending inhibitory pain control system at the spinal level. A multitude of neurotransmitter systems contributes to the fine-tuning of the local circuitry, of which cholinergic and GABAergic signaling are particularly emerging as relevant components of affective pain processing within the prefrontal cortex. Accordingly, factors such as distraction, positive mood, and anticipation of pain relief such as placebo can ameliorate pain by affecting mPFC function, making this cortical area a promising target region for medical as well as psychosocial interventions for pain therapy.

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“…The at-level measurements performed in this study may have lowered the overall recorded allodynia frequency, but it enabled the testing of patients with complete and incomplete injuries, thus allowing for the generalization of results regardless of CNP location. Interestingly, animal models of post-SCI pain developed allodynia two to three weeks after injury, 3,11,16,41,48 corresponding to the delayed hyperexcitability observed herein. As these animals did not present hyperexcitability pre-SCI, it was likely an acquired rather than inherent trait.…”

Section: Pain Excitability After Spinal Cord Injurymentioning

confidence: 52%

From acute to long-term alterations in pain processing and modulation after spinal cord injury: mechanisms related to chronification of central neuropathic pain

Defrin

Gruener

Gaidukov

et al. 2021

Pain

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A severe and debilitating consequence of a spinal cord injury (SCI) is central neuropathic pain (CNP). Our aim was to investigate the processes leading to CNP emergence and chronification by analyzing causal relationship over time between spinothalamic function, pain excitability, and pain inhibition after SCI. This longitudinal follow-up study included 53 patients with acute SCI and 20 healthy controls. Spinothalamic, pain excitability, and intrasegmental and extrasegmental pain inhibition indices were repeatedly evaluated at 1.5, 3, and 6 months post-SCI. Between-and within-group analyses were conducted among those patients who eventually developed CNP and those who did not. Healthy controls were evaluated twice for repeatability analysis. Patients who developed CNP, compared with those who did not, exhibited increased thermal thresholds (P , 0.05), reduced pain adaptation (P , 0.01), and conditioned pain modulation (P , 0.05), early post-injury, and the CNP group's manifestations remained worse throughout the follow-up. By contrast, allodynia frequency was initially similar across SCI groups, but gradually increased in the subacute phase onward only among the CNP group (P , 0.001), along with CNP emergence. Early worse spinothalamic and pain inhibition preceded CNP and predicted its occurrence, and early worse pain inhibition mediated the link between spinothalamic function and CNP. Crossover associations were observed between early and late pain inhibition and excitability. Inefficient intrasegmental and extrasegmental inhibition, possibly resulting from spinothalamic deafferentation, seems to ignite CNP chronification. Pain excitability probably contributes to CNP maintenance, possibly via further exhaustion of the inhibitory control. Preemptive treatment promoting antinociception early post-SCI may mitigate or prevent CNP.

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Fatty acid suppression of glial activation prevents central neuropathic pain after spinal cord injury

Abstract: Provide an accurate summary of the background, research objectives, including details of the species or strain of animal used, key methods, principal findings and conclusions of the study.

Cited by 21 publications

References 63 publications

ACT001 Inhibits TLR4 Signaling by Targeting Co-Receptor MD2 and Attenuates Neuropathic Pain

ACT001 Inhibits TLR4 Signaling by Targeting Co-Receptor MD2 and Attenuates Neuropathic Pain

The Medial Prefrontal Cortex as a Central Hub for Mental Comorbidities Associated with Chronic Pain

From acute to long-term alterations in pain processing and modulation after spinal cord injury: mechanisms related to chronification of central neuropathic pain

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