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In vivo luminescent imaging of NF-?B activity and NF-?B-related serum cytokine levels predict pain sensitivities in a rodent model of peripheral neuropathy.

ABSTRACT: Methods for the detection of the temporal and spatial generation of painful symptoms are needed to improve the diagnosis and treatment of painful neuropathies and to aid preclinical screening of molecular therapeutics.In this study, we utilized in vivo luminescent imaging of NF-?B activity and serum cytokine measures to investigate relationships between the NF-?B regulatory network and the presentation of painful symptoms in a model of neuropathy.The chronic constriction injury model led to temporal increases in NF-?B activity that were strongly and non-linearly correlated with the presentation of pain sensitivities (i.e. mechanical allodynia and thermal hyperalgesia). The delivery of NEMO-binding domain peptide reduced pain sensitivities through the inhibition of NF-?B activity in a manner consistent with the demonstrated non-linear relationship. Importantly, the combination of non-invasive measures of NF-?B activity and NF-?B-regulated serum cytokines produced a highly predictive model of both mechanical (R(2) = 0.86) and thermal (R(2) = 0.76) pain centred on the NF-?B regulatory network (NF-?B, IL-6, CXCL1).Using in vivo luminescent imaging of NF-?B activity and serum cytokine measures, this work establishes NF-?B and NF-?B-regulated cytokines as novel multivariate biomarkers of pain-related sensitivity in this model of neuropathy that may be useful for the rapid screening of novel molecular therapeutics.

SUBMITTER: Bowles RD

PROVIDER: S-EPMC4830349 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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In vivo luminescent imaging of NF-κB activity and NF-κB-related serum cytokine levels predict pain sensitivities in a rodent model of peripheral neuropathy.

Bowles R D RD Karikari I O IO VanDerwerken D N DN Sinclair M S MS Bell R D RD Riebe K J KJ Huebner J L JL Kraus V B VB Sempowski G D GD Setton L A LA

European journal of pain (London, England) 20150529 3

<h4>Background</h4>Methods for the detection of the temporal and spatial generation of painful symptoms are needed to improve the diagnosis and treatment of painful neuropathies and to aid preclinical screening of molecular therapeutics.<h4>Methods</h4>In this study, we utilized in vivo luminescent imaging of NF-κB activity and serum cytokine measures to investigate relationships between the NF-κB regulatory network and the presentation of painful symptoms in a model of neuropathy.<h4>Results</h ...[more]

PMID: 26032161

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Project description:Elevations in plasma levels of pro-inflammatory cytokines and C-reactive protein (CRP) in patient blood have been associated with impairments in cognitive abilities and more severe psychiatric symptoms in people with schizophrenia. The transcription factor nuclear factor kappa B (NF-κB) regulates the gene expression of pro-inflammatory factors whose protein products trigger CRP release. NF-κB activation pathway mRNAs are increased in the brain in schizophrenia and are strongly related to neuroinflammation. Thus, it is likely that this central immune regulator is also dysregulated in the blood and associated with cytokine and CRP levels. We measured levels of six pro-inflammatory cytokine mRNAs and 18 mRNAs encoding NF-κB pathway members in peripheral blood leukocytes from 87 people with schizophrenia and 83 healthy control subjects. We then assessed the relationships between the alterations in NF-κB pathway genes, pro-inflammatory cytokine and CRP levels, psychiatric symptoms and cognition in people with schizophrenia. IL-1β and IFN-γ mRNAs were increased in patients compared to controls (both p < 0.001), while IL-6, IL-8, IL-18, and TNF-α mRNAs did not differ. Recursive two-step cluster analysis revealed that high levels of IL-1β mRNA and high levels of plasma CRP defined 'high inflammation' individuals in our cohort, and a higher proportion of people with schizophrenia were identified as displaying 'high inflammation' compared to controls using this method (p = 0.03). Overall, leukocyte expression of the NF-κB-activating receptors, TLR4 and TNFR2, and the NF-κB subunit, RelB, was increased in people with schizophrenia compared to healthy control subjects (all p < 0.01), while NF-κB-inducing kinase mRNAs IKKβ and NIK were downregulated in patients (all p < 0.05). We found that elevations in TLR4 and RelB appear more related to inflammatory status than to a diagnosis of schizophrenia, but changes in TNFR2 occur in both the high and low inflammation patients (but were exaggerated in high inflammation patients). Further, decreased leukocyte expression of IKKβ and NIK mRNAs was unique to high inflammation patients, which may represent schizophrenia-specific dysregulation of NF-κB that gives rise to peripheral inflammation in a subset of patients.

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Dataset Information

In vivo luminescent imaging of NF-?B activity and NF-?B-related serum cytokine levels predict pain sensitivities in a rodent model of peripheral neuropathy.

Publications

In vivo luminescent imaging of NF-κB activity and NF-κB-related serum cytokine levels predict pain sensitivities in a rodent model of peripheral neuropathy.

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