Kynurenine, Tetrahydrobiopterin, and Cytokine Inflammatory Biomarkers in Individuals Affected by Diabetic Neuropathic Pain

Abstract

Neuropathic pain is a common complication of diabetes with high morbidity and poor treatment outcomes. Accumulating evidence suggests the immune system is involved in the development of diabetic neuropathy, whilst neuro-immune interactions involving the kynurenine (KYN) and tetrahydrobiopterin (BH4) pathways have been linked to neuropathic pain pre-clinically and in several chronic pain conditions. Here, using a multiplex assay, we quantified serum levels of 14 cytokines in 21 participants with type 1 diabetes mellitus, 13 of which were classified as having neuropathic pain. In addition, using high performance liquid chromatography and gas chromatography-mass spectrometry, all major KYN and BH4 pathway metabolites were quantified in serum from the same cohort. Our results show increases in GM-CSF and IL-8, suggesting immune cell involvement. We demonstrated increases in two inflammatory biomarkers: neopterin and the KYN/TRP ratio, a marker of indoleamine 2,3-dioxygenase activity. Moreover, the KYN/TRP ratio positively correlated with pain intensity. Total kynurenine aminotransferase activity was also higher in the diabetic neuropathic pain group, indicating there may be increased production of the KYN metabolite, xanthurenic acid. Overall, this study supports the idea that inflammatory activation of the KYN and BH4 pathways occurs due to elevated inflammatory cytokines, which might be involved in the pathogenesis of neuropathic pain in type 1 diabetes mellitus. Further studies should be carried out to investigate the role of KYN and BH4 pathways, which could strengthen the case for therapeutically targeting them in neuropathic pain conditions.

T lymphocyte and monocyte subsets are dysregulated in type 1 diabetes patients with peripheral neuropathic pain

“…Our laboratory demonstrated an increase in serum levels of granulocyte-macrophage colony stimulating factor (GM-CSF) and IL-8 in a similar cohort of DNP patients ( Staats Pires et al., 2020 ). GM-CSF prompts monocytes to differentiate into macrophages ( Boyette et al., 2017 ; Trus et al., 2020 ) and acts on macrophages to release pro-inflammatory mediators that can interact with nociceptors ( Tewari et al., 2020 ).…”

Proinflammatory cytokines and their receptors as druggable targets to alleviate pathological pain

“…6,11,173,255,277,375,376 Neuroinflammation and specifically proinflammatory cytokines are further critical regulators of neuropathic pain resulting from nerve damage, such as traumatic nerve lesions or complex regional pain syndrome (CRPS), as well as antineoplastic chemotherapies, diabetes, or postherpetic neuralgia. 26,42,148,195,212,303 Emerging evidence supports the idea that cytokines may even be relevant at brain level for the development of mental comorbidities. Depressive mood, cognitive impairment, and sleep disturbance are not only highly prevalent comorbidities in chronic pain disorders but also more generally prevalent in inflammatory diseases, such as RA, where they even contribute to the maintenance and progression of the disease.…”

Kynurenines in the Pathogenesis of Peripheral Neuropathy During Leprosy and COVID-19

“…Despite the lack of studies showing the role of the kynurenine metabolites in COVID-19 pain, many studies have shown its relationship with neuropathic pain and other painful conditions ( Rojewska et al, 2016 ; Rojewska et al, 2018 ; Staats Pires et al, 2020 ; Jovanovic et al, 2020 ; Ciapała et al, 2021 ; Tanaka et al, 2021 ). Some metabolites can act as immunomodulators depending on the dose or the situation, perpetuating low-grade inflammation ( Tanaka et al, 2020 ).…”