BDNF as a biomarker for neuropathic pain: Consideration of mechanisms of action and associated measurement challenges

Abstract

Introduction:The primary objective of this paper is to (1) provide a summary of human studies that have used brain derived neurotrophic factor (BDNF) as a biomarker, (2) review animal studies that help to elucidate the mechanistic involvement of BDNF in the development and maintenance of neuropathic pain (NP), and (3) provide a critique of the existing measurement techniques to highlight the limitations of the methods utilized to quantify BDNF in different biofluids in the blood (i.e., serum and plasma) with the intention of presenting a case for the most reliable and valid technique. Lastly, this review also explores potential moderators that can influence the measurement of BDNF and provides recommendations to standardize its quantification to reduce the inconsistencies across studies. Methods:In this manuscript we examined the literature on BDNF, focusing on its role as a biomarker, its mechanism of action in NP, and critically analyzed its measurement in serum and plasma to identify factors that contribute to the discrepancy in results between plasma and serum BDNF values.Results: A large heterogenous literature was reviewed that detailed BDNF's utility as a potential biomarker in healthy volunteers, patients with chronic pain, and patients with neuropsychiatric disorders but demonstrated inconsistent findings. The literature provides insight into the mechanism of action of BDNF at different levels of the central nervous system using animal studies. We identified multiple factors that influence the measurement of BDNF in serum and plasma and based on current evidence, we recommend assessing serum BDNF levels to quantify peripheral BDNF as they are more stable and sensitive to changes than plasma BDNF. Conclusion:Although mechanistic studies clearly explain the role of BDNF, results from human studies are inconsistent. More studies are needed to evaluate the methodological challenges in using serum BDNF as a biomarker in NP.

P2X4 signalling contributes to hyperactivity but not pain sensitization comorbidity in a mouse model of attention deficit/hyperactivity disorder

“…Other markers did not show any significant difference in their levels of expression following the deletion of the P2X4 receptor under ADHD-like conditions. Remarkably, some of these molecules were previously shown to be involved in neuropathic pain (MMP9, BDNF) ( Kawasaki et al, 2008 ; Thakkar and Acevedo, 2023 ) or pain pathogenesis (Wnt5a) ( Wang et al, 2020 ; Liu et al, 2023 ). These results are in line with the absence of effects of P2X4 deletion on pain sensitization.…”

Response to experimental cold-induced pain discloses a resistant category among endurance athletes, with a distinct profile of pain-related behavior and GABAergic EEG markers: a case–control preliminary study

“…This plausible dual role of brain hyperexcitability (and therefore of GABAergic decrease) in trained pain-free population versus in CP patients further illustrates the above-hypothesized multifaceted role of GABAergic changes according to the training regime and to the existence of pain. Interestingly, the increase in brain-derived neurotrophic factor (BDNF), which is considered as a marker of a “virtuous” brain neuroplasticity (e.g., following PE; Nicolini et al, 2021 ), participates at the same time to the (neuropathic) pain pathological neuroinflammatory cascade resulting in the nervous hyperexcitability ( Sikandar et al, 2018 ; Thakkar and Acevedo, 2023 ). Thus, nociception and pain regulation players could differently change according to homeostatic conditions and their modifications should be interpreted with caution.…”

Potential biomarkers and therapeutic targets for obsessive compulsive disorder

“…Enzyme-linked immuno-sorbent assay (ELISA) is the diagnostic standard widely followed under clinical settings, utilizing either anti-BDNF antibodies or TrKB as ligands ( 16 ). Blood sera and plasma are the most commonly used sources for BDNF-based diagnostics, and whole blood or serum samples are preferred over plasma for ELISA because of stability and sensitivity reasons ( 17 ). In addition, type of anticoagulant used, clotting duration, and temperature and duration of sample preparation and storage have been shown to influence BDNF quantification in human serum samples ( 18 ).…”