Alterations in the inflammatory cytokines and brain-derived neurotrophic factor contribute to depression-like phenotype after spared nerve injury: improvement by ketamine

Abstract

Although pain is frequently accompanied with depression, little is known about the risk factors contributing to individual differences to the comorbidity of pain and depression. In this study, we examined whether cytokines and brain-derived neurotrophic factor (BDNF) might contribute to the individual differences in the development of neuropathic pain-induced depression. Rats were randomly subjected to spared nerved ligation (SNI) or sham surgery. The SNI rats were divided into two groups by the data from depression-related behavioral tests. Rats with depression-like phenotype displayed higher levels of pro-inflammatory cytokines (e.g., interleukin (IL)-1β, IL-6) as well as imbalance of pro/anti-inflammatory cytokines compared with rats without depression-like phenotype and sham-operated rats. Levels of BDNF in the prefrontal cortex of rats with depression-like phenotype were lower than those of rats without depression-like phenotype and sham-operated rats. A single dose of ketamine ameliorated depression-like behaviors in the rats with depression-like phenotype. Interestingly, higher serum levels of IL-1β and IL-6 in the rat with depression-like phenotype were normalized after a single dose of ketamine. These findings suggest that alterations in the inflammatory cytokines and BDNF might contribute to neuropathic pain-induced depression, and that serum cytokines may be predictable biomarkers for ketamine’s antidepressant actions.

Brain-derived neurotrophic factor-TrkB signaling in the medial prefrontal cortex plays a role in the anhedonia-like phenotype after spared nerve injury

“…We found decreased BDNF-TrkB signaling in the mPFC and hippocampus from rats with anhedonia-like phenotypes on day 23 after SNI, consistent with the previous study [31]. Low levels of BDNF in the mPFC are associated with the development of depression-like phenotypes including anhedonia in rodents [19][20][21][22][23][24][25][26][27][28]41].…”

“…The previous clinical studies demonstrated that the incidence of comorbid chronic pain and depression is around 30-50% [1,4,5], which is in line with the present study. In this study, we found that rats with or without anhedonia-like phenotypes showed similar mechanical withdrawal thresholds, suggesting that the alterations in mood-related behaviors were independent of the degree of nociceptive damage, consistent with the previous studies [8,31,[38][39][40].…”

“…Accumulating evidence suggests that BDNF-TrkB signaling also plays a crucial role in pain [29,30]. A recent study showed that alterations in inflammatory cytokines and BDNF might contribute to neuropathic pain-induced depression [31]. However, little is known about the detailed role of BDNF-TrkB signaling in individual emotional responses to peripheral nerve injury.…”

Possible role of the gut microbiota–brain axis in the antidepressant effects of (R)-ketamine in a social defeat stress model

“…The precise mechanisms underlying antidepressant actions of ketamine and ( R )-ketamine are not fully understood. It has been suggested that anti-inflammatory actions of ketamine might play a role in its antidepressant effects 62 – 65 . Given the role of gut microbiota in the immune system 33 – 35 , 42 , 66 , it is likely that anti-inflammatory action of ( R )-ketamine might play a role in its antidepressant effects through the immunomodulation by the gut microbiota.…”

Putative neuroprotective pharmacotherapies to target the staged progression of mental illness

“…In rat models of depression, low‐dose ketamine acutely influences anti‐inflammatory pathways thought to be neuroprotective. Ketamine reduces hippocampal and serum levels of pro‐inflammatory cytokines IL1β, IL6 and TNFα while concurrently reducing depressive symptoms (N. Wang et al, ; Xie et al, ). This culminates in an overall reduction in ROS (Demirdas, Naziroglu, & Ovey, ).…”