Etanercept May Be Useful in Treating Depression, Study Suggests

There is a strong connection between the immune system and the brain in the context of depression. Chronic stress induces an inflammatory response in the body, which in the central nervous system includes an increase in pro-inflammatory cytokines. A recent study investigated whether peripheral injections of the anti—tumor necrosis factor (anti-TNF) inhibitor etanercept can help treat depression.

The study was conducted in an animal model comprising 24 male Long-Evans rats. The rats were randomly assigned to one of the following treatment groups:

• Corticosteroid plus saline (n = 6)
• Corticosteroid plus etanercept (n = 6)
• Vehicle plus saline (n = 6)
• Vehicle plus etanercept (n = 6)

All steroid and vehicle injections were administered once a day subcutaneously for 21 consecutive days. Etanercept and saline injections were given subcutaneously twice per week for 21 days. In addition, behavioral tests were conducted in the form of a forced swim test, an object-recognition memory test, and an object-in-place paradigm test.

The results of the experiment show that prolonged exposure to steroids produces a cluster of effects characterized by increased immobility in the swim test, impaired spatial memory on the object location and object-in-place tests, and reduced hippocampal neurogenesis. However, semi-weekly etanercept giving concurrently with steroids prevented all of these effects, which suggested that anti-TNF drugs could have a role in treating depression.

A particularly noteworthy finding of the study was that peripheral administration of etanercept restored steroid-induced deficits in hippocampal neurogenesis. However, the role of hippocampal neurogenesis in depression is a controversial issue, as the removal of hippocampal neurogenesis does not always induce depression-like behavior, and antidepressant effects can be seen without increases in neurogenesis.

The study also found that peripheral injections of etanercept normalize steroid-induced deficits in hippocampal reelin (a glycoprotein) expression. This idea comes from previous observations that reelin-overexpressing mice have increased neurogenesis, and that exogenous reelin can recover cognitive deficits in mouse models of both Angelman syndrome and Alzheimer disease. These observations correlate with the findings of this study that etanercept restores both object-location and object-in-place memory.

The researchers found that peripheral injections of etanercept normalize the depressive effects of repeated steroid administration. These results add to previous studies that suggested inflammatory events are a critical component of the pathogenesis of depression, and that there could be a key link between the immune system and the brain.

Reference

Brymer K, Fenton E, Kalychuk L, Caruncho H. Peripheral etanercept administration normalizes behavior, hippocampal neurogenesis, and hippocampal reelin and GABA_A receptor expression in a preclinical model of depression [published online February 20, 2018]. Front Pharmacol. doi:10.3389/fphar.2018.00121.