The Effect of Exercise on Reducing Tumor Necrosis Factor Alpha Levels and Attenuating Serotonin Transporter Gene Expression: A Research Protocol

Introduction: The intricate relation between depression and inflammation has become a prevalent topic of discussion among the scientific community. Pro-inflammatory cytokines exert depressogenic effects by crossing the blood brain barrier and disrupting serotonin (5-hydroxytryptamine, 5-HT) homeostasis through serotonin transporters (SERTs). SERTs induce 5-HT reuptake, causing 5-HT deficiency. This study demonstrates that (1) exercise decreases levels of the pro-inflammatory cytokine, Tumor Necrosis Factor alpha (TNF-α), and (2) a decline in TNF-α attenuates SERT activity through the proposed mechanism of activating the p38 mitogen-activated protein kinase (MAPK) pathway in the hippocampus. Methods: 32 Sprague-Dawley rats are randomly divided into four groups. Rats not exercising serve as control. Exercising rats, exposed to 6 weeks of treadmill exercise, receive either vehicle intracerebroventricular injection, intracerebroventricular injection of TNF-α antibody Infliximab, or intracerebroventricular injection of MAPK inhibitor SB203580. Control rats also receive vehicle intracerebroventricular injection. 24 hours post-injection, blood is collected, and serum is separated for an ELISA test to assess TNF-α levels. To measure SERT gene expression, RNA is isolated from hippocampal tissue and PCR is performed.  Results: Exercising rats are anticipated to show reduced TNF-α levels compared to control, confirming exercise decreases pro-inflammatory cytokines. Exercising rats should also show decreased SERT gene expression, as exercise attenuates TNF-α mediated stimulation of SERTs. SERT expression is expected to be similar in rats injected with Infliximab and SB203580, suggesting that TNF-α exerts its effect through the p38 MAPK pathway. Discussion: Moderate intensity exercise reduces TNF-α levels, which limits 5-HT uptake by attenuating the expression of the SERT gene, thus mitigating depressive symptoms. It is also postulated that TNF-α modulates levels of SERT expression through the p38 MAPK pathway, as rats injected with SB203580 have shown to have similar gene expression as rats injected with Infliximab. Conclusion: Understanding the negative correlation between exercise and depression provides insight into viable treatment alternatives for depression. Exercise may be used alone or in conjunction with current treatments to prevent or minimize symptoms of mood disorders. Further investigation may reveal the effects of other cytokines on extracellular 5-HT levels, and their consequent influence on depression and its symptoms.