Anti-inflammatory and immunomodulatory effects of valproate and carbamazepine involve distinct signaling in human peripheral blood mononuclear cells.

OBJECTIVES Epilepsy is a chronic neurological condition with complex etiopathogenesis, treated with antiepileptics. In addition to their ability to regulate the activation threshold of neurons, antiepileptics have demonstrated a potential in shaping inflammation and the immune response. The main objective of our study was to analyze the effects of valproate, carbamazepine, and lamotrigine (commonly used antiepileptics) on viability, lymphocyte proliferation, and cytokine production by human peripheral blood mononuclear cells (PBMCs). METHODS PBMCs were treated with different concentrations of antiepileptics, with or without phytohemagglutinin (PHA). Cytotoxicity, assessed by viability and apoptosis/necrosis assay, was determined by flow cytometry using the Annexin V/Propidium iodide (PI) staining method. Proliferation was determined using the MTT assay, whereas cytokine levels were assessed by the ELISA assay. A selective peroxisome proliferator-activated receptor gamma (PPAR-γ) antagonist (SR-202) was used to evaluate the involvement of PPAR-γ. RESULTS Nontoxic concentrations of valproate and carbamazepine reduced the levels of three major proinflammatory cytokines (IL-1β, TNF-α, and IL-6) and impaired Th1 and Treg responses, without affecting the Th2 response. Lamotrigine did not exhibit immunomodulatory properties in this model. The effect of valproate on the production of proinflammatory and Th1 cytokines was significantly reversed by inhibiting PPAR-γ. In contrast, the blockade did not modify the effects of carbamazepine. CONCLUSION Our results demonstrated that valproate and carbamazepine, although similarly modulating the immune response in vitro, utilize different signaling mechanisms, in contrast to lamotrigine, which did not exhibit immunomodulatory effects.