Effect of ethyl pyruvate on central nervous system inflammation

Abstract

The ongoing success of dimethyl fumarate (DMF; Tecfidera) opens a perspective for further development of the redox strategy in multiple sclerosis (MS) treatment. The mechanisms of anti-inflammatory and neuroprotective effects of DMF involve the formation of adducts with redox-sensitive thiol switches on the surface of T cell resulting in suppressed activity, proliferation and pro-inflammatory cytokine release, and the activation of antioxidative defense in the central nervous system (CNS) cells. Ethyl pyruvate (EP) appears to be a safer non-toxic redox analogue of DMF, as they share common molecular targets. We examined the effects of EP on CNS resident cells (astrocytes, microglia) and encephalitogenic T cells, as well as its influence on the clinical course of actively induced experimental autoimmune encephalomyelitis (EAE). Astrocytes and microglia were stimulated with pro-inflammatory cytokines and treated with EP in vitro. Encephalitogenic immune cells were isolated from draining lymph nodes of rats that were immunized with myelin basic protein (MBP) and complete Freund's adjuvant (CFA) and treated with EP in vivo. EP modulated cytokine generation in the examined cells in an anti-inflammatory manner: (i) the production of interleukin (IL)-6, but not IL-10, was down-regulated in astrocytes; (ii) the release of IL-6, tumor necrosis factor and nitric oxide from microglial cells was reduced; (iii) the production of interferon-gamma and IL-17, but not IL-10, was suppressed in lymph node cells isolated from MBP + CFA-immunized rats. In addition, EP alleviated EAE course in rats, delaying the onset, shortening the relapse, and lowering clinical scores. These results imply that EP has a potency to inhibit inflammation in the CNS. While further studies on the effect of EP on the CNS inflammation are warranted, we believe that EP might be applicable and beneficial in MS treatment.