Inflammatory demyelination of the central nervous system (CNS) is the hallmark of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Current MS medications are mainly immunomodulatory, having little or no effect on neuroregeneration of damaged CNS tissue; they are thus only effective in the acute, but not the chronic stage of disease. An MS therapy that has both immunomodulatory and neuroregenerative effects would be highly beneficial. This goal could be achieved by using P7C3, a small molecule that easily penetrates the blood-brain barrier (BBB) and has a protective effect on neurons. We, for the first time, show that P7C3 treatment effectively suppresses ongoing EAE, inhibits Th17 cells, induces IL-10 production and shifts macrophages/microglia from an inflammatory Type 1 (M1) to an immunomodulatory M2 phenotype. These immunomodulatory capacities are likely through induction of SOCS3 expression. The central hypothesis of this proposal is that P7C3 is a novel immunomodulator, in addition to its known effect in direct neuroregeneration. From the therapeutic perspective, we will in Specific Aim 1 test the effects of P7C3 on chronic-progressive and relapsing-remitting models of EAE. We will also test the direct effect of P7C3 treatment on axonal myelination in vivo in a hypomyelination model. From the biological perspective, we will in Specific Aim 2 dissect the mechanisms of P7C3 action through a SOCS3-induced immunomodulation in macrophages/microglia and CD4+ T cells. In addition, potential side effects and safety issues of long-term P7C3 treatment will also be closely monitored. This project will form an exploratory foundation to define the remarkable promise of P7C3, in addition to its neuroregenerative effect, as a novel, safe and low-cost immunomodulator for autoimmune/ inflammatory disorders, through a well-defined SOCS3-induced signaling pathway.
We have recently found that P7C3, a small molecule, may have anti-inflammatory effect in addition to its known neuroreparative one. We propose to study the therapeutic effect of P7C3 on animal models of multiple sclerosis to define a safe and low-cost immunomodulatory agent for autoimmune disorders.
