Guanabenz Modulates Microglia and Macrophages in EAE

Abstract

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by peripheral immune cell infiltration, demyelination, and axonal damage. Microglial activation has also long been recognized as an early event in MS pathogenesis and is generally considered harmful as it can contribute to pro‐inflammatory responses and neuronal damage. However, microglia are also capable of releasing factors that can suppress the immune response and promote remyelination and repair. Therefore, a valid therapeutic strategy is to prevent pro‐inflammatory microglial activation and/or shift their phenotype towards neuroprotective and anti‐inflammatory. We have previously characterized the immunomodulatory tetrapeptide, tuftsin, that attenuates the experimental autoimmune encephalomyelitis (EAE) model of MS by inducing an anti‐inflammatory shift in microglia and infiltrating monocyte‐derived macrophages. As tuftsin is not FDA‐approved, we sought to investigate the repurposing of an already approved drug that may act similarly. We identified guanabenz, an FDA‐approved antihypertensive shown to possess anti‐inflammatory properties, using a virtual screen against tuftsin's receptor, neuropilin‐1 (NRP1). Although guanabenz does not bind NRP1, it does provide beneficial anti‐inflammatory effects in EAE. Using two EAE models that represent chronic and relapsing‐remitting (RR) MS disease courses we observe that guanabenz has beneficial, microglia/macrophage‐targeted immunomodulatory properties. In the chronic EAE model guanabenz improves disease scores, reduces demyelination and the amount of harmful, pro‐inflammatory microglia when administered therapeutically. In the RR‐EAE model guanabenz attenuates relapses, reduces demyelination and pro‐inflammatory microglia numbers when administered immediately after the initial symptom peak. Expression of pro‐inflammatory genes, such as TNF‐a, is reduced in stimulated primary macrophages and microglia. Overall, we report that guanabenz is capable of dampening the pro‐inflammatory responses of microglia and macrophages and improving pathological hallmarks and motor deficits in EAE. Further, combination of guanabenz with clemastine, an FDA‐approved antihistamine now in clinical trials for inducing remyelination in MS, offers additional benefits.Support or Funding InformationThis work was supported by NMSS CA1044A1 and PP1815 (SET) and PhRMA predoctoral fellowship (KKT).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.