Oral administration of the nitroxide radical TEMPOL exhibits immunomodulatory and therapeutic properties in multiple sclerosis models

Abstract

Therapies with both immunomodulatory and neuroprotective properties are thought to have the greatest promise in reducing the severity and progression of multiple sclerosis (MS). Several reactive oxygen (ROS) and reactive nitrogen species (RNS) are implicated in inflammatory-mediated damage to the central nervous system (CNS) in MS and its animal model, experimental autoimmune encephalomyelitis (EAE). TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) is a stable nitroxide radical with potent antioxidant activity. The goal of our studies was to investigate the immunomodulatory effects and therapeutic potential of orally-delivered TEMPOL in the mouse EAE model. Mice receiving TEMPOL chow ad libitum for 2 weeks prior to induction of active EAE showed delayed onset and reduced incidence of disease compared to control-fed animals. Reduced disease severity was associated with limited microglial activation and fewer inflammatory infiltrates. TEMPOL’s effects were immunomodulatory, not immunosuppressive: T cells produced less interferon-γ and tumor necrosis factor-α, and TEMPOL-fed mice exhibited a shift towards TH2-type antibody responses. Both myeloid and myeloid-dendritic cells of TEMPOL-fed EAE animals had significantly lower levels of MHC class II expression than controls; CD40 was also significantly reduced. TEMPOL administration was associated with an enrichment of CD8+ T cell populations and CD4+FoxP3+regulatory populations. TEMPOL reduced the severity of clinical disease when administered after the induction of disease, and also after the onset of clinical symptoms. To exclude effects on T cell priming in vivo, TEMPOL was tested with the passive transfer of encephalitogenic T cells and was found to reduce the incidence and peak severity of disease. Protection was associated with reduced infiltrates and a relative sparing of neurofilaments and axons. The ability of oral TEMPOL to reduce inflammation and axonal damage and loss demonstrate both anti-inflammatory and protective properties, with significant promise for the treatment of MS and related neurological disorders.

Potential Therapeutic Applications of MnSODs and SOD‐Mimetics

“…When in vivo, nitroxides can be reduced to hydroxylamine, which functions as an antioxidant. [80] Animals that were administered TEMPOL avoided severe clinical disease. [77] The latter is capable of passing through biological membranes due to its low molecular weight.…”

“…[79] The study performed by Neil et al,d emonstrates that oral administration of TEMPOL restricts CNS autoimmuned isease and damage in establishedm odels of multiple sclerosis. [80] Animals that were administered TEMPOL avoided severe clinical disease. Besides, little evidenceo fm icroglial activation was displayed.…”

The cyclic nitroxide antioxidant 4-methoxy-TEMPO decreases mycobacterial burden in vivo through host and bacterial targets

“…MetT has been shown to be potently anti-inflammatory, inhibiting the expression of inflammatory cytokines and reducing leukocyte recruitment to sites of active inflammation [21-23]. Given this documented anti-inflammatory effect we investigated the effect that MetT had on the production of inflammatory genes during mycobacterial infection by quantitative real-time PCR (qPCR) at 5 dpi.…”

Modulating inflammation and neuroprotection in multiple sclerosis

“…In characterizing compounds with both immunomodulatory as well as neuroprotective effects as therapeutics in MS, our laboratory has recently described the ability of nitroxide radicals to both prevent and treat disability in models of MS (Neil et al, ). Nitroxide radicals have the potential to react with ROS and RNS and exhibit antioxidant activity.…”

“…TEMPOL administered orally prophylactically and therapeutically decreases the severity of clinical disease through immunomodulation with lessened TNF‐α and IFN‐γ production by immune cells. The potential to treat established disease in both chronic and passive models of disease, while limiting microglial activation and preserving axonal neurofilament, is suggestive of TEMPOL's potential to moderate disease processes and afford neuroprotection in the target tissue itself (Neil et al, ).…”