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Multiple Sclerosis and Related Conditions
Published in John W. Scadding, Nicholas A. Losseff, Clinical Neurology, 2011
In addition to these agents, there are a number of drugs which modify the immune response by interfering with lymphocyte trafficking or viability, including rituximab, teriflunomide, laquinimod and fumarate, and which are currently undergoing clinical trials. At the moment, the extent to which these and the other emerging treatments for relapsing MS can prevent long-term disability is simply not known, and there is a great deal of interest in alternative routes to so-called neuroprotection to control this major aspect of the illness.
Emerging drugs for primary progressive multiple sclerosis
Published in Expert Opinion on Emerging Drugs, 2018
Ram Narendra Narayan, Thomas Forsthuber, Olaf Stüve
Laquinimod is a carboxamide compound that is thought to have both anti-inflammatory and neuroprotective properties making it appropriate for the treatment of PPMS [89]. It is thought to reduce the TH1 and TH17 cell population in the CNS, favors shift of cytokines to an anti-inflammatory profile, and reduces the ability of dendritic cells to induce a CD4 response [90]. Interestingly, it is also thought to increase brain-derived neuroprotective factor [91] and inhibit the inflammatory response of astrocytes and microglia [92]. Most recently, the phase II trial to evaluate the efficacy and safety of low-dose laquinimod (0.6 mg) in PPMS (ARPEGGIO) failed to meet its primary end point which was percentage change in brain volume.
Ah receptor ligands and their impacts on gut resilience: structure–activity effects
Published in Critical Reviews in Toxicology, 2020
Stephen Safe, Arul Jayaraman, Robert S. Chapkin
Intestinal microbiota and microbial metabolites are influenced by multiple factors including the diet and drugs and these changes can also impact multiple distal organs/tissues (Maruvada et al. 2017). Moreover, very little is known about dose-response and metabolic effects of microbial metabolites and their interactions with more than one signaling pathway. For example, gut microbiota-derived tryptophan metabolites such as indole-3-acetate and tryptamine modulate inflammatory responses in the liver that are AhR dependent (Krishnan et al. 2018). Moreover, AhR-active tryptophan metabolites also attenuated central nervous system inflammation and EAE in mouse models and demonstrate a powerful AhR-dependent influence on the gut–brain axis (Rothhammer et al. 2016, 2018). Thus, the AhR is targetable not only in the gut for treating gut inflammatory diseases but also in distal organs where microbial formation of AhR active metabolites can be therapeutic. Despite these observations, progress on the development and clinical applications of AhR-active drugs or dietary methods to enhance production of AhR active microbial metabolites has been limited. One notable exception is the AhR-active drug laquinimod which has been in phase III clinical trials for treatment of multiple sclerosis (Comi et al. 2012). One reason for the slow development of AhR-active drugs has been the association of the AhR with toxic outcomes since this receptor was first identified and characterized as the “dioxin (TCDD) receptor”. Another reason for caution in developing drugs that act through the AhR is based on evidence demonstrating that AhR ligands are SAhRMs which exhibit structure-dependent and tissue-specific AhR agonist or antagonist activities. For example, in the DSS/TNBS-induced colitis models in mice both nontoxic dietary/microbial-derived AhR ligands and TCDD exhibit anti-inflammatory activity. Evidence for SAhRM-like activity of AhR ligands in the gut includes studies showing that tryptophan metabolites and indole-3-carbinol act as inhibitors of colitis and gut inflammation in mouse models whereas oxazolone and related AhR active compounds induce gut inflammation. Thus, development of AhR ligands for enhancing gut resilience needs to assess their possible SAhRM-like adverse responses.