Amyotrophic Lateral Sclerosis, Neuroinflammation, and Cromolyn Theoharis C. Theoharides, MS, MPhil, PhD, MD 1,2 ; and Irene Tsilioni, PhD 1 1 Laboratory of Molecular Immunopharmacology and Drug Discovery, Department of Immunology, Tufts University School of Medicine, Boston, MA, USA; and 2 Department of Internal Medicine, Tufts University School of Medicine, Boston, MA, USA ABSTRACT Amyotrophic lateral sclerosis (ALS) is an upper motor neuron disease with an unknown pathogenesis and no effective treatment. A recent study found that treatment of a mouse model of ALS (TgSOD1 mice) intraperitoneally with the mast-cell blocker disodium chromoglycate (cromolyn) had a small but significant effect on disease onset, improvement of neurologic symptoms, and decrease in the expression of proinflammatory cytokines and chemokines in the spinal cord and plasma of the TgSOD1 mice. Treatment with cromolyn also reduced degranulation of mast cells in the tibialis anterior muscle. There was no effect on survival. These findings are important in their support of the involvement of mast cells in the pathogenesis of ALS but are limited by the small effect of cromolyn, which was given intraperitoneally and is poorly absorbed after oral administration. Instead, use of the structurally related flavonoid tetramethoxyluteolin, which is a more potent inhibitor of proinflammatory cytokine release from mast cells and also inhibits activated microglia, may offer significant advantages over cromolyn. Development of mast cell inhibitors could benefit not only allergic disorders but also inflammatory and neurodegenerative disorders. (Clin Ther. xxxx;xxx:xxx) © 2020 Elsevier Inc. All rights reserved. Keywords: ALS, Cromolyn, Inflammation, Mast cells, Microglia, Tetramethoxyluteolin. Amyotrophic lateral sclerosis (ALS) is a devastating upper motor neuron disease with an unknown pathogenesis and no effective treatment. 1 Immune dysregulation has been suspected, and a recent article by Granucci et al 2 reported that treatment of a mouse model of ALS (TgSOD1 mice) intraperitoneally with the mast-cell blocker diosodium chromoglycate (cromolyn) had a small but apparently significant effect on disease onset, improvement of neurologic symptoms, and decrease in the expression of proinflammatory cytokines and chemokines, especially interleukin (IL) 6 and tumor necrosis factor (TNF) a, in the spinal cord and plasma of the TgSOD1 mice but had no effect on survival. 2 Treatment with cromolyn also reduced degranulation of mast cells in the tibialis anterior muscle of the TgSOD1 mice. Mast cells are effector immune cells that are ubiquitous in the body and are involved classically in allergies and inflammatory processes. 3 Mast cells have also been implicated in the pathogenesis of neuroinflammatory diseases, 4 such as multiple sclerosis 5 and autism spectrum disorder. 6 For instance, degranulated mast cells were reported to be increased and were associated with myofibers and motor endplates in the quadriceps muscles of patients with ALS but not in controls. 7 Mast cells are responsible for IgE-mediated allergic reactions 3 via secretion of numerous mediators 8,9 after activation of the high-affinity IgE receptor and specific antigen. 10 Some of these mediators are prestored in secretory granules (eg, histamine, tryptase, and TNFa), whereas others are synthesized de novo (eg, leukotrienes, prostaglandins, chemokines [eg, CCXL8 and CCL2] and cytokines [eg, IL-6 and IL-31]). 11 Mast cells are also stimulated by nonallergic agents, 12e14 especially neuropeptides, 15 including substance P, which is augmented by IL-33 and stimulates human mast cells to release impressive amounts of proinflammatory vascular endothelial growth factor, Accepted for publication January 17, 2020 https://doi.org/10.1016/j.clinthera.2020.01.010 0149-2918/$ - see front matter © 2020 Elsevier Inc. All rights reserved. ▪▪▪ xxxx 1 Clinical Therapeutics/Volume xxx, Number xxx, xxxx