Tyrosine Kinase Inhibitors Ameliorate Autoimmune Encephalomyelitis in a Mouse Model of Multiple Sclerosis

Abstract

Multiple sclerosis is an autoimmune disease of the central nervous system characterized by neuroinflammation and demyelination. Although considered a T cell-mediated disease, multiple sclerosis involves the activation of both adaptive and innate immune cells, as well as resident cells of the central nervous system, which synergize in inducing inflammation and thereby demyelination. Differentiation, survival, and inflammatory functions of innate immune cells and of astrocytes of the central nervous system are regulated by tyrosine kinases. Here, we show that imatinib, sorafenib, and GW2580—small molecule tyrosine kinase inhibitors can each—prevent the development of disease and treat established disease in a mouse model of multiple sclerosis. In vitro, imatinib and sorafenib inhibited astrocyte proliferation mediated by the tyrosine kinase platelet-derived growth factor receptor (PDGFR), whereas GW2580 and sorafenib inhibited macrophage tumor necrosis factor (TNF) production mediated by the tyrosine kinases c-Fms and PDGFR, respectively. In vivo, amelioration of disease by GW2580 was associated with a reduction in the proportion of macrophages and T cells in the CNS infiltrate, as well as a reduction in the levels of circulating TNF. Our findings suggest that GW2580 and the FDA-approved drugs imatinib and sorafenib have potential as novel therapeutics for the treatment of autoimmune demyelinating disease.

Imatinib ameliorates neuroinflammation in a rat model of multiple sclerosis by enhancing blood–brain barrier integrity and by modulating the peripheral immune response

“…Together, these effects could possibly account for generally lower disease incidence and/or severity observed in the imatinibtreated group. To this end, it has been recently shown that sorafenib and GW2580, both small molecule tyrosine kinase inhibitors, besides being able to ameliorate EAE in mice even more effective than imatinib, they could suppress M-CSF or PDGF-BB induced TNFa production by macrophages in vitro [29]. Besides macrophages, Th17 cells could also be potentially targeted by imatinib, as these cells also express CCR2 [30] and have an important role in EAE pathogenesis [31].…”

Platelets Provide a Bounty of Potential Targets for Therapy in Multiple Sclerosis

“…Remarkably, modulation of platelet-derived growth factor with drugs like imatinib has strong effects in the EAE model to reverse paralytic disease. 7 Modulation of the blood-brain barrier by inhibition of platelet-derived growth factor with drugs like imatinib has been shown to impair transendothelial migration of small and large molecules across the blood-brain barrier. 8 The platelets themselves may provide a key switch for modulation of the blood-brain barrier to restore homeostasis or for promoting drug delivery.…”

“…Understanding platelet physiology in the pathobiological processes associated with venules in the inflamed brain will provide new targets for therapy in MS. Platelet-activating factor and platelet-derived growth factor are certainly two molecules that merit consideration as targets for therapy. 7,9 Some of these targets already have available drugs that could be merely repurposed for use in demyelinating diseases. Finally, there is evidence that platelets themselves are highly activated in some patients with MS, 10 again emphasizing that modulating platelet activity may be beneficial.…”

Tyrosine Kinase Inhibitor Tyrphostin AG490 Inhibits Osteoclast Differentiation in Collagenase-Induced Osteoarthritis

“…Protein tyrosine kinase inhibitors (PTKIs) were first investigated as anti-cancer agents and then used in clinical trials (10). Now, they have been evaluated in various animal models of multiple sclerosis (11), intestinal inflammation (12), and septic shock (13). Recently, over 20 drugs that target kinases have been introduced in medical practice and many are currently in preclinical studies (14).…”