Abstract
The treatment of progressive multiple sclerosis (MS) is unsatisfactory. One reason is that the drivers of disease, which include iron-mediated neurotoxicity, lymphocyte activity, and oxidative stress, are not simultaneously targeted. Here we present a systematic screen to identify generic, orally available medications that target features of progressive MS. Of 249 medications that cross the blood–brain barrier, 35 prevent iron-mediated neurotoxicity in culture. Of these, several antipsychotics and antidepressants strongly reduce T-cell proliferation and oxidative stress. We focus on the antidepressant clomipramine and found that it additionally inhibits B-lymphocyte activity. In mice with experimental autoimmune encephalomyelitis, a model of MS, clomipramine ameliorates clinical signs of acute and chronic phases. Histologically, clomipramine reduces inflammation and microglial activation, and preserves axonal integrity. In summary, we present a systematic approach to identify generic medications for progressive multiple sclerosis with the potential to advance rapidly into clinical trials, and we highlight clomipramine for further development.
Highlights
The treatment of progressive multiple sclerosis (MS) is unsatisfactory
We sought to shortlist a compound for further activity against Tlymphocytes and B-lymphocytes, given that the adaptive immune response continues to be active within the CNS compartment in progressive multiple sclerosis[15], and we sought to interrogate whether the compound affects experimental autoimmune encephalomyelitis (EAE), a model of MS
Based on a screen of potential microglial inhibitors performed by our group[14], we investigated the potential of promising generic compounds to prevent iron-mediated neurotoxicity
Summary
The treatment of progressive multiple sclerosis (MS) is unsatisfactory. One reason is that the drivers of disease, which include iron-mediated neurotoxicity, lymphocyte activity, and oxidative stress, are not simultaneously targeted. The blood–brain barrier in progressive multiple sclerosis appears to be repaired compared to the breach in relapsing-remitting disease[5], so medications will require the capacity to enter the CNS. Another pathologic feature seen in all types of multiple sclerosis but appears exacerbated in progressive cases is intense focal microglia activation[5,12,13]. We expanded our screen to investigate other features relevant to progressive multiple sclerosis, including the potential of generic compounds to affect iron-mediated neurotoxicity, maintain mitochondria integrity, and scavenge free radicals. The tricyclic antidepressant clomipramine affected B-lymphocyte proliferation, reduced clinical signs in acute EAE concomitant with improved histology, and improved the chronic phase in two EAE models
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