Systematic screening of generic drugs for progressive multiple sclerosis identifies clomipramine as a promising therapeutic

Nat Commun. 2017 Dec 19;8(1):1990. doi: 10.1038/s41467-017-02119-6.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / drug effects
  • Axons / physiology
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / immunology
  • Blood-Brain Barrier / drug effects
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Clomipramine / pharmacology
  • Clomipramine / therapeutic use*
  • Drug Evaluation, Preclinical
  • Drugs, Generic / pharmacology
  • Drugs, Generic / therapeutic use*
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy*
  • Female
  • Healthy Volunteers
  • Humans
  • Iron / toxicity
  • Lymphocyte Activation / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Microglia / drug effects
  • Microglia / immunology
  • Molecular Targeted Therapy / methods
  • Multiple Sclerosis / drug therapy*
  • Oxidative Stress / drug effects
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / physiology


  • Drugs, Generic
  • Iron
  • Clomipramine