Faissner S, Mishra M, Kaushik DK, Wang J, Fan Y, Silva C, Rauw G, Metz L, Koch M, Yong VW. 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 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.
Clomipramine, is a tricyclic antidepressant (TCA) that blocks seratonin re-uptake. Common side effects include dry mouth, constipation, loss of appetite, sleepiness, weight gain, sexual dysfunction, and trouble urinating, which are indicative of an anti-cholinergic (block acetyl-choline nerve transmitter) effects. Serious side effects include an increased risk of suicidal behavior in those under the age of 25, seizures, mania, and liver problems. If stopped suddenly a withdrawal syndrome may occur with headaches, sweating, and dizziness.
Clomipramine is on the World Health Organization’s List of Essential Medicines, the most effective and safe medicines needed in a health system. This study took the view that iron deposition and nerve death was a central problem and screened drugs for their potential to block iron-induced nerve death. The compounds could block microglial activity. They searched for things that block T and B cell activity too.
They found effects in excess of the human peak blood concentrations and found doses that completely inhibited EAE, and so stopped one finding cytokines produced by cells that would not be present as there was no disease.
However the drug accumulated in the CNS, so we will wait and see what happens when it is tried in man.