Clomipramine, an approved antidepressant, shows potential in treating people with progressive multiple sclerosis (MS) — a disease form with few treatments — by protecting nerves from various processes thought to underly progressive MS, early research shows.
The lab and animal study, which focused on already-approved treatments, was titled “Systematic screening of generic drugs for progressive multiple sclerosis identifies clomipramine as a promising therapeutic” and published in the journal Nature Communications.
A variety of therapies exist for people with relapsing-remitting MS (RRMS), which is marked by exacerbations or flares. But fewer exist for people with progressive MS, and only one, Ocrevus (ocrelizumab), is approved for those with primary progressive disease. Among reasons for this are the markedly different underlying processes underlying these two types of MS.
“The mechanisms causing damage in progressive MS are not always the same as in relapsing-remitting MS. This is why the latter requires different therapeutic approaches,” Simon Faissner, a researchers with the Hotchkiss Brain Institute, University of Calgary, Canada and the study’s first author, said a press release.
Progressive MS involves severe aspects of neurodegeneration, accompanied by iron-mediated neurotoxicity, immune cell activity, and oxidative stress. An effective treatment essentially needs to address all these mechanisms.
Researchers screened 1,040 generic, orally available medications available at the NINDS Custom collection II (U.S. Drug Collection). They studied drugs that were already approved for other indications, which ensured their safety for human use.
From the initial pool, researchers identified 249 well-tolerated therapies that are able to cross the blood-brain barrier, the protective membrane that selectively excludes most blood-borne substances from entering the brain. Therapies that cross the barrier are better able to penetrate the central nervous system, where chronic inflammation that characterizes progressive MS occurs. The blood-brain barrier is also relatively intact in progressive MS compared to RRMS, the researchers noted.
Of the 249 medicines selected, 35 prevented iron-induced damage to nerve cells in vitro (iron is released due to cell damage, damaging nerve cells in turn).
To narrow further their selection, these 35 medicines were tested for their potential to protect mitochondria (organelles seen as powerhouses as they provide energy to cells) from damage, and their capacity to reduce the immune attack mediated by T-cells against nerve cells seen in MS.
The screening first identified several antipsychotics and antidepressants as capable of strongly reducing T-cell proliferation and damage to mitochondria.
From this screen, the antidepressant clomipramine, sold under the brand name Anafranil among others, showed “outstanding effects in several in vitro settings such as against iron-mediated neurotoxicity, hydroxyl scavenging capacity, and inhibition of T-cell and B-cell proliferation,” the researchers wrote.
This antidepressant is very well-tolerated and described as being able to effectively cross the blood–brain barrier.
The team next tested the therapeutic effects of clomipramine in a mouse model of human MS, so-called experimental autoimmune encephalomyelitis (EAE) mice. They used different models, one of acute and two others of chronic MS.
In the acute EAE model, early treatment with clomipramine completely suppressed clinical signs of the disease, with the therapy reducing inflammation and microglial activation (the activation of specific immune cells in the central nervous system), and preserving nerve cells.
In the two mouse models of chronic EAE, the MOG-EAE and the immunized Biozzi ABH mouse (known to resemble more closely human secondary progressive MS), researchers found that clomipramine therapy given at symptom onset also led to a significant reduction of clinical severity, namely in the degree of paralysis.
No EAE model fully captures all aspects of progressive MS, however, so the therapy needs further testing in humans.
“Based on promising preclinical data, our long-term objective is to study clomipramine as well as other therapeutics selected in the screening process on patients in clinical studies,” Faissner said.
Since clomipramine is approved “there is ample clinical experience regarding [its] potential side effects,” meaning that researchers can start clinical trials to assess its efficacy in MS more quickly, skipping the Phase 1 trials in healthy volunteers essential to determining a potential therapy’s tolerance.