Summary: A new study published in Nature Communications reports that the antidepressant clomipramine may relieve symptoms of primary progressive multiple sclerosis.
Source: RUB.
The antidepressant clomipramine shows promise for progressive multiple sclerosis
Researchers working with Professor V. Wee Yong (University of Calgary) and Dr. Simon Faissner (Ruhr-Universität Bochum) conducted a large-scale screen of approved medicines and found that the antidepressant clomipramine may help protect the nervous system in progressive multiple sclerosis (MS). Their preclinical results were published in Nature Communications on December 19, 2017.
Targeting a form of MS with few treatment options
While a dozen drugs are approved for relapsing-remitting MS, effective treatments for progressive forms of the disease remain scarce. Progressive MS, which can develop after years of relapsing-remitting disease or be present from onset, often involves continuous neurodegeneration and chronic inflammation that respond differently to therapy. The research team therefore focused on identifying compounds already known to be safe in humans that might address mechanisms relevant to progressive MS.
Drug repurposing approach and screening process
The researchers began by screening 1,040 approved, generic drugs to identify candidates suitable for repurposing. From that initial set they selected 249 medications that are well tolerated and known to cross into the central nervous system—important because progressive MS involves chronic inflammation within the brain and spinal cord. Using cell-based assays, the team tested these 249 drugs for their ability to protect neurons from iron-mediated toxicity, a process that contributes to nerve cell injury in MS when iron is released from damaged cells.
Of the 249 drugs, 35 prevented iron-induced damage in culture. Those 35 were then evaluated further for additional protective properties: whether they reduced mitochondrial damage (mitochondria are critical for neuronal energy supply), whether they limited oxidative stress, and whether they influenced immune cell activity, including the actions of lymphocytes that can attack the insulating myelin around nerve fibers.
Clomipramine emerges as a lead candidate
Among the promising candidates, the tricyclic antidepressant clomipramine stood out. In follow-up experiments, clomipramine not only protected neurons from iron-mediated toxicity but also reduced oxidative stress and suppressed immune cell functions relevant to MS, including effects on both T and B lymphocytes. These complementary actions suggested the drug might address multiple drivers of progressive disease.
Positive results in animal models
To test efficacy in vivo, the researchers used mouse models of MS. In a model resembling relapsing-remitting MS, clomipramine treatment markedly reduced neurological symptoms, lowered inflammatory responses, and preserved nerve fibers. In a second model that mimics aspects of progressive MS, clomipramine also reduced clinical signs—particularly when treatment began immediately after the first observable symptoms. Treated animals showed less paralysis and less tissue damage compared with controls given placebo.
Plans for clinical evaluation
Dr. Faissner, who participated in the Calgary study as a visiting scholar and returned to Bochum in 2017, emphasizes that the goal is to move promising repurposed drugs rapidly into clinical trials. An advantage of testing generic, approved drugs is the extensive clinical experience already available regarding their safety and side-effect profiles, which can reduce the need for early-phase tolerance studies in healthy volunteers. Nevertheless, organizing and funding clinical trials remains a significant challenge.
Progressive multiple sclerosis: a brief overview
Multiple sclerosis is a leading cause of neurological disability in young adults in Western countries. The disease is driven by immune cells that damage the myelin sheath, the protective insulation around nerve fibers, producing symptoms such as visual problems, weakness, numbness, and coordination difficulties. About 85% of patients initially experience a relapsing-remitting course with distinct attacks and periods of recovery. Over time, many of these patients develop gradual neurological decline—progression—usually after 15 to 20 years. Approximately 10% of patients have progressive disease from the outset, without relapses.
About the research and next steps
The study presents a systematic screening approach to repurpose generic, orally available medications that target multiple mechanisms implicated in progressive MS—iron-mediated neurotoxicity, lymphocyte-driven inflammation, and oxidative stress. The authors highlight clomipramine for further development because it demonstrated neuroprotective and immunomodulatory effects in cell assays and beneficial outcomes in animal models of both relapsing and progressive disease phases. The researchers intend to pursue clinical studies to evaluate clomipramine and other selected compounds in patients.
Article and research details
Source: Simon Faissner – RUB
Publisher: NeuroscienceNews.com (organized coverage)
Image source: Public domain image used by NeuroscienceNews.com
Original research: Faissner S., Mishra M., Kaushik D.K., Wang J., Fan Y., Silva C., Rauw G., Metz L., Koch M., & V. Wee Yong. “Systematic screening of generic drugs for progressive multiple sclerosis identifies clomipramine as a promising therapeutic.” Nature Communications. Published online December 19, 2017. DOI: 10.1038/s41467-017-02119-6.
Abstract (paraphrased)
Progressive multiple sclerosis remains difficult to treat because the disease is driven by multiple, overlapping mechanisms such as iron-mediated neurotoxicity, lymphocyte activity, and oxidative stress. The authors performed a systematic screen of generic, orally available drugs that penetrate the central nervous system and identified 35 compounds that protect neurons from iron-related damage in culture. Several antidepressants and antipsychotics among these also reduced T-cell proliferation and oxidative stress. The study focused on clomipramine, which additionally inhibited B-lymphocyte activity. In mouse models of experimental autoimmune encephalomyelitis, clomipramine improved clinical signs in both acute and chronic phases, reduced inflammation and microglial activation, and preserved axons. The screen offers a practical pathway to advance repurposed medications for progressive MS into clinical trials, with clomipramine recommended for further development.