Eperisone, Muscle Relaxant, Seen to Safely Treat IPF in Mouse Model
Eperisone — an oral muscle relaxant used to treat muscle spasms and rigidity — significantly eased lung scarring and improved lung function in a mouse model of idiopathic pulmonary fibrosis (IPF), a study shows.
Comparisons between eperisone and the approved IPF therapies Ofev (nintedanib) and Esbriet (pirfenidone) in cell and animal models of the disease also suggest that eperisone may be a safer and more effective option.
While its effectiveness may be related to its specific, suppressing effects on fibroblasts — cells involved in lung fibrosis (scarring) — further studies are needed to confirm this and eperisone’s therapeutic potential in IPF patients, the researchers noted.
The study, “Therapeutic effects of eperisone on pulmonary fibrosis via preferential suppression of fibroblast activity,” was published in the journal Cell Death Discovery.
IPF, a form of pulmonary fibrosis with no clear cause, is characterized by damage to alveolar epithelial cells (AECs) and excessive wound healing that leads to fibrosis and increased stiffness of lung tissue, making it difficult for patients to breathe. AECs are the cells that line the tiny air sacs in the lungs where gases are exchanged.
This excessive wound healing is associated with fibroblast maturation into myofibroblasts — the main drivers of lung fibrosis that overly produce extracellular matrix (ECM) molecules. ECM molecules surround and support cells, but in excess can cause tissue scarring.
In addition, AECs in the lungs of IPF patients are more likely to die than fibroblasts, resulting in a higher proportion of fibrosis-mediating fibroblasts.
As such, “compounds that are not toxic to alveolar epithelial cells but exert their effects preferentially on lung fibroblasts are promising candidates for IPF therapy,” the researchers wrote.
Ofev and Esbriet are known to ease lung fibrosis and slow lung function decline. But these approved therapies can also cause side effects, such as higher-than-normal levels of liver damage markers and gastrointestinal problems. Safer therapies that are at least as effective are needed.
A research team in Japan looked at a repository of approved therapies for other conditions. They were screening for those showing greater potential to specifically suppress the growth of lung fibroblasts, without affecting other cells.
Repurposing compounds already approved — and thus tested for safety — for one health condition to their potential in treating another disease helps to accelerate the development of a safe and effective treatment while reducing costs.
The screen identified idebenone and eperisone as those showing the greatest potential. Idebenone is used to treat Alzheimer’s disease and other brain-damaging conditions, while eperisone is a central muscle relaxant agent approved in several Asian countries for treating musculoskeletal disorders causing muscle spasm and pain.
Given that idebenone’s preferential suppression of fibroblast activity and its efficacy in a mouse model of IPF were reported in a previous study, the current work focused on eperisone.
Survival analyses on lab-grown human AECs and lung fibroblasts showed that eperisone significantly reduced the number of fibroblasts in a dose-dependent manner, while AEC survival was nearly unchanged.
While TGF-beta 1, a major pro-fibrotic molecule, promoted fibroblast maturation into myofibroblasts, use of the therapy significantly suppressed such maturation in the presence of TGF-beta 1.
Notably, treating these lab-grown lung cells with either Ofev or Esbriet led to distinct outcomes. While Ofev reduced the survival of both cell types and in a similar way, Esbriet had no major impact on any of them.
In addition, nine days of treatment with oral eperisone significantly reduced lung fibrosis and nearly restored lung function in a mouse model of IPF with established fibrosis at treatment start. These benefits were accompanied by a significant suppression of fibroblast maturation, reaching levels similar to healthy mice.
In contrast, Ofev and Esbriet were found to be less effective than eperisone at easing lung fibrosis and improving lung function in this animal model.
The team then looked at eperisone’s effects in the liver and gastrointestinal tract of these mice by using a dose five times higher than that showing therapeutic benefits in the previous analysis.
Results showed that eperisone treatment did not change the levels of pancreatic, liver, and kidney damage markers, nor cause gastrointestinal problems or damage in these mice.
These findings suggest that eperisone “may be safer and more therapeutically beneficial for IPF patients than current therapies,” the researchers wrote, adding that “its current clinical dose (150 mg/day) is expected to be effective against IPF.”
Further studies are needed to determine the molecular mechanisms behind eperisone’s anti-fibrotic effects, which could also be of benefit for other fibrotic conditions, the team noted.