Lung disease treatment shown to ease symptoms in Huntington’s rat model
Roflumilast, also seen to reduce brain inflammation, may be novel therapy option
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Roflumilast, an oral therapy approved in the U.S. to treat inflammatory lung disease, was shown to reduce brain inflammation, promote the health of connections between brain cells, and ease symptoms in a rat model of Huntington’s disease.
According to the research team, from Cairo University in Egypt, these beneficial effects were driven by reductions in pyroptosis and ferroptosis, two proinflammatory forms of programmed cell death previously shown to be associated with neurodegeneration in Huntington’s. The researchers noted that “conclusively, roflumilast exerts therapeutic and neuroprotective effects in [disease]-like neurodegeneration.”
The scientists noted that further research is needed to evaluate this therapy as a potential Huntington’s treatment.
Still, “these findings may establish the impact of pyroptosis and ferroptosis alleviation in HD [Huntington’s disease] and pave the way for roflumilast as a novel therapeutic option in HD management,” the team wrote.
The study, “Roflumilast Elicits Therapeutic and Neuroprotective Effects in 3-Nitropropionic Acid-Induced Huntington’s Disease-Like Neurodegeneration in Rats by Mitigating NLRP3 Inflammasome-Mediated Pyroptosis, Ferroptosis, and Glial Activation,” was published in the journal Neurochemical Research by a four-person team.
Huntington’s is a genetic disorder in which certain brain cells progressively sicken and die. This causes a wide range of symptoms, including movement issues, cognitive difficulties, and behavioral changes.
Inflammation in the brain, known as neuroinflammation, is thought to play a role in driving the progression of Huntington’s and other neurological diseases.
“The treatments available only aim to control HD symptoms, with no current treatment to prevent its progression,” the researchers wrote. That gap “[opens] the path for discovering new drugs for HD management,” according to the team.
Investigating the potential protective effects of roflumilast in HD
Roflumilast is approved in the U.S. under the brand name Daliresp for chronic obstructive pulmonary disease, a condition marked by lung inflammation. The medication works to reduce inflammation by blocking phosphodiesterase-4 (PDE-4), a protein that regulates inflammation.
PDE-4 is also produced in the brain, and roflumilast is able to cross from the blood into the brain.
There’s an increasing body of evidence suggesting that this therapy may have protective effects in neurological diseases such as Huntington’s “through its anti-inflammatory and antioxidant effects,” the researchers wrote.
In this preclinical study, the research team evaluated the effects of roflumilast in a rat model of Huntington’s-like disease. In the model, brain damage is induced by injecting the rats with a nerve-damaging toxin called 3-nitropropionic acid (3-NP).
Rats given 3-NP showed markedly impaired performance on several motor function and muscle strength tests. These deficits were significantly eased when the rats were treated with roflumilast, the data showed.
Importantly, the team noted, comparable results were obtained when the medication was started 21 days before 3-NP — and was thus given as a preventive treatment — or seven days after 3-NP, as a therapeutic approach.
“Our results revealed that roflumilast administration, either as a preventative agent or a therapy, dramatically improved the behavioral and motor function of 3-NP-injected rats,” the researchers wrote.
Treatment led to drop in markers of nerve cell death
The rat model also showed reduced levels of the signaling molecules p-CREB and BDNF, which are key for maintaining healthy synapses, or connections between nerve cells, in the striatum. That part of the brain is hit hardest by Huntington’s. Roflumilast treatment significantly increased striatal levels of these two molecules, per the data.
Further analyses indicated that roflumilast also significantly reduced striatal levels of several markers of pyroptosis and ferroptosis, two pro-inflammatory types of programmed cell death that have been “recently linked to neuronal loss in HD,” the researchers wrote.
Pyroptosis is typically triggered by infection or danger signals, while ferroptosis depends on iron and is marked by the breakdown of fatty molecules in cell membranes. Both usually occur when cells are under extreme stress, and cause dying cells to release proinflammatory signaling molecules to alert the rest of the body that something is wrong.
In diseases like Huntington’s, where there’s continual damage, this may contribute to ongoing inflammation that helps to drive the disease.
Roflumilast was also associated with significantly higher nerve cell survival in the striatum of rats given 3-NP. The therapy also reduced inflammatory activation of astrocytes and microglia, brain cells that normally help promote nerve health and protect the brain from infections but go awry in neurodegenerative diseases.
Researchers call for clinical trials to test treatment in people
The researchers noted that the treatment effects were generally more pronounced when roflumilast was given as a therapeutic approach. The team hypothesized that this may be because 3-NP can compromise the integrity of a barrier that prevents potentially harmful and large molecules in circulation from entering the brain, thereby increasing the amount of roflumilast that enters the brain.
“To our knowledge, this is the first study to demonstrate the dual [preventive] and therapeutic effects of roflumilast in an experimental model of HD via concurrent modulation of pyroptosis, ferroptosis, and neuroinflammation,” the scientists wrote.
Additional statistical analyses showed that reductions in pyroptotic and ferroptotic markers and increases in markers of synapse health were significantly associated with improvements in tests of motor function and muscle strength.
To our knowledge, this is the first study to demonstrate the dual [preventive] and therapeutic effects of roflumilast in an experimental model of [Huntington’s disease]. … Clinical trials are necessary to confirm this therapeutic approach, investigate [roflumilast’s] optimal dosing, and evaluate its efficacy [and] safety profile.
“These findings highlight the multifaceted neuroprotective potential of roflumilast and offer new insights into its role in targeting emerging [disease-driving] mechanisms in HD,” the researchers wrote.
Still, the team emphasized that the 3-NP model does not carry the genetic cause of Huntington’s and does not represent “the full disease picture,” and that further studies in genetic animal models are needed.
Following that, “clinical trials are necessary to confirm this therapeutic approach, investigate [roflumilast’s] optimal dosing, and evaluate its efficacy, safety profile, and individual response variability,” the team concluded.
