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Blocking certain inflammatory signaling pathways may be one way to reverse nerve cell alterations that drive the symptoms of <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), according to preclinical research using a mouse model of the disease.
In the mice, an ALS-associated mutation in the FUS gene caused caused motor neurons — the nerve cells involved in motor control — to lose the branches and connections needed to function properly. It also disrupted cellular energy production and caused neuroinflammation, a complex inflammatory response typically seen within the brain or spinal cord.
A blockade of the inflammatory signaling pathway NF-kappa B was shown to reverse these cellular changes and improve motor and cognitive function in these animals.
In addition to further elucidating the role of FUS in driving <a href="https://alsnewstoday.com/symptoms-of-als/">ALS symptoms</a>, the study indicates that &#8220;modulation of the [NF-kappa B] pathway &#8230; is an important therapeutic approach to attenuate disease,&#8221; the researchers wrote.
The study, &#8220;<a href="https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-023-01671-1">Neuronal dysfunction caused by FUSR521G promotes ALS-associated phenotypes that are attenuated by NF-κB inhibition</a>,&#8221; was published in <a href="https://actaneurocomms.biomedcentral.com/">Acta Neuropathologica Communications</a>.
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<h3>Investigating the impact of FUS gene mutations on motor neurons</h3>
ALS is characterized by the degeneration of motor neurons, the specialized nerve cells involved in motor control. <a href="https://alsnewstoday.com/causes-of-als/#Genetics_of_ALS">Mutations</a> in FUS are thought to underlie the disease in about 5%-10% of people with <a href="https://alsnewstoday.com/forms-of-als-familial-als/">familial ALS</a> and less than 1% of those with <a href="https://alsnewstoday.com/sporadic-als/">sporadic ALS.</a>
These mutations lead to the production of an abnormal version of the FUS protein that toxically accumulates in the wrong part of the cell. While the FUS protein is normally seen in the nucleus — the core of the cell where DNA is housed — ALS-associated FUS instead gathers outside the nucleus in the cytoplasm and disturbs cellular function.
In mouse models, FUS mutations are associated with motor and cognitive deficits, activation of cells that promote inflammation, and structural changes to motor neurons that are also seen in the human condition. Specifically, motor neurons are found to lose dendrites, the branches they use to reach out to and communicate with other cells. The synapses, or connections, made with other cells via structures called dendritic spines also are lost.
Despite this knowledge, gaps still remain in scientists&#8217; understanding of how FUS mutations lead to these neuronal changes and contribute to disease progression.
Now, a team of researchers from Laval University, in Canada, genetically engineered mice to house a human ALS-associated FUS mutation specifically in neurons, using them to further explore the effects of FUS. 
At 1 month old, these mutant mice exhibited cognitive defects and reduced dendritic branching of upper motor neurons — the motor neurons that originate in the brain and travel to the spinal cord.
By 6 months of age, loss of dendritic branches and synapses had spread to affect the lower motor neurons, or those that travel from the spinal cord and innervate the muscles to coordinate movement. This was accompanied by progressive motor impairments.
A number of other cellular alterations also corresponded with the deteriorating cognitive and motor function of the mice. This included mis-localization of mutant FUS to the cytoplasm and signs of dysfunctional mitochondria, which are cells&#8217; energy-producing organelles.
Moreover, activation of <a href="https://alsnewstoday.com/news/astrocytes-microglia-als-friends-foes-amyotrophic-lateral-sclerosis/">astrocytes and microglia</a>, the nerve support cells (glia) that can drive neuroinflammation, was observed in the symptomatic mice.
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<h3>Researchers use compound based on plant used in traditional Indian medicine</h3>
Activation of the NF-kappa B inflammatory signaling pathway — a series of molecular events that cells use to respond to signals of inflammation or infection — is thought to promote glial activation in ALS and other neurodegenerative diseases. That, in turn, has been linked to motor neuron damage and disease progression.
As such, the researchers aimed to investigate whether blocking inflammatory signaling might help restore more normal nerve cell connections and ease symptoms.
To that end, they treated the mice with the NF-kappa B inhibitor IMS-088, a synthetic compound based on the naturally occurring Ashwagandha plant.
That plant has been &#8220;used for thousands of years in traditional Indian medicine,&#8221; Chantelle F. Sephton, PhD, assistant professor at the University of Laval and the study&#8217;s senior author, said in a <a href="https://salledepresse.ulaval.ca/2024/01/10/sla-bloquer-linflammation-pour-reduire-les-symptomes-a:7163fae3-28bf-45c7-ba00-218cd8782b65">press release</a>.
The treatment reversed many of the observed cellular deficits, leading to restored motor neuron dendrites and synapses, reduced glia activation, decreased FUS mis-localization, and increased mitochondrial function. This was accompanied by cognitive and motor improvements.
&#8220;Neurons regenerate without activated immune cells,&#8221; Sephton noted.
&#8220;The dendrites of motor neurons start to grow and make connections again, increasing the number of synapses between motor neurons and muscles,&#8221; Sephton said.
Lab studies of neurons from the mice further indicated that IMS-088 treatment promotes more normal mitochondrial function.
Altogether, the researchers believe the findings demonstrate the key role of neuroinflammation in ALS disease processes.
&#8220;Future studies will examine the mechanistic actions of inhibiting the [NF-kappa B] pathway on FUS function and the dynamic interplay between pro-inflammatory signals and mitochondrial function,&#8221; the team concluded.
The findings likely also have implications for other related diseases, including frontotemporal dementia (FTD), a neurodegenerative disease that has significant clinical and cellular overlap with ALS, as well as other inflammatory neurodegenerative conditions.

Blocking signaling pathways may reverse nerve cell changes in ALS

Inhibiting the NLRP3 inflammasome — an immune system protein complex believed to contribute to the inflammation that drives <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) — alone was not sufficient to ease spinal cord inflammation in a mouse model of the disease, according to recent research.
NLRP3 is overactive in ALS and has been a focus of therapeutic development, but there are other inflammasome complexes that could be involved.
<a href="https://www.zyversa.com/">ZyVersa Therapeutics</a> believes the study findings support its development of inflammasome inhibitors that target multiple pathways — not just NLRP3 — to control inflammation in ALS and other inflammatory diseases.
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“The research &#8230; reinforces the need to inhibit more than the NLRP3 inflammasome pathway to control inflammation associated with activation of multiple inflammasomes,” Stephen C. Glover, co-founder, chairman, CEO and president of ZyVersa, said in a <a href="https://www.globenewswire.com/news-release/2023/09/12/2741445/0/en/ZyVersa-Therapeutics-Announces-Research-Published-in-Frontiers-in-Immunology-Reinforcing-IC-100-s-Rationale-for-Inhibiting-Multiple-Inflammasomes-to-Control-Inflammation-in-Various.html">press release</a>.
The study, &#8220;<a href="https://www.frontiersin.org/articles/10.3389/fimmu.2023.1190219/full">Divergent functional outcomes of NLRP3 blockade downstream of multi-inflammasome activation: therapeutic implications for ALS</a>,&#8221; was published in <a href="https://www.frontiersin.org/journals/immunology">Frontiers in Immunology</a>. It was funded by <a href="https://www.ucb.com/">UCB BioPharma</a> and all study authors are UCB employees.
Inflammasomes are protein complexes that sense threats (i.e., microbes or other foreign molecules) and respond by inducing inflammatory attacks against them. Their excessive activation can contribute to the chronic inflammation that&#8217;s involved in a wide range of diseases.
<h3>Understanding inflammasomes</h3>
There are several types of <a href="https://www.zyversa.com/inflammasomes">inflammasomes</a> in the body. Each contains a unique sensor molecule that responds to different environmental threats.
That sensor binds to ASC, a protein that recruits caspase-1, which initiates the production of pro-inflammatory molecules called cytokines and inflammatory cell death, or pyroptosis. Additional ASC molecules gather and form structures called specks that are critical for perpetuating cytokine release.
The most widely studied inflammasome in the context of neurological diseases is the type that contains the NOD-Like Receptor Family Pyrin Domain Containing 3  (NLRP3) sensor molecule.
Indeed, a growing body of evidence indicates that activation of NLRP3 contributes to inflammation and nerve cell death in ALS. As such, it is <a href="https://alsnewstoday.com/news/trial-potential-als-therapy-vtx3232-sees-1st-healthy-volunteer-dosed/">being investigated</a> as a potential therapeutic target for the neurodegenerative disease.
Yet, evidence suggests that other inflammasome types also are dysregulated in ALS and other neurological diseases. As such, ZyVersa believes that targeting NLRP3 alone may not be enough to dampen inflammation in these conditions.
<h3>Investigational antibody IC 1oo inhibits the ASC protein</h3>
The company is developing IC 1oo, an investigational antibody that inhibits the ASC protein. Because ASC is integral to the formation and function of multiple inflammasome types, including NLRP3, its blockade could inhibit the initiation of inflammatory signaling across multiple disease-associated complexes.
“ZyVersa’s Inflammasome ASC inhibitor IC 100 is designed to inhibit formation of multiple types of inflammasomes to attenuate initiation of the inflammatory cascade, and to inhibit ASC specks to attenuate perpetuation of damaging inflammation,” Glover explained.
IC 100 has been found to <a href="https://investors.zyversa.com/static-files/64964310-ab95-4a06-bc47-dd44c63dc5c7">suppress inflammation</a> in preclinical studies, including in models of <a href="https://multiplesclerosisnewstoday.com/multiple-sclerosis-overview/">multiple sclerosis</a>, age-related inflammation, <a href="https://alzheimersnewstoday.com/what-is-alzheimers-disease/">Alzheimer&#8217;s disease</a>, traumatic brain injury, and spinal cord injury.
In the study, scientists examined the impacts of specific NLRP3 inhibition in various cell and animal models of ALS. Various immune cell types from healthy people and ALS patients were exposed to inflammatory stimuli meant to activate the NLRP3 inflammasome.
Genetic or pharmacological NLRP3 inhibition in these cells led to reduced release of cytokines and less pyroptosis. However, in cells stimulated to activate other inflammasome complexes, the NLRP3 inhibitor, called MCC950, led to variable responses in terms of cytokine release or pyroptosis.
In healthy mice and an ALS mouse model, MCC950 also was able to block NLRP3-induced pyroptosis, but it failed to prevent cell death induced by other types of inflammasomes.
Notably, in a mouse model of ALS, NLRP3 inhibition alone was not sufficient to ease spinal cord inflammation.
<h3>Limitations of NLRP3 inhibition</h3>
&#8220;Our study highlights potential limitations of NLRP3 inhibition in attenuating cytokine release and inflammatory cell death when other inflammasomes are active,&#8221; the researchers wrote.
&#8220;As such we suggest future therapeutic focus in neurological indications with multi-inflammasome activation should be on converging executer nodes downstream of inflammasomes, rather than single inflammasome-inhibiting approaches,&#8221; they added.

NLRP3 inhibition alone does not ease ALS inflammation: Study

Dimethyl fumarate (DMF) — an oral medication approved for <a href="https://multiplesclerosisnewstoday.com/multiple-sclerosis-overview/">multiple sclerosis</a> — and H-151, an experimental treatment, can suppress inflammatory and abnormal immune pathways thought to be involved in <a href="https://alsnewstoday.com/sporadic-als/">sporadic amyotrophic lateral sclerosis</a> (ALS).
These are the findings of a study using immune cells from sporadic ALS patients that also showed DMF worked better when given in combination with epoxyeicosatrienoic acids (EETs), signaling fatty molecules that can be found in certain foods.
The results suggest DMF, in combination with a diet rich in certain fatty molecules, and H-151 could be therapeutic candidates for sporadic ALS patients not responding to currently available therapies, according to a research team led by scientists at the University of California, Los Angeles (UCLA).
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<h3>Researchers plan to file application to test medications in clinical trial</h3>
With these preclinical data, the researchers plan to file an application to test the medications in a clinical trial, according to a <a href="https://www.uclahealth.org/news/researchers-report-advance-immune-therapy-against-als">UCLA press release</a>. But before moving to clinical testing, they’ll do more research on immune cells of more patients.
The study, “<a href="https://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.202300573R">Therapy of autoimmune inflammation in sporadic amyotrophic lateral sclerosis: Dimethyl fumarate and H-151 downregulate inflammatory cytokines in the cGAS-STING pathway</a>,” was published in the <a href="https://faseb.onlinelibrary.wiley.com/journal/15306860">FASEB Journal</a>.
ALS is a progressive neurodegenerative disease that affects motor neurons, the specialized nerve cells that control voluntary movement, in the brain and spinal cord. Motor neuron damage and death result in muscle weakness, breathing difficulties, and <a href="https://alsnewstoday.com/symptoms-of-als/">other symptoms</a> that worsen over time.
While the exact <a href="https://alsnewstoday.com/causes-of-als/">causes of ALS</a> remain largely unclear, they are thought to involve a combination of genetic and environmental factors. In sporadic ALS, the most common and non-inherited form of the disease, evidence suggests the involvement of inflammation and autoimmunity, or abnormal immune attacks against the body’s own healthy molecules.
The UCLA team, along with a colleague at Saint John&#8217;s Cancer Institute, in California, first set out to assess exactly what immune cells are involved in sporadic ALS and how they behave over the course of the disease.
By analyzing spinal cord samples from a 68-year-old man with sporadic ALS, the researchers showed that the spinal cord was invaded by cytotoxic T-cells, a type of immune cell that can kill microbes and certain cells.
These cells tested positive for interleukin (IL)-17A, a pro-inflammatory molecule, and granzyme B, an enzyme that can trigger nerve cell death and long-lasting inflammation.
[quote=&#8221;center&#8221;]Future investigation and eventually clinical trials need to determine whether the combination of H-151 with DMF would be synergistic against autoimmune inflammation in [sporadic ALS] patients.[/quote]
<h3>Study analyzed immune cells from 8 men with sporadic ALS, 4 healthy people</h3>
Given that immune cells travel from the blood to tissues throughout the body, the researchers analyzed the gene activity profile of immune cells in blood samples from eight men with sporadic ALS and four healthy people (three women and one man).
In the early stages of disease, genes coding for the pro-inflammatory molecules IL-12A, IFN-gamma, and TNF-alpha, as well as granzymes, were more active in patients than in healthy controls.
Later on, at more advanced stages of disease, immune cells turned on genes coding for IL-17B, a signaling molecule involved in autoimmune reactions, as well as two chemokines called CXCL9 and CXCL10. Chemokines can attract immune cells, including cytotoxic T-cells, into the brain and spinal cord.
In turn, genes coding for the anti-inflammatory molecules IL-10 and TGF-beta became less active over the course of the disease.
The researchers then tested whether certain medications — DMF and H-151 — could tone down these inflammatory and autoimmune signals linked to sporadic ALS.
Sold as <a href="https://multiplesclerosisnewstoday.com/tecfidera-dimethyl-fumarate-multiple-sclerosis/">Tecfidera</a> by <a href="https://www.biogen.com">Biogen</a> and also available as generic versions, DMF is an oral small molecule approved for treating multiple sclerosis and psoriasis, two autoimmune conditions. It works by reducing inflammation and modulating immune system activity.
H-151, an experimental treatment, can decrease the production of pro-inflammatory molecules by lab-grown immune cells. It suppresses a signaling pathway called cGAS/STING, which is involved in immune cell activation.
Lab-grown immune cells from two sporadic ALS patients, a 40-year-old man and a 65-year-old woman, were exposed to either DMF alone or in combination with EETs, or H-151.
EETs are a type of fatty molecule with anti-inflammatory effects that are derived from arachidonic acid, a polyunsaturated fatty acid (PUFA). PUFAs are generally considered good fats, being found in fatty fish, such as salmon and mackerel, seafood, nuts, and certain seeds.
Results showed that both DMF and H-151 reduced the activity of genes coding for granzymes and pro-inflammatory molecules, such as IL-6, IL-15, and IFN-gamma. The effect of DMF was even greater when combined with EETs.
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<h3>Both medications suppressed inflammatory, autoimmune signaling in cells</h3>
These findings indicate that both medications suppressed “inflammatory and autoimmune signaling” in immune cells from sporadic ALS patients, the team wrote, supporting “their investigation in a clinical trial.”
The researchers noted that DMF has been previously tested in an ALS clinical trial, in combination with the standard treatment riluzole (sold as <a href="https://alsnewstoday.com/rilutek-riluzole-for-als/">Rilutek</a>, <a href="https://alsnewstoday.com/exservan-riluzole-oral-film/">Exservan</a>, and <a href="https://alsnewstoday.com/tiglutik-riluzole-oral-suspension/">Tiglutik</a>). Results showed that while the combination treatment was generally safe, it did not result in significant benefits in terms of ALS progression.
The current study’s results “suggest that DMF may be effective when combined with a diet rich in certain polyunsaturated fatty acids,” the team wrote.
“Future investigation and eventually clinical trials need to determine whether the combination of H-151 with DMF would be synergistic against autoimmune inflammation in [sporadic ALS] patients,” the researchers wrote. A synergy occurs when the combined effect of two medications is greater than the sum of their separate effects.

Tag: Inflammation

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