Histamine-Related Genes May Become Biomarkers and Therapeutic Targets for ALS, Mouse Study Suggests

Histamine-Related Genes May Become Biomarkers and Therapeutic Targets for ALS, Mouse Study Suggests
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Histamine-related genes are promising disease biomarkers and therapeutic targets to slow amyotrophic lateral sclerosis (ALS) progression, a mouse study suggests.

The study, “Histaminergic transmission slows progression of amyotrophic lateral sclerosis,” was published in the Journal of Cachexia, Sarcopenia and Muscle.

ALS is a progressive neurodegenerative disorder caused by the gradual destruction of motor neurons — nerve cells responsible for voluntary muscle control — in the spinal cord and in the brain.

“A number of different genes, aberrant cellular pathways, and molecular mechanisms are involved in ALS, and strong evidence points to the impairment of the neuro‐immune axis in causing motor neuron death and muscular wasting in both animal models and patients,” the researchers wrote.

Histamine is a neurotransmitter — a chemical substance that allows communication between nerve cells — that also has important immune functions, especially controlling the body’s inflammatory response and protecting neurons from damage.

“[D]rugs enhancing histamine transmission, such as histidine or H3R [histamine receptor] antagonists, exhibit beneficial effects in animal models of Parkinson’s disease, attention‐deficit/hyperactivity disorders, schizophrenia, dementia, and depression and are under scrutiny in clinical trials for Alzheimer’s disease and multiple sclerosis. Their efficacy in affecting ALS disease progression has still to be proven,” the researchers wrote.

In this study, a group of scientists from the IRCCS Fondazione Santa Lucia in Italy and their collaborators set out to explore the potential use of histamine as a disease biomarker and therapeutic target for ALS.

To explore histamine’s potential as an ALS biomarker, researchers used a combination of techniques that allowed them to analyze the gene expression profiles, as well as the number of genetic variants in post-mortem spinal cord samples from patients who had been diagnosed with sporadic ALS.

To assess the therapeutic potential of histamine release in ALS, they administered a brain-permeable histamine precursor called histidine by an intraperitoneal (through the abdominal wall) injection to SOD1‐G93A mice (ALS mouse model) displaying typical signs of ALS, and evaluated the animals’ clinical improvement.

Genetic analyses revealed a total of 13 histamine-related genes that were deregulated in spinal cord samples from two ALS patient subgroups. These genes were involved in histamine metabolism, release, transport and receptors’ function.

Interestingly, some of these genes were located in regions that had been associated previously with the onset of ALS, confirming their potential as future ALS biomarkers.

In addition, experiments performed in SOD1‐G93A mice showed that histidine treatment led to improvements in animals’ lifespan, motor function, microgliosis (overactivation of microglia — nerve cells that support neurons — caused by damage to the brain) and motor neurons’ survival.

“Our gene set/pathway enrichment analyses and preclinical studies started at the onset of symptoms establish that histamine-related genes are modifiers in ALS, supporting their role as candidate biomarkers and therapeutic targets,” the researchers wrote.

“Our results now add ALS disease to the growing promise of histaminergic strategies. By proposing the histamine modulation as a candidate mechanism to be further challenged in ALS, we trust not only that histamine will answer to the many questions still unsolved about ALS but also that a viable histamine‐related therapy might be proven to work for patients. Our further trials will validate H3 antagonists against ALS progression,” they added.

Joana holds a BSc in Biology, a MSc in Evolutionary and Developmental Biology and a PhD in Biomedical Sciences from Universidade de Lisboa, Portugal. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that made up the lining of blood vessels — found in the umbilical cord of newborns.
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Joana holds a BSc in Biology, a MSc in Evolutionary and Developmental Biology and a PhD in Biomedical Sciences from Universidade de Lisboa, Portugal. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that made up the lining of blood vessels — found in the umbilical cord of newborns.
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