Anti-Inflammatory Delays ALS Symptoms and Progression in Mouse Model, Study Reports

Cromolyn sodium — a U.S. Food and Drug Administration (FDA)-approved anti-inflammatory medication — delayed disease onset and prevented motor neuron degeneration and loss in a mouse model of amyotrophic lateral sclerosis (ALS), researchers report.

These neuroprotective effects were accompanied by a decrease in inflammation, highlighting the potential role of inflammatory processes in ALS. Findings also suggest that anti-inflammatories like cromolyn sodium might be potential treatments.

The study, “Cromolyn sodium delays disease onset and is neuroprotective in the SOD1G93A Mouse Model of amyotrophic lateral sclerosis,” was published in the journal Scientific Reports.

While the underlying cause of ALS remains to be fully understood, increasing evidence suggests that neuroinflammation plays an important part in the disease’s development and progression.

An abnormal activation of both microglial cells (the main immune defense of the brain and spinal cord) and astrocytes (cells that support and protect neurons) has been implicated in neuroinflammation and excessive neuronal (nerve cell) death in ALS.

Studies also suggest that during ALS progression, microglia shift from an anti-inflammatory and neuroprotective state to one that is pro-inflammatory and neurotoxic. (Activated cells are those that are changing in response to a stimulus.)

“One therapeutic approach would be to use pharmacological agents that convert microglial cells from the pro-inflammatory to an anti-inflammatory and neuroprotective state,” the researchers wrote.

Previous studies in cell and animal models of Alzheimer’s disease have shown that cromolyn sodium has neuroprotective properties, working to alter microglial cell activation.

Cromolyn sodium is FDA approved to treat mastocytosis, a rare disease associated with higher-than-normal levels of mast cells, immune cells involved in inflammatory and allergic reactions. It is also used as an over-the-counter treatment for allergies, such as asthma.

Researchers at Harvard-affiliated Massachusetts General Hospital (MGH) evaluated cromolyn sodium’s effectiveness in treating an animal model of ALS called SOD1 transgenic mice.

They analyzed ALS-associated symptoms, survival, neuromuscular function, motor neuron degeneration and survival, as well as inflammation-associated cells and molecules in ALS and healthy mice, some of whom were given cromolyn sodium.

Use of cromolyn sodium was seen significantly delay ALS symptom onset and less some disease-associated motor problems in the ALS mice compared with diseased mice left untreated. Evidence of motor neuron damage or loss in these mice include hind leg shaking, foot dragging, toes curling under while walking, and rigid paralysis.

However, only treated female mice showed a significant benefit in terms of extended survival.

Further analyses indicated that cromolyn sodium significantly reduced the loss of motor neurons in the spinal cord, and the degeneration of connections between motor nerve cells and muscle cells in treated ALS mice.

In addition, treated ALS mice showed a significant reduction in the levels of several pro-inflammatory molecules in both the spinal cord (CXCL1 and TNF-alpha) and blood (IL-2, IL-6, and IL-10), and a lesser activation of mast cells compared with untreated mice.

While the team found no change in microglia and astrocytes numbers, “the significant decrease in the levels of pro-inflammatory [molecules] … in response to cromolyn treatment may induce a shift in microglial activation states from pro- to anti-inflammatory,” the researchers wrote.

These findings suggest that cromolyn sodium can help to protect motor neurons from degeneration and to preserve their connections with muscle cells by lowering the inflammatory response.

“Our study supports the notion that inflammation has a significant role in the progression of ALS and therefore exploring anti-inflammatory treatments may be of great value for developing an effective treatment,” Ghazaleh Sadri-Vakili, PhD, the study’s senior investigator, said in a press release.

Sadri-Vakili is also a director of the NeuroEpigenetics laboratory at the Sean M. Healey & AMG Center for ALS and the MassGeneral Institute for Neurodegenerative Disease.

“It remains to be seen whether these effects will translate to people living with the disease,” she added. “Therefore, we will continue to explore inflammation’s role in disease development and progression in hopes of translating this research into potential ALS treatments.”