Cromolyn Sodium Provides Neuroprotection in Animal Model of ALS

There's increasing evidence that neuroinflammation has a key role in the initiation and progression of amyotrophic lateral sclerosis (ALS). It's mediated at least in part by activated microglia and reactive astrocytes—immune cells in the central nervous system that produce reactive oxygen species, nitric oxide and proinflammatory cytokines that lead to neuronal cell death.

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Microglial cells can assume activation states that range from anti-inflammatory to proinflammatory. In previous research, published in Molecular and Cellular Neuroscience, in transgenic SOD1^G93A (TgSOD1^G93A) mice, an animal model of ALS, activated microglia were detected near motor neurons well before the onset of weakness, and the neuroinflammatory response correlated with disease progression.

The same research group subsequently showed in TgSOD1^G93A mice that early-stage anti-inflammatory microglia enhanced motor neuron survival, whereas proinflammatory microglia were toxic to motor neurons. That research was published in Experimental Neurology. Thus, it appears that during ALS progression, the microglial activation state shifts from anti-inflammatory and neuroprotective to proinflammatory and neurotoxic. A potential therapeutic strategy in ALS would be to use a pharmacologic agent that converts microglial cells from proinflammatory to anti-inflammatory.

Rudolph E. Tanzi, PhD, director of the Genetics and Aging Research Unit at Massachusetts General Hospital and colleagues recently reported in Scientific Reports that by using cromolyn sodium, they were able to induce a neuroprotective anti-inflammatory microglial activation state in a mouse model of Alzheimer's disease. Cromolyn promoted microglial clustering around amyloid-beta plaques, which were subsequently removed through phagocytosis.

Ghazaleh Sadri-Vakili, MS, PhD, director of the NeuroEpigenetics Laboratory at the MassGeneral Institute for Neurodegenerative Disease, Dr. Tanzi, Merit E. Cudkowicz, MD, director of the Sean M. Healey & AMG Center for ALS, and colleagues describe similar findings in an ALS mouse model, reporting that cromolyn appears to provide neuroprotective effects by regulating the immune response in TgSOD1 mice. Cromolyn is already approved by the Food and Drug Administration for the treatment of asthma, allergic rhinitis and other chronic inflammatory diseases.

Methods

149 age- and litter-matched TgSOD1^G93A mice and wild-type (Wt) mice received injections of either vehicle or cromolyn from post-natal day 60 until euthanasia. Four groups of animals were treated: TgSOD1-Cromolyn, TgSOD1-Vehicle, Wt-Cromolyn and Wt-Vehicle.

Neuroprotection and Survival

Cromolyn treatment delayed disease onset in TgSOD1^G93A mice. The onset of motor symptoms was significantly later in the TgSOD1-Cromolyn group than in the TgSOD1-Vehicle group.

Performance on the paw grip endurance task, an assessment of muscle strength, was significantly better in the TgSOD1-Cromolyn group than in the TgSOD1-Vehicle group, as was motor neuron survival in the lumbar spinal cord.

Cromolyn treatment did not influence survival except in female TgSOD1^G93A mice.

Neuromuscular Junction Innervation and Mast Cell Stability

Mast cells in ALS patients accumulate around the muscle and other regions of neurodegeneration and may accelerate denervation. Intriguingly, the current study suggests that in the tibialis anterior muscle, cromolyn treatment improved the integrity of neuromuscular junction (NMJ), stabilized mast cells and decreased mast cell degranulation.

Specifically, denervation of the NMJ in the tibialis anterior was significantly decreased in the TgSOD1-Cromolyn group compared with the TgSOD1-Vehicle group. Concomitantly, there was an increase in the number of mast cells in the tibialis anterior in the TgSOD1-Cromolyn group compared with the Wt-Cromolyn group, and there were significantly fewer degranulated mast cells in the tibialis anterior in the TgSOD1-Cromolyn group than in the TgSOD1-Vehicle group.

Microgliosis and Astrogliosis

Cromolyn treatment had no effect on the total number/cell area of microglia or astrocytes in the lumbar spinal cord of TgSOD1^G93A mice. In contrast to the researchers' earlier results in the mouse model of Alzheimer's disease, cromolyn did not shift microglia from a proinflammatory to a prophagocytic state.

Proinflammatory Cytokines/Chemokines

• Spinal cord — Confirming human research, the proinflammatory cytokines IL-1β and TNFα and the chemokine CXCL1 were significantly increased in the spinal cord of TgSOD1^G93A mice compared with Wt mice, while the cytokines IL-5 and IL-6 were decreased. Cromolyn treatment significantly decreased the CXCL1 and TNFα levels compared with vehicle
• Plasma — The cytokines IL-2, IL-6 and IL-10 were significantly increased in the plasma of TgSOD1^G93A mice compared with Wt mice, as was TNFα. Cromolyn treatment significantly decreased the levels of IL-2, IL-6 and IL-10, and there was a trend toward decreased TNFα, suggesting that cromolyn treatment reduces inflammation in the blood of TgSOD1^G93A mice

Toward the Future

In a previous study, published in Scientific Reports, inflammatory cytokines in peripheral blood showed promise as diagnostic biomarkers for ALS. The data from this study imply that certain proinflammatory cytokines might also be useful as therapeutic biomarkers, to indicate target engagement during the drug discovery process or in clinical trials of investigational drugs.

The findings also provide a rationale for further investigating cromolyn as a therapeutic approach to dampening inflammation for the treatment of ALS.

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