Astrocytes May Promote MS Inflammation via D2 Receptors

Dopamine D2 receptors appear to initiate signaling cascades in early study

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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A set of receptors involved in dopamine signaling may play a key role in the activation of astrocytes, nerve support cells that contribute to the inflammation that drives multiple sclerosis (MS), according to a study in a mouse model of the neurodegenerative disease.

Mice lacking these receptors — called dopamine D2 receptors — showed an easing in symptoms, and blocking D2 receptors also significantly lowered inflammation.

These data suggest that D2 receptors in astrocytes are essential players in the inflammatory responses that drive MS, and may be targeted to slow disease progression.

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The study, “Inhibition of astrocytic DRD2 suppresses CNS inflammation in an animal model of multiple sclerosis,” was published in the Journal of Experimental Medicine

Astrocytes are star-shaped cells that provide support to nerve cells by performing a variety of functions needed to keep neurons healthy. Among their roles is helping to maintain sites of nerve cell communication, provide nutrients, maintain blood flow, and repair nerve cells after injury.

Astrocyte activation tied to MS

In response to brain injury such as inflammatory demyelination, astrocytes become activated, or reactive, undergoing changes in structure and function that mediate inflammatory responses.

Astrocyte reactivity has been implicated in many chronic disease states characterized by damaging inflammation, including MS. But the mechanisms underlying this activation are not fully understood.

Recent evidence suggested that activation of certain receptors for dopamine — a major chemical messenger in the brain — on astrocytes could initiate signaling cascades responsible for astrocyte activation.

Researchers at the Chinese Academy of Sciences investigated the potential role of D2, a type of dopamine receptor, on astrocytes in a mouse with experimental autoimmune encephalomyelitis (EAE), which is commonly used to mimic MS in mice.

Results from their experiments showed that D2 levels are increased in reactive astrocytes in the mouse model.

When mice were engineered to lack D2 receptors in astrocytes, the cells were no longer reactive and MS symptoms eased, supporting a role for astrocyte D2 in disease mechanisms.

Further experiments highlighted a potential mechanism through which the dopamine receptors might mediate inflammation in MS. Data showed that D2 receptor activity regulated levels of a particular enzyme called 6-pyruvoyl-tetrahydropterin synthase.

This protein, in turn, modulates the activity of nuclear factor kappa B, a major contributor to inflammatory signaling cascades in the brain.

To evaluate the therapeutic potential of blocking D2 receptors in MS, EAE mice were treated with dehydrocorybulbine, a compound derived from the Corydalis herb that is known to inhibit D2 receptors.

This treatment resulted in significant reductions in inflammation, even when D2 receptors were deleted from nerve cells, providing additional evidence that the importance of D2 receptors in MS primarily lies within astrocytes.

“Together, our findings reveal previously an uncharted role for [dopamine D2 receptors] in astrocyte activation during EAE-associated [central nervous system] inflammation,” the researchers wrote.

“Its therapeutic inhibition may provide a potent lever to alleviate autoimmune diseases,” they added, noting these findings may be relevant to other autoimmune conditions marked by astrocyte reactivity.

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