Blocking P2X7 Receptors May Be Therapeutic Target for Rett, Mouse Study Shows

Blocking P2X7 Receptors May Be Therapeutic Target for Rett, Mouse Study Shows
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Blocking the activity of pro-inflammatory P2X7 receptors — a class of receptors found in immune cells and in glial cells (cells that support and protect neurons) — can reduce brain inflammation and ease defects in social behavior, a study of a mouse model of Rett syndrome shows.

The research, study authors say, may represent a potential therapeutic target in the treatment of Rett syndrome and other neurodevelopmental disorders.

The study, “P2X7 receptor inhibition ameliorates dendritic spine pathology and social behavioral deficits in Rett syndrome mice,” was published in the journal Nature Communications.

Rett syndrome is caused by mutations in the MECP2 gene, which provides instructions to make a protein called MeCP2. This protein is responsible for maintaining synapses (the sites where nerve cells communicate) and controlling the activity of other genes.

Although the lack of MeCP2 in the central nervous system (CNS, includes the brain and spinal cord) typically accounts for nearly all neurological symptoms of Rett, having no MeCP2 outside the CNS also may contribute to at least some manifestations of the disease.

Recent studies have linked mutations in MECP2 with altered levels and responses of immune cells. However, “whether and to what extent dysregulated peripheral immunity contributes to brain dysfunction and RTT [Rett] symptoms is unknown,” researchers wrote.

P2X7 receptors — mainly found on the surface of immune cells and in glial cells in the CNS — are channels that, when activated by a molecule known as adenosine triphosphate (ATP), release pro-inflammatory molecules such as interleukin-1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF alpha), as well as toxic oxidant substances. ATP is a small molecule used as fuel (energy) by all cells in the body.

Due to their pro-inflammatory function, P2X7 receptors “have been proposed as therapeutic targets for various inflammatory and neurological disorders, as well as for autism-like behavior in mice,” researchers wrote.

To explore the role and the therapeutic potential of pro-inflammatory P2X7 receptors in Rett, researchers at Columbia University Medical Center, in collaboration with colleagues at New York University School of Medicine, started by evaluating the numbers of immune cells in the brain of mice lacking Mecp2, an animal model of Rett.

They discovered that, compared to healthy animals, mice engineered to mimic Rett symptoms had higher numbers of monocytes and macrophages in the cerebral cortex (the outermost part of the brain). That suggested a predisposition to brain inflammation caused by the lack of MeCP2. (Monocytes and macrophages are immune cells that ingest other cells seen as threats by the immune system.)

In addition, they found that both monocytes and macrophages contained high levels of pro-inflammatory P2X7 receptors on their surface.

Then, to test if blocking the production of P2X7 receptors could reduce brain inflammation, the investigators created animals that lacked both Mecp2 and P2x7r (the mouse gene that encodes P2X7 receptor).

Compared to mice able to produce P2X7Rs, animals unable to produce  both MeCP2 and P2X7 receptors had lower levels of monocytes and macrophages and, consequently, less brain inflammation. Also, such animals had milder neurological impairments and did not show any defects in social behavior, unlike mice that retained the ability to produce P2X7Rs.

Finally, systemic treatment with a blocker of P2X7 receptors that is able reach the bran (known as JNJ-47965567) led to the same improvements seen in animals genetically modified to lack the receptors. In particular, giving the blocker for three days reduced the number of inflammatory cells and improved social behavior.

“In summary, our study reveals that P2X7R [P2X7 receptor] inhibition reduces cortical inflammation (…) and various behavioral deficits [in the mouse model of Rett],” researchers wrote.

“Therefore, P2X7Rs may serve as a potential therapeutic target in the treatment of RTT and other neurodevelopmental disorders,” 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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José holds a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease.

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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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