How do neuroactive steroids suppress inflammatory signals in the immune system and brain?

A study published in Nature Scientific Reports, in collaboration with UNC medical school and the University of Maryland, have shown how the neurosteroid allopregnanolone blocks the activation of pro-inflammatory proteins important for gene regulation, as well as the production of cytokines known to be involved in many different types of inflammation. The study also suggested that inhibition of inflammatory signaling may contribute to these effects, and suppression of TLR4 signaling may be a new target for these conditions

This is the first time that scientists have discovered how naturally occurring neuroactive steroids in the brain and blood inhibit the activity of a specific protein called toll-like receptor, also known as TLR4, which is thought to play a role in inflammation in many organs, including the brain.

Signal transduction by inflammatory cells in the brain is enhanced in many neuropsychiatric disorders, including alcohol use disorders, depression, and post-traumatic stress. It is also found in sepsis, epilepsy, multiple sclerosis, and Alzheimer's disease.

Treating brain diseases involving inflammation is difficult, but allopregnanolone's inhibition of the activation of TLR4 signals in macrophages and the brain offers hope that researchers can develop better treatments to help millions of people with these diseases.

Neuroactive steroids are naturally present in the brain and other parts of the body. They are involved in the regulation of emergency responses such as anxiety and depression, as well as in the regulation of learning and memory, convulsion, sleep, eating, nerve regeneration and biological circadian rhythm. These steroids decline with age and are lacking in many neuropsychiatric disorders such as depression. Therefore, solving this kind of diseases is key to learn more about the relationship between neuroactive steroids and proteins which involve in the process.

Working with other researchers, they found that allopregnanolone inhibited the activation of TLR4 in macrophages, the white blood cells and parts of the immune system, including the brain. In particular, allopregnanolone has been shown to prevent the binding of TLR4 to MD2 proteins, which together produce transcription factors that regulate genes that cause inflammation in cells and tissues. Allopregnanolone can also destroy chemokines and cytokines such as NFKB, HMGB1, MCP-1, and TNF-alpha, which are all part of the immune system and are participating in many different inflammatory diseases.

In addition, they found that progesterone also inhibited TLR4 signaling in macrophages. The effects of progesterone on the brain are less pronounced, but suppression of peripheral inflammation can also protect the brain since systemic inflammation indirectly affects organs throughout the body.

Now, scientists have identified the inhibitory mechanisms that inhibit inflammatory signals, researchers can create new compounds to fill in the special role of neurosteroids without unnecessary side effects. Besides, researchers can now plan clinical studies to determine the optimal dose, formulation, and mode of administration under different conditions.

This model of collaborative and translational research offers physiological insights with the potential to generate new, more effective primary and ancillary treatments for many people with brain disorders characterized by so-called neuroinflammation.

Cite this article

CUSABIO team. How do neuroactive steroids suppress inflammatory signals in the immune system and brain?.


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