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Rapid Response for Inflammation Control in Bird Brains May Lead to Human Therapies

A biological process in the brains of zebra finches shows that the songbirds respond quickly to trauma and are capable of controlling the natural inflammation that occurs to protect the brain from injury.

Understanding the process well enough could lead to therapies in humans to control inflammation and hasten recovery from brain injury such as stroke, said American University Prof. Colin Saldanha, whose study “Centrally Synthesized Estradiol is a Potent Anti-Inflammatory in the Injured Zebra Finch Brain” has published in Endocrinology. Through experiments, Saldanha and his colleagues found that estrogen-producing glial cells play a role in the rapid response.

“The most surprising thing to me is that the inflammation control is happening within hours, and that estrogen is made in the brain around an injury site in response to an injury,” Saldanha said. “These animals have evolved a mechanism to protect their brains from injury very quickly.”

Preserving brain function

Inflammation is a normal part of the body’s immune response. It affects the brain differently compared with other parts of the body. In the brain, too much inflammation can cause degenerative effects, or in the worst case scenario, death. Chronic inflammation causes cell damage and the loss of important neurons that regulate memory, mood and movement. Being able to control and limit inflammation in an injured brain may preserve vital brain function.

As a neurobiologist and member of AU’s Center for Behavioral Neuroscience, Saldanha studies estrogen in songbirds. The birds produce the common sex steroid in their brains, as do humans and other mammals. It’s been known that hormones affect the brain since the 1850s, but realizing that similar hormones could be made in the brain itself, took until the 1980s. The animals make good research subjects for neuroscience for many reasons, including because of their brain plasticity.

Previous work by Saldanha and his colleagues explored how hormones communicate with neurons. They discovered a new method of communication, synaptocrine signaling, by which neurons create and feed high levels of estrogen to one another. That’s when they also discovered which cells were synthesizing estrogen under conditions of brain injury: the glial cells, which are important, non-neuronal cells that live in the brain.

For more than a decade, National Institutes of Health has funded Saldanha’s research because of the implications it has for treating neurodegenerative conditions such as Alzheimer’s disease, Parkinson’s disease, strokes and inflammatory diseases.

Controlling inflammation

The release of estrogen in the brain to control inflammation is a natural process. It happens within about 24 hours in songbirds. The same process occurs in mammals over several days – perhaps far too late to stop brain degeneration or an end to life.

In the current experiments, Saldanha discovered another important function of glial cells — that they activated the rapid response to protect the birds’ brains. However more needed to be understood about how the protective process was keeping inflammation in check.

The researchers conducted three experiments using a type of acute injury, similar to a stroke. The injury spurred the secretion of small proteins called cytokines, which trigger an inflammatory response.

At certain points during the response, Saldanha and his colleagues controlled the levels of estrogen by preventing aromatase – the key protein needed for estrogen production – from working.

Image shows a zebra finch.

The birds produce the common sex steroid in their brains, as do humans and other mammals. Image is for illustrative purposes only.

In the first experiment, researchers injured both sides of the brain, but flooded only one side with estrogen. The side flooded with estrogen showed less inflammation.

In a second experiment, researchers injured both sides of the songbird brain and limited aromatase function to only one side of the brain. On the side without aromatase, the inflammatory cytokines remained dangerously elevated.

That’s when researchers knew estrogen controls inflammation and its very production occurs in response to injury.

Estrogen is a complex chemical, which makes it exciting to study, Saldanha said.

“We can’t just pump people full of estrogen. It can have very bad effects on systems other than the brain,” Saldanha said. “It’s very tricky, which is why exploring this is so important, so we can figure out how to harness its power without any deleterious side-effects.”

About this neurology research

Source: Rebecca Basu – American University
Image Source: The image is in the public domain.
Original Research: Abstract for “Centrally Synthesized Estradiol is a Potent Anti-Inflammatory in the Injured Zebra Finch Brain” by Alyssa L. Pedersen, Lars H. Nelson and Colin J. Saldanha in Endocrinology. Published online March 10 2016 doi:10.1210/en.2015-1991


Abstract

Centrally Synthesized Estradiol is a Potent Anti-Inflammatory in the Injured Zebra Finch Brain

In homeotherms, injury to the brain, such as a penetrating wound, increases microglial cytokine expression and astroglial aromatase (estrogen synthase). In songbirds, injury-induced synthesis of estrogens is neuroprotective as aromatase inhibition and replacement with estradiol (E2) exacerbates and mitigates the extent of damage respectively. The influence of induced aromatization on inflammation, however, remains unstudied. We hypothesized that injury-induced aromatization, via E2 synthesis, may affect neuroinflammation following a penetrating brain injury. Using adult zebra finches, we first documented an increase in the transcription of cytokines but not aromatase, 2hr post-injury. 24hr post-injury, however, aromatase was dramatically elevated and cytokine expression had returned to baseline, suggesting that aromatization may be involved in the decrease of cytokines and neuroinflammation. In two subsequent experiments, we tested the influence of (a) inhibition of induced aromatization, and (b) aromatase inhibition with concomitant central E2 replacement, on the transcription of the cytokines TNFα, IL-1β, and IL-6, the enzyme cox-2 and its product prostaglandin E2 (PGE2). Administration of fadrozole, an aromatase inhibitor, caused a sustained elevation of IL-1β in females, and TNFα, cox-2 and PGE2 in both sexes. This prolonged neuroinflammation appears to be due to a failure to synthesize E2 locally, since intracranial E2 replacement lowered IL-1β in females, TNFα in males, and cox-2 and PGE2 in both sexes. IL-6 was not affected by injury, aromatase inhibition or E2 replacement in either sex. These data suggest that E2 synthesis following penetrating brain injury is a potent and inducible anti-inflammatory signal, with specific modulation of discrete cytokine signaling. –

“Centrally Synthesized Estradiol is a Potent Anti-Inflammatory in the Injured Zebra Finch Brain” by Alyssa L. Pedersen, Lars H. Nelson and Colin J. Saldanha in Endocrinology. Published online March 10 2016 doi:10.1210/en.2015-1991

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