SYDNEY: The mechanism that enables zebrafish to re-grow brain cells after injury has been identified, with potential implications for the way we treat brain trauma and diseases in humans, according to new research.
Scientists have long known zebrafish brains can, unlike human brains, regenerate after injury by activating stem cells, called radial glial cells – but the mechanism behind this, and why it is so limited in mammal brains, remained a mystery.
Now, researchers have discovered that regeneration in zebrafish brains is, surprisingly, linked to inflammation – a relatively poorly understood side effect of brain trauma.
“It’s previously been thought that inflammation would actually be very harmful, because it’s seen as a hallmark for poor regenerative outcomes [in humans],” said Jan Kaslin co-author of the paper, published in Science, and neurobiologist at Monash University in Melbourne, Australia. “But what we show in our paper is that inflammation is very beneficial to kick start the regeneration response in zebrafish.”
Acute versus chronic inflammation
By triggering inflammation in the brains of zebrafish – a small tropical freshwater fish and commonly studied model organism – scientists were able to set the regenerative process on course, in which a specialised signalling molecule coaxes stem cells into producing new neurones.
In mammals, including humans, chronic brain inflammation – inflammation that persists long after a brain trauma, such as a stroke – is linked with brain scarring and has been associated with diseases such as Alzheimer’s. Acute brain inflammation, on the other hand, is short lived and occurs directly after an injury, such as a blow to the head during a football match.
When a brain trauma occurs, immune cells build up at the site of the injured tissue. While these cells are associated with the detrimental scarring in humans, they did not appear to hamper new-neuron growth following acute inflammation in zebrafish – but in fact initiated regeneration.
“Let inflammation run its course”
To find the specific molecules mediating this response in zebrafish, the scientists screened for the response by injecting various candidate molecules along with fluorescent probes into uninjured and regenerating zebrafish brains. In doing so, they discovered a convincing candidate – a molecule called leukotriene C4 (LTC4) – which, when injected into the uninjured zebrafish brain, mimicked the regenerative response.
“This is exciting because it threads a link between the immune system’s first response – inflammation – and the induction of neural regenerative mechanisms,” commented Adam Svahn from the Brain and Mind Institute at the University of Sydney, Australia, who is an expert in inflammatory responses in the brain, but was not involved in this research.
“Using the accessibility of the zebrafish, it will be fascinating to start to understand the abilities and limitations of neural regeneration,” he said.
While taking anti-inflammatory drugs such as ibuprofen or aspirin is already advised against after a mild head injury, as it could increase the risk of bleeding, this latest research suggests doing so could also impede the brain’s ability to renew brain cells.
“What our study would sauggest is that it would be better to initially let inflammation have its course, because it may be important as a pro-regenerative mechanism,” Kaslin said. “However, it is important to keep in mind that brain injury and regeneration are very dynamic and complex processes.”
Treating trauma, slowing down disease
Kaslin said more research is needed to apply the findings to our much bigger, more complex human brains. However, he also said the discovery of LTC4 could assist in the development of treatments for humans.
“The pro-regenerative mechanisms identified in zebrafish could in the future be used to restrict damage after traumatic injury and to slow down neurodegenerative disorders,” he said. Such disorders include Alzheimer’s and Parkinson’s.
Simon Koblar, a neurologist at the Queen Elizabeth Hospital in Adelaide, South Australia, and neuroscientist at the University of Adelaide, said the research, which he wasn’t involved with, was “very exciting” and may provide a “window” onto why neuron regeneration is so limited in mammals, including humans.
“There’s a lot of data that shows that in humans, under a whole range of brain injuries, there is a limited regenerative response, [but] it’s not enough to repair the damage, like it is in zebrafish, and we don’t really understand why,” he said.
Koblar said the next step would be to see what LTC4 “looks like” in mice, and then in human brain tissue from brain banks, to see if a similar response is observed.
Kaslin added that another key step would be to identify further “molecular players”, like LTC4, that are associated with neurone regeneration.
The paper is published online at Science Express.