New compound protects brain from degeneration after an early-life traumatic injury

Myelin is better preserved in TBI mice following LM22A-4 treatment.
Fletcher et al., (2021) Exp Neurol.

In young children under 5 years of age, there is a high risk of experiencing a traumatic brain injury, which can lead to death and life-long disability. Importantly, paediatric traumatic brain injury can be a life-long disability which often worsens over time into adolescence or adulthood, alongside ongoing brain development - making treatment more challenging.

A study led by Dr Bridgette Semple in the Central Clinical School’s Department of Neuroscience, has demonstrated that treatment with a novel compound was able to protect the brain from degeneration after an early-life brain injury. 

The study was the result of a successful collaboration with Research Fellow Dr Jessica Fletcher while in the Murray Laboratory, in the School of Biomedical Sciences at the University of Melbourne. Dr Fletcher has since recently relocated to the University of Tasmania.  

The novel compound, known as LM22A-4, is a chemical that binds in the brain to a a growth factor receptor produced by the body, tropomyosin related kinase B (TrkB. Although not yet in clinical use, the compound activates the TrkB receptor and downstream signalling pathways. It was identified in 2010 by a team in California from in-silico screening experiments. 

The neuroprotective potential of the compound has been shown in other pre-clinical models of neurological disorders, such as in multiple sclerosis (MS) by Dr Fletcher’s group. The findings demonstrate that the TrkB receptor is a druggable target with therapeutic potential - and that signalling via this pathway is key to secondary degeneration after brain injury. 

In the current study, LM22A-4 was able to protect myelin, which itself protects nerve fibres from injury in the brain, which was damaged in a model of traumatic brain injury in young mice. This protection was also associated with a reduction in behavioural problems (e.g. reduced hyperactivity, and changes in anxiety) as tested in a battery of rodent behavioural tests. Dr Fletcher commented that she was most encouraged by these findings, which “reinforced that to make these improvements to both brain health and behaviours, we have to take a holistic perspective.”

Of note, the team used a new microscopy technique called spectral confocal reflectance microscopy (or SCoRe) that allowed them to visualise and measure the amount of intact versus damaged myelin in white matter tracts of the brain, without needing to stain the tissue. Dr Fletcher commented that the collaboration with Dr. Semple’s group allowed them to “apply and use cutting-edge discoveries about how oligodendrocytes and myelin actively contribute to learning, memory formation and social behaviour throughout adolescence and adulthood, in a context where this will hopefully make a difference to people’s lives in the future”.

The findings pave the way for future studies to better understand the fundamental biology of how myelin is damaged by a brain injury, particularly in a brain that is still maturing, and why the myelin debris is not cleared over time. Further studies are now planned to examine whether neuroprotective benefit from the TrkB agonist compound persists more chronically after injury, and how exactly it has this effect. “By dissecting this out, we can provide absolutely critical insight into what we need to achieve for a therapy to be really effective in preventing the brain dysfunction that happens as a consequence of childhood brain injury,” said Dr Fletcher.

The collaboration between Dr. Semple and Dr. Fletcher began a few years back, through mutual involvement in the Committee for the Medicine, Dentistry and Health Sciences (MDHS) Early Career Researcher (ECR) Network when they were both working at The University of Melbourne. Dr Semple said, “I realised that she and I had complementary expertise in oligodendrocytes/myelin and brain injury/neuropathology, respectively; and so we started a project with big ideas but minimal independent funding!” Subsequently, Dr Fletcher was able to apply and secure a small grant from the University of Melbourne, Department of Anatomy and Neuroscience, and both co-supervised a Monash Honours student as well as a Monash HUP3990 student to work on the project. 

Dr Fletcher commented that their partnership works so well because they are both very passionate about their science and its clinical impact, up-to-date, and engaged with each others’ respective fields of expertise. She said, “We both learn something new every time we interact.”

Jessica L. Fletcher, Larissa K. Dill, Rhiannon J. Wood, Sharon Wang, Kate Robertson, Simon S. Murray, Akram Zamani, Bridgette D. Semple. Acute treatment with TrkB agonist LM22A-4 confers neuroprotection and preserves myelin integrity in a mouse model of pediatric traumatic brain injury. Experimental Neurology. 2021. 339: 113652, https://doi.org/10.1016/j.expneurol.2021.113652.