When negative results are positive: Monash Trauma Group researchers feature in new journal Special Collection

Dr Rhys Brady is first author on the paper

by Dr Loretta Piccenna
Research Manager, Department of Neuroscience

Research fellow Dr Rhys Brady, from the Monash Trauma Group and equal first author Stephanie Bird (Department of Medicine, The University of Melbourne) published a study earlier this month in Neurotrauma Reports special collection: Null Hypothesis Initiative.

 

The study by Dr Brady and colleagues found that in mice with moderate traumatic brain injury there was an initial activation of one particular pathway which disappeared after four weeks, and they tested whether one specific compound would improve recovery.
They found that the protein-kinase R-like endoplasmic reticulum pathway (PERK) and eukaryotic translation initiation factor-a (eIF2a) was activated for the first four weeks, but not chronically (i.e. 4 weeks following injury). Activation of PERK has been observed in other neurodegenerative diseases similar to traumatic brain injury, for instance Alzheimer's disease and Amyotrophic Lateral Sclerosis. 

Dr Brady and the study team were interested to see if the pathway had a role as a potential target to improve the long term outcomes of mice with moderate traumatic brain injury, as currently no intervention is available for patients.  

Treatment with a potent and selective inhibitor of PERK, GSK4606414, was provided to the mice who had moderate brain injury and compared with mice without treatment or brain injury to see if it improved their outcomes. There was no significant reduction in the activation of the PERK pathway. The inhibitor also did not have any effects on neuronal loss or lesion loss following moderate brain injury, or on behavioural deficits after 4 weeks. 

Interestingly, in a different type of traumatic brain injury rodent model to the one in this study, acute and chronic activation of the PERK pathway has been observed. The team are now working to find out why this might have occurred and to understand exactly what role the PERK pathway is playing in traumatic brain injury as the key research focus of the Monash Trauma Group. 

This study was published in the second edition of Neurotrauma Reports, a companion to the Journal of Neurotrauma. with the first published in October last year through Mary Ann Liebert, Inc., publishers and Cohen Veterans Bioscience. 

Negative or inconclusive results in research studies have traditionally not been a popular addition in academic journals, carrying with them a degree of stigma among the scholarly field. Consequently these findings were omitted from the evidence base, which created inaccurate reporting and understanding in that research area. 

Dr Sandra Petty 

However, back in 2017 this changed when Dr Sandra Petty, a neurologist at Alfred Health and medical educator in the Department of Neuroscience, CCS (Monash University), and her colleague Dr Hugo Stephenson, founded a not-for-profit organisation called The Center for Biomedical Research Transparency (CBMRT). The aim of the organisation is to: 

'ensure that all biomedical results – including negative and inconclusive results - are accessible to researchers and clinicians in the interests of full transparency, patient safety and research efficiency.'

One of the activities of the organisation is to publish an annual supplement (Null Hypothesis) in partnership with academic journal publishers or scholarly societies. CBMRT launched their first edition in partnership with the journal Neurology on 30 April 2019.

The study was funded by a grant from the MND Research Institute of Australia and Mick Rodger and Benalla Act to d’feet MND.

 

Reference

 

Rhys D. Brady, Stefanie Bird, Mujun Sun, Glenn R. Yamakawa, Brendan P. Major, Richelle Mychasiuk, Terence J. O'Brien, Stuart J. McDonald, and Sandy R. Shultz. Activation of the Protein Kinase R–Like Endoplasmic Reticulum Kinase (PERK) Pathway of the Unfolded Protein Response after Experimental Traumatic Brain Injury and Treatment with a PERK Inhibitor. Neurotrauma Reports 2021 2:1, 330-342. https://doi.org/10.1089/neur.2021.0001 Open Access