Monash University scientists have identified a potential new drug target to alleviate neuroinflammation which is reported in many neurodegenerative diseases, such as Alzheimer’s, Parkinson’s and motor neurone disease.
In the new pre-clinical study, published in the Journal of Neuroimmune Pharmacology, the Monash Institute of Pharmaceutical Sciences (MIPS) team assessed whether a family of inhibitors (drug candidates) could reduce neuroinflammation triggered by ‘microglia’ – an immune cell of the brain which, when activated, contributes to neurodegenerative diseases and cognitive decline.
The goal is for the inhibitors to target ‘fatty acid-binding protein 4’ (FABP4) – a protein whose microglial levels are elevated in neuroinflammation. The first study, using a commercially-available FABP4 inhibitor, showed promise of this approach in reducing inflammation, as identified by MIPS researchers in 2023.
However, until now, the characteristics of the commercially-available compounds likely hinder their ability to traverse the ‘blood-brain barrier’ and complete their assigned mission.
The blood-brain barrier separates the blood from the brain tissue. For diseases of the central nervous system, medicines must have the right characteristics to get through the blood-brain barrier to effectively do their job (i.e. target the microglia).
Co-lead author Professor Joseph Nicolazzo from MIPS said four potential FABP4 inhibitors were assessed, with one standing out as a frontrunner candidate for moving forward in the drug development process.
“Of the four FABP4 inhibitors we assessed, there was one that markedly alleviated microglia-induced neuroinflammation, and its physicochemical properties are much more aligned with what we’d like for good blood-brain barrier permeability,” Professor Nicolazzo said.
Professor Martin Scanlon, a co-author from MIPS, said the study builds on several years of exploration into developing inhibitors of FABP4.
“For the last few years medicinal chemists at MIPS have been elaborating compounds that were identified by fragment screening to develop new FABP4 inhibitors with more drug-like properties that are capable of getting through the blood-brain barrier,” Professor Scanlon said.
Professor Nicolazzo said: “Neurodegenerative diseases are particularly challenging to treat, with no known cure available for most people living with Alzheimer’s disease, Parkinson’s disease and motor neurone disease. Although our drug discovery program has a long way to go, we are excited to have identified a promising approach to enable the next step in the drug development process.”
The next step for the team will be further studies into the candidate’s drug characterisation, pharmacokinetic/pharmacodynamic studies, and efficacy studies.
In 2021, The Lancet Neurology published a study which showed that more than 3 billion people worldwide were living with a neurological condition, making it the leading cause of ill health and disability worldwide.
Research
Yi Ling Low, Ethan Kreutzer, Indu R. Chandrashekaran, Luke A. Adams, Jason Pun, Bradley C. Doak, Yijun Pan, Jennifer L. Short, Martin J. Scanlon & Joseph A. Nicolazzo
DOI: https://doi.org/10.1007/s11481-025-10191-9
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