A class of drugs currently used to treat cancer may also help stroke patients recover by protecting neurons and limiting damage following a stroke.
Known as HDACi (histone deacetylase inhibitors), these drugs work by altering gene expression in microglia – the brain’s immune cells – following stroke.
Instead of driving damaging inflammation, HDACi appear to reprogramme microglia to support repair.
In research led by the Yong Loo Lin School of Medicine at the National University of Singapore (NUS Medicine), scientists found that HDACi – already in use or under investigation for cancers and neurological conditions such as Alzheimer’s disease – could be repurposed to reduce stroke-related brain damage and aid recovery.
Professor S Thameem Dheen from the Department of Anatomy at NUS Medicine led the study with Dr Kevin Jayaraj and Dr Jai S. Polepalli.
Dheen said: “HDACi are already being explored in cancer and neurodegeneration therapy.
What we now show is that they can be repurposed to dampen inflammation in the brain and promote recovery in stroke, through a microglia-centric mechanism.
Laboratory models in which blood flow was blocked in the middle cerebral artery to simulate stroke, and then treated with HDACi, showed a 60 per cent reduction in brain damage.
The treated models also demonstrated improved behavioural performance and significant changes in microglial activity.
Using spatial transcriptomics – a technique that allows for the mapping of gene activity across different brain regions – the researchers identified how stroke disrupts genetic pathways involved in inflammation, cell survival, neuroprotection, and phagocytosis, the process by which cells clear away debris.
HDACi treatment was found to rescue these pathways, with different regions of the brain showing distinct patterns of microglial response during recovery.
Current stroke therapies are time-limited and mainly focus on restoring blood flow.
Few target the secondary inflammatory phase that causes further brain injury in the hours and days following stroke.
Professor Thiruma V. Arumugam from the Centre for Cardiovascular Biology and Disease Research at La Trobe University in Australia is a co-author of the study.
The researcher said: “HDACi drugs precisely reprogram microglia in stroke-affected brain regions, transforming them from inflammatory agents to healing promoters.
“By targeting these immune cells, our study has the potential to address both acute damage and long-term recovery post-stroke.”
The research also found that HDACi can restore neuroprotective gene activity in microglia in a region-specific way, including in the hippocampus – a brain region essential for memory consolidation.
Dr Jayaraj said: “Our study demonstrates for the first time that HDACi can restore neuroprotective gene activity in microglia in a region-specific manner across the brain, including critical areas such as the hippocampus, which is responsible for memory consolidation.
“More importantly, we have identified alternative targets that essentially represent an out-of-the-box approach for treating stroke and other conditions where neuroinflammation plays a significant role.”
Stroke continues to pose a major public health challenge globally.
In Singapore, the ageing population faces increasing risks, with the condition linked to high rates of death, disability, and reduced quality of life, as well as a growing economic burden on the healthcare system.
The team now plans to develop therapies that extend beyond the acute phase of stroke, aiming to reprogramme glial cells to support long-term recovery, brain circuit repair, and the preservation of neurological function.
