Australian researchers in Melbourne and China have used experimental drugs to target a recently described molecular pathway that damages brains after a stroke, bringing these treatments one step closer to the clinic for stroke sufferers.
Dr Peng Lei and Professor Ashley Bush, at Sichuan University in China and the Florey Institute of Neuroscience and Mental Health in Melbourne respectively, have been interested in a protein called tau for many years as it is known to play a leading role in Alzheimer’s disease progression.
Using pre-clinical animal models of ischaemic stroke, the pair have now shown that the tau protein, which stabilises the cellular ‘train track’ that transports molecules around cells, is also involved in stroke.
Dr Lei and Professor Bush have published their new findings in Molecular Psychiatry, showing that tau levels are markedly reduced following a stroke. One of the main functions of tau is to transport iron out of brain cells. Lower tau levels therefore lead to a build-up of iron in cells. This increase leads to brain cell death through a newly described molecular pathway, called ferroptosis, which depends on iron.
Dr Lei, who performed the work, says “Excitingly, we were able to intervene following stroke with five different experimental drugs designed to either lower iron levels, or block the ferroptosis pathway. Although all the treatments helped prevent brain damage, the ferroptosis-inhibiting drugs performed the best, reducing the damaged area by more than half, with the animals functioning significantly better on tests of motor coordination and cognitive performance.”
Ischaemic strokes are caused by a blocked blood vessel, meaning the brain is starved of oxygen. They comprise 85 per cent of all strokes in Australia, and acute treatment involves removing the blockage either by surgery or giving a clot-busting drug. Unfortunately, only 11 per cent of stroke patients receive this treatment in the prescribed time, and of those, only half show functional improvement. Better treatments are urgently needed.
In this study, the ferroptosis-inhibiting drugs liproxstatin-1 and ferrostatin-1 were delivered via the nose, which allowed their rapid, direct uptake by the damaged brain cells. This route, and the pathway they target, also means they could potentially be easily carried and administered by ambulance paramedics without the need for special brain scans or blood chemistry to be analysed.
The director of the Florey, stroke neurologist Professor Geoffrey Donnan, says “These findings really highlight the need to study potential stroke treatments in older animals, at an age that better reflects when the majority of Australians suffer a stroke. Much promising work from preclinical studies in younger animals has simply failed to translate into successful clinical trials. This work highlights exactly how well-conducted animal research is more translatable to clinical populations.”
· Experimental drugs have been trialled in animals that reduce brain damage following a stoke
· These drugs improved the cognitive and motor outcomes for animals, equivalent to improving quality of life indicators in human stroke patients
· The research was performed in older animals that closely resemble the majority of human stroke sufferers, with more than 80 percent of strokes occurring in people over 55 years of age
· Stroke reduces the levels of the tau protein in brain cells, which leads to an increase in iron in those cells
· Increased iron leads to brain cell death via the ‘ferroptosis’ pathway, which was blocked by the experimental drugs, thereby saving vital brain tissue
Can existing treatment for Alzheimer's disease also be effective for strokes? Prof Geoffrey Donnan explains. pic.twitter.com/MxFJl4bfTc— News Breakfast (@BreakfastNews) September 11, 2017
Facts on stroke (from strokefoundation.org.au)
· Stroke is one of Australia’s biggest killers and a leading cause of disability
· Stroke kills more women than breast cancer and more men than prostate cancer
· In 2017 there will be almost 56,000 new and recurrent strokes – that is one stroke every nine minutes
· More than 80% of strokes can be prevented through lifestyle changes and medication
· In 2017 there will be more than 475,000 people living with the effects of stroke. This is predicted to increase to one million by 2050
· Around 30% of stroke survivors are of working age (under the age of 65)
· 65% of stroke survivors suffer a disability which impedes their ability to carry out daily living activities unassisted
· The financial cost of stroke in Australia is estimated to be $5 billion each year.