Successful free radical therapy? Targeting is key

SFRRI President-Elect Giovanni Mann reveals why targeting cellular antioxidant pathways needs to be as precise as possible – and how this could lead to a therapy for stroke and other diseases.

We were delighted to be a sponsor of the Society for Free Radical Research biennial congress. For four days last week, researchers and scientists from all over the globe came together virtually to provide valuable updates and promote new insights into the exciting and developing area of redox biology and medicine.

Longevity.Technology: Understanding the role free radicals play in health, wellbeing and aging is important. The SFRR-I Meeting 2021 was based on the scientific programme of SFRR-I Taiwan 2020 which was cancelled due to COVID-19, and we were lucky enough to catch up with Professor Giovanni Mann, Professor of Vascular Physiology at King’s College London and President-Elect of the Society for Free Radical Research-International (SFRRI) to find out what some of his congress highlights were. When it comes to redox research, he is certainly a Mann for all reasons.

Generated both in normal cell metabolism or acquired from external sources (pollution, cigarette smoke, radiation, medication, &c.), free radicals are important – in moderation.  Free radicals generated by the cell’s mitochondria are beneficial in wound-healing, and others elsewhere act as important signal substances. Used as weapons by the body’s defence system, free radicals destroy invading pathogenic microbes to prevent disease.

“… if we could target a nanoparticle containing a plant-derived compound or drug that activates cellular antioxidant defences, to the brain or to the heart, then that would be fantastic! Targeting and precision – that strategy is the new world.”

However, too many free radicals and oxidants can lead to oxidative stress, which damages cell membranes and other structures such as proteins, lipids, lipoproteins and DNA.

Oxidative damage to DNA can cause mutations, cause aging and induce a variety of chronic and degenerative diseases and conditions, such as cancer or stroke. This yin and yang nature of free radicals is why research is so important, hopefully leading to therapies that leverage their power, without the deleterious effects of oxidative stress.

Professor Mann and his team have been studying a molecule called sulforaphane, which is found in broccoli and other cruciferous vegetables, and which boosts a molecule called Nrf2. Nrf2 protects cells from damage by switching on antioxidant genes that help protect against free radicals. In mice, sulforaphane has been shown to protect the blood vessels in the brain from damage, and dietary pretreatment protect rodents against a stroke.

Sulforaphane acts on the blood-brain barrier (BBB) to make it less permeable to dangerous chemicals. Exploring the role Nrf2 plays in our body’s pathways could reveal novel ways to prevent or treat stroke and to preserve the integrity of the BBB.

Professor Mann was delighted with the congress and the variety and knowledge of the participants. “There were 5 plenary lectures, 13 symposia with 52 symposia speakers and 150 oral presentations and a range of young and experienced investigators – quite an undertaking online!

“One of the highlights for me was a keynote lecture by Masayuki Yamamoto [Discovery of the KEAP1-NRF2 pathway regulating cellular response against oxidative and electrophilic stresses] that focused on the redox sensitive Nrf2 transcription factor, and its multitude of functions: in cancer, in aging, in disease. He gave an outstanding lecture. There was also a symposium related to that lecture on Nrf2 organised by Young-Joon Surh of South Korea.”
Leveraging NRF2 could have enormous potential for therapies for several age-related diseases and conditions, including stroke.

“What we’d like to do, if we had a magic bullet, is to take a drug – sulforaphane for example – and put it in a vehicle, a carrier that can be eaten,” explains Professor Mann.

“Sulforaphane is rapidly absorbed through the gut and into the bloodstream and it would be fantastic if this activator Nrf2 could be targeted to an organ of interest.

“This transcription factor is everywhere in the body, although it is not always intuitively correct to upregulate its target genes in every tissue. Upregulation in vascular tissue in patients with atherosclerosis, for example, may not be advisable.

“However, if we could target a nanoparticle containing a plant-derived compound or drug that activates cellular antioxidant defences, to the brain or to the heart, then that would be fantastic! Targeting and precision – that strategy is the new world.”

Even though we understand many of the mechanisms, it is really important that we understand the application in modern science, says Mann. “For example the COVID RNA vaccines were created in just six months on the back of the CRISPR Nobel Prize – that just shows you what science can do,” he says.

“In the free radical field, we need to understand how to use precision medicine or patient-designed medicine to alleviate issues; it’s not that easy, because free radical damage occurs everywhere, but a patient with renal or liver disease, or an issue in the brain, would need a therapy that targets that specific area.

“A normal cell – tissue, muscle, fibre, brain – needs a certain basal, control level of free radicals because they are molecules that signal, they activate protective pathways. So if you take them all away by scavenging them with Vitamin E or Vitamin C, you are preventing the normal protective role of radicals in a cell of governing homeostasis.”

A key take-away for Longevity.Technology readers would not be that people should eat antioxidants to scavenge free radicals; rather, says Mann, look for the activators, such as sulforaphane, of the transcription factor NRF2. “Use these products to activate the endogenous antioxidant enzymes inside the cell,” he says. “Triggering the pathway that switches on the protective genes is the key – targeting the cellular antioxidant pathways, rather than just a blanket scavenging of free radicals.

“If we have the precision medicine from natural products that we know how they work at a molecular level, and we can target them to the cell in the brain, we are in a position to modulate the environment and to protect.”

Further information on SFRR-International is available here with insights to previous SFRRI meetings in London (2012), Kyoto (2014), San Francisco (2016), Lisbon (2018) available here.

Longevity.Technology’s interviews with key SFRRi speakers Professor Barry Halliwell ergothioneine on ergothioneine and Professor José Viña on supplements and Alzheimer’s are also available.

Image courtesy of Giovanni Mann