Tocotrienol, a vitamin E compound, has shown great promise in the prevention of stroke.
IMAGINE half of your body suddenly just going limp, or even worse, paralysed. Think of how life would be like going through every day without control of your bladder or bowel. Or not being able to speak clearly, or just living in constant pain.
These are just some of the more typical consequences of stroke, a common cardiovascular incident.
A stroke occurs when one or more of the arteries supplying the brain either gets blocked by a blood clot or artherosclerotic plaque (ischaemic stroke), or bursts and bleeds into the surrounding area (haemorrhagic stroke).
In either case, the brain tissue supplied by the blocked or burst artery is deprived of oxygen and nutrients, causing cell damage, and eventually, death of the affected tissue.
According to the National Stroke Association of Malaysia, stroke is the third most common cause of death in Malaysia, preceded only by heart attacks and cancer.
Every year, an estimated 40,000 people in the country suffer a stroke, and it is estimated to be the single largest cause of severe disability in Malaysia.
If that were not bad enough, as many as two out of five stroke victims are likely to experience another stroke within the first five years of the original attack, according to the United States National Stroke Association.
Now, the good news is that about 80% of strokes are actually preventable.
The key is to control those risk factors for stroke that can be modified. This includes managing high blood pressure, high cholesterol levels and diabetes, quitting smoking, increasing physical activity, and consuming a healthier diet, among others.
Stroke survivors are also usually given antiplatelet agents like aspirin, and anticoagulants like warfarin and heparin, to prevent another stroke.
These drugs work to decrease the ability of the blood to clot, as over 80% of strokes are ischaemic in nature.
However, as with all drugs, they are not without their side effects.
These side effects primarily affect the gastrointestinal system, resulting in irritation of the stomach or bowel, nausea and indigestion.
Cell cultures and rats
In recent years, a team of researchers at The Ohio State University (OSU) in the United States have been looking into the effects of tocotrienols in preventing strokes.
Tocotrienols are one of two types of vitamin E compounds, with the other being tocopherols.
While tocopherols have long been researched, scientists have only started focusing on tocotrienols over the last two decades.
OSU Wexner Medical Centre assistant professor of vascular diseases and surgery Dr Cameron Rink shares that his doctorate supervisor Prof Dr Chandan Sen first described the unique neuroprotective properties of tocotrienols in the very same labs at the University of California, Berkeley, where anatomist Prof Dr Herbert Evans originally discovered vitamin E back in the 1920s.
“In early experiments published in 2000, Dr Sen found that tocotrienols at very low concentrations (nano-molar) could strikingly protect neurons grown in culture against cell death, whereas tocopherols could not.
“These early studies paved the way to study tocotrienol protection against brain injury in animal models when I joined his laboratory in 2002,” explains Dr Rink in an email interview.
As a graduate research assistant, Dr Rink’s work focused on identifying and testing the mechanisms of how tocotrienols protect the brain against ischaemic stroke injury and cell death.
This led to a 2005 paper published in Stroke, an American Heart Association journal, which showed that prophylactic supplementation of natural vitamin E tocotrienols – but not tocopherols – protected against stroke-induced brain injury in rodents.
From there, they moved on to larger animal models.
“To that end, my doctoral training included the development of a large animal model of ischaemic stroke that more closely mimicked the anatomy and pathophysiology of the stroke event as it occurs in the human brain,” says Dr Rink.
“A key benefit of this model is that it enabled, for the first time, a glimpse of the cerebrovascular response during stroke injury by real-time angiographic evaluation of blood flow.”
Not just cell protection
Two important findings were to come out of this research.
Firstly, as with the rodents, the preventive palm tocotrienol complex fed to the larger animals did indeed significantly reduce the size and severity of their stroke-induced injury,
Dr Rink explains that this particular tocotrienol formulation was used as palm oil contains some of the highest concentrations of tocotrienols found in nature.
Secondly, a blinded retrospective review of the cerebral angiograms (X-rays of the brain’s blood vessels) later found that aside from protecting neurons from cell death, tocotrienols also help improve the cerebrovascular collateral blood flow during a stroke.
“Cerebrovascular collaterals refer to a network of blood vessels in the brain with different anatomic origins, such that if one vessel is blocked, another can compensate for loss of blood flow,” he says.
“In humans, collaterals have been documented to provide blood to otherwise stroke-affected brain tissue, and protect against injury.”
He adds: “Interestingly, it is known that stroke survivors with enhanced cerebrovascular collateral blood supply fare better after stroke compared to those with poor collateral circulation.
“However, therapeutic strategies to improve collateral blood flow in the brain remain unknown.”
With this discovery, Dr Rink’s current work is focused on pinpointing how exactly tocotrienols cause the remodelling of collateral blood vessels for improved blood flow during a stroke.
He says: “It is important to note that decades of clinical research now support that neuroprotective agents alone are ineffective at mitigating stroke injury in the brain.
“Specifically, recent reviews have identified more than 1,000 neuroprotective agents that showed promise in a pre-clinical setting, but ultimately failed in clinical trials.
“It is now believed that neuroprotection represents only one of many factors that contribute to effective protection against stroke injury in the brain.
“In this light, evidence that palm tocotrienol complex enables multi-modal mechanisms of protection against stroke-induced brain injury (i.e. neuro and vascular protection) is paramount for clinical translation.”
Moving on to humans
With that in mind, Dr Rink and his colleagues are currently involved in two human clinical trials looking at the protective effects of tocotrienols against stroke.
The first one is a combined phase I and IIA clinical trial that is looking at, and comparing, the effect of tocotrienols in lowering both platelet function and cholesterol levels in healthy individuals and those with high cholesterol levels.
Participants in both groups are randomly assigned to take either a placebo, the palm tocotrienol complex, low-dose aspirin as commonly prescribed to prevent stroke, or a combination of the tocotrienols and aspirin.
The data collection period for this trial is expected to end in October.
The other clinical trial, which started last March, is an observational study involving stroke survivors who had their first stroke or transient ischaemic attack (TIA) within the six months prior to joining the study.
This phase IIB trial aims to look at the effects of providing tocotrienol supplements on top of standard preventive stroke care to the platelet function and cholesterol levels of stroke survivors.
The participants will either receive a placebo, 400mg of palm tocotrienol complex or 800mg of the complex daily throughout the study.
This trial is expected to end in April 2016.
Successful conclusions to these trials will most likely lead to phase III and IV clinical trials, where larger groups of stroke and TIA patients will be observed to see if taking tocotrienols do indeed significantly help to prevent another stroke.
If tocotrienol supplementation does indeed fulfil its promise in preventing stroke in humans – especially without side effects, it will certainly be a game-changer in the management and prevention of stroke.