Hope for stroke patients as pig brain cells revived four hours after death

In a breakthrough research study, scientists at Yale University, United States, have restored cellular activity in the brains of dead pigs.
The results of the study titled, Restoration of brain circulation and cellular functions hours post-mortem, were published last week in the journal Nature.

The scientists restored the cellular activity of many of the brain cells within the pigs four hours after death. They were able to maintain the function of the cells for the next six hours. While many are comparing the experiment to the sci-fi novel, Frankenstein, those in the scientific community are fascinated.

While the cells were technically alive, there was no electrical activity or consciousness, according to lead researcher Dr. Nenad Sestan, Professor of Neuroscience at the Yale School of Medicine: “This is not a living brain, but it is a cellular active brain. We found no evidence that these brains have any activity, which is associated with perception or consciousness. Activity was completely flat. These brains are really not clinically live brains.”

Until now, it was believed that brain cells die rapidly due to the loss of blood supply after death, and that this process is irreversible.

In humans, similar scenarios can be seen in conditions such as stroke and other brain disorders where a single part of the brain could be affected. “By doing this, we can possibly come up with better therapies for stroke and other disorders that cause cells in the brain to die,” said Sestan.

Also, a new landmark clinical trial shows that a drug lowers the risk of kidney failure by a third in people with Type 2 diabetes and kidney disease.

Professor of medicine at the Stanford University School of Medicine, United States (US) and co-principal investigator of the trial, Dr. Kenneth Mahaffey, said: “For the first time in 18 years, we have a therapy for patients with Type 2 diabetes and chronic kidney disease that decreases kidney failure.

“Now, patients with diabetes have a promising option to guard against one of the most severe risks of their condition.”

The trial involved 4,401 participants in 34 countries.

The drug, canagliflozin, improves on a nearly two-decades-old therapy that is currently the only treatment approved to protect kidney function in people with Type 2 diabetes. In the trial, canagliflozin also was found to reduce the risk of major cardiovascular events.

Canagliflozin increases the excretion of glucose through the kidneys. It has already been approved by the Food and Drug Administration to lower blood glucose in patients with Type 2 diabetes and to reduce the risk of major adverse cardiovascular events in patients with Type 2 diabetes and existing heart disease.

A paper describing the findings of the CREDENCE trial was published in The New England Journal of Medicine and presented at the International Society of Nephrology’s World Congress of Nephrology in Melbourne. Mahaffey, who is director of the Stanford Center for Clinical Research, is the study’s senior author.

The lead author is Vlado Perkovic, MBBS, PhD, executive director of The George Institute for Global Health Australia, and a professor of medicine at the University of New South Wales in Sydney.

Also, researchers at the Icahn School of Medicine at Mount Sinai have demonstrated that the recently developed anti-diabetic drug empagliflozin can treat and reverse the progression of heart failure in non-diabetic animal models. Their study also shows that this drug can make the heart produce more energy and function more efficiently. The results were published in the April 23 issue of the Journal of American College of Cardiology.

“This drug could be a promising treatment for heart failure in both non-diabetic and diabetic patients,” said lead author Juan Badimon, MD, Professor of Cardiology and Director of the Atherothrombosis Research Unit at the Cardiovascular Institute at the Icahn School of Medicine at Mount Sinai.

“Our research can lead to a potential application in humans, save lives, and improve quality of life.”

Meanwhile, Stephen Latham, Director of the Yale Interdisciplinary Center for Bioethics and co-author of the pig brain study published in Nature added that this process of restoration of a highly vascular organ could mean that other organs could also be similarly restored and harvested for donation and use. “It is safe to assume that if this works for preservation of brain cells, it would also work after some tinkering with less sensitive organs in terms of keeping them preserved and keeping their function intact.”

How do you restore cellular function after death? The experiment involved three stages. In the first stage, the scientists developed a blood like solution made of chemicals that could preserve and restore the brain cells. The next step was to find a device that could circulate this chemical solution throughout the brain in the same way as the circulatory system of a living animal.

Finally, the scientists used delicate surgery to isolate the brain and connect it to the essential arteries and veins so as to simulate circulation. The researchers called their system BrainEx.

To prove that their system worked, the team carried out the experiment on around 300 freshly severed heads of pigs from a food processing plant around New Haven, Connecticut over a period of months.

Latham said, “No animals were sacrificed for the research. The heads with the brains in them were obtained from the plant after the pigs had already been slaughtered for food.”

First authors of the study Zvonimir Vrselja and Stefano G. Daniele worked on preparing the brains in the lab and setting up the whole system.

Lantham said that they were trying to revive the cells and were not trying to restore consciousness to the brains of the dead animals. The chemical solution that was substituted for the blood was made in such a way that it would block the neuronal activities of the brain and they also had sedatives ready in the eventuality that the solution brought back the brains to active consciousness.

Sestan said this experiment and its success proves that brain cell death is and does not have to be irreversible. The team explains that this also means that brain death is a much more complex process than earlier believed; “This indicates that cells in the postmortem brain have the capacity to be revived.”

The team will now work on applying the research to patients who have had a stroke and those who have been patients declared brain dead. “It’s very hard to see at the moment that we can do anything where this could be applied to anybody who is in that state,” he concluded.

Andrea Beckel-Mitchener of the National Institute of Mental Health has been working on the BRAIN Initiative that began in 2013. This initiative works to advance neurological research and funded the current study. Beckel-Mitchener said, “This is a real breakthrough for brain research. It’s a new tool that bridges the gap between basic neuroscience and clinical research.”

Meanwhile, Perkovic said: “People with diabetes and kidney disease are at extremely high risk of kidney failure, heart attack, stroke and death. With this definitive trial result, we now have a very effective way to reduce this risk using a once-daily pill.”

Participants in the trial received the best care available for kidney disease under current guidelines, a type of therapy called renin-angiotensin-aldosterone system, or RAAS, blockade. In addition, half were randomly selected to receive canagliflozin, while the other half were given a placebo.

The primary results of the study found that participants who took canagliflozin were 30 percent less likely than the placebo group to develop kidney failure or die from either renal failure or cardiovascular disease. Their risk of kidney failure or death from kidney failure was reduced by 34 percent, and the risk of hospitalization for heart failure or death due to cardiac causes decreased by 31 percent.

People with diabetes can develop kidney disease because prolonged high blood sugar harms blood vessels in the kidney. In addition, diabetes often causes high blood pressure, which can stretch and weaken blood vessels in the organ.

For the past two decades, physicians have largely relied on RAAS blockade to prevent the deterioration of kidney function in diabetic patients. Although RAAS blockade lowers blood pressure and delays progression of kidney disease, patients undergoing this treatment remain at a high risk for renal failure and cardiovascular disease, as well as death from these conditions.

Given that the number of people with Type 2 diabetes worldwide is estimated to rise by 20 percent to 510 million in 2030, “a drug like canagliflozin that improves both cardiovascular and renal outcomes has been eagerly sought by both patients with Type 2 diabetes and clinicians caring for them,” Mahaffey said.

Meanwhile, the United States Food and Drug Administration (FDA) approved Empagliflozin in 2014. It limits renal sugar resorption and is the first drug in the history of type 2 diabetes proven to prolong survival.

While diabetes patients are typically at higher risk of heart failure, past studies have suggested that those who take empagliflozin don’t commonly develop heart failure. Those observations led a team of researchers to question if the drug contains a mechanism, independent of anti-diabetic activity that is linked to heart failure prevention, and whether it could have the same impact on non-diabetics.

Investigators from the Atherothrombosis Research Unit tested the hypothesis by inducing heart failure in 14 non-diabetic pigs. For two months, they treated half of the animals with empagliflozin and the other group with a placebo.

The team evaluated the pigs with cardiac magnetic resonance, 3D-echocardiography, and invasive catheterization at three different points in the study (before inducing, one day after inducing, and at the two-month mark).

At two months, all animals in the group treated with empagliflozin experienced improved heart function. Specifically, those pigs had less water accumulation in the lungs (less pulmonary congestion, which is responsible for causing shortness of breath) and lower levels of biomarkers of heart failure.

Importantly, the left ventricles had stronger contractions (enhanced systolic function), got smaller (less dilated), and were less thick (less hypertrophy), and the heart was a normal shape (less architectural remodeling).

The researchers also found that the drug addressed heart failure by improving cardiac metabolism. The hearts of pigs on the medication were consuming more fatty acids and ketone bodies (three related compounds — acetone, acetoacetic acid, and beta-hydroxybutyric acid — produced during the metabolism of fats) and less glucose, as contrasted with heart failure patients (diabetic and non-diabetic), whose hearts consume more glucose and almost no fatty acids and produces less energy. This boost in metabolism helped the hearts produce more energy and function more strongly and efficiently.

“This study confirmed our hypothesis that empagliflozin is an incredibly effective treatment for heart failure and not only an anti-diabetic drug. Moreover, this study demonstrated that empagliflozin is useful for heart failure independently of a patient’s diabetic status.

Importantly, empagliflozin switches cardiac metabolism toward fatty acid and ketone body consumption, thus allowing the production of more energy in the heart,” explained co-lead author Carlos Santos-Gallego, MD, postdoctoral fellow at the Icahn School of Medicine at Mount Sinai.

“Empagliflozin may be a potentially effective treatment for heart failure patients. This is extremely important because heart failure is a disease with mortality above 50 percent at five years. This study offers a new therapeutic strategy in heart failure, something badly needed given that there have not been new effective drugs for heart failure since the 1990s.”

The authors are currently studying whether empagliflozin is an effective heart failure treatment in non-diabetic human patients in the EMPATROPISM clinical trial.

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