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After 50 years of research and the testing of over 1,000 drugs, there is new hope for preserving brain cells for a time after stroke. Treating acute ischemic stroke patients with an experimental neuroprotective drug, combined with a surgical procedure to remove the clot improves outcomes as shown by clinical trial results published today in The Lancet.

The multi-center, double-blinded, randomized trial, led by a team at the Cumming School of Medicine's (CSM) Hotchkiss Brain Institute and Alberta Health Services, investigates the use of the neuroprotective drug nerinetide, developed by NoNO Inc, in two scenarios in the same trial. In one scenario, nerinetide is given to patients in addition to the clot-busting drug alteplase. In the second scenario, patients who were not suitable for alteplase received only nerinetide. Both groups of patients had concurrent endovascular treatment (EVT) to remove the clot.

"Compared to placebo, almost 20 per cent more patients who received nerinetide along with endovascular treatment, but did not receive alteplase, recovered from a devastating stroke – a difference between paralysis and walking out of the hospital," says Dr. Michael Hill, MD, a neurologist at Foothills Medical Centre (FMC) and professor in the departments of Clinical Neurosciences and Radiology at the CSM. "In the patients who received both drugs, the alteplase negated the benefits of the nerinetide."

Hill says the study provides evidence of a biological pathway that protects brain cells from dying when they are deprived of blood flow. Nerinetide targets the final stage of the brain cell's life by stopping the production of nitric oxide within the cell.

"We really believe this is a new scientific observation," says Hill. "There is evidence nerinetide promotes brain cell survival, offering neuroprotection until we can extract the clot. It opens the door to a new way of treating stroke."

Images of patients' brains from the study show the expected size of the damage from the stroke is sizeably reduced when nerinetide is administered and EVT is performed among patients not concurrently receiving alteplase.

After so many studies investigating neuroprotective drugs failed, we are extremely excited by these results. While nerinetide is not approved for use yet, it shows the potential of a new tool to promote recovery from stroke."

Dr. Mayank Goyal, MD, PhD, neuroradiologist at the FMC, and clinical professor in the Department of Radiology at the CSM

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Worldwide, 15 million people suffer a stroke each year – that's one every nine minutes in Canada and every 90 seconds in the United States. The results can be devastating. Ischemic stroke, the most common, is caused by a clot in a blood vessel in the brain. The sudden loss of blood flow causes brain cells to die, which can permanently affect speech, vision, balance and movement.

The international trial enrolled 1,105 patients between March 2017 and August 2019 at centres in North America, Europe, Australia, and Asia – a global academic collaboration bringing together scientists, clinicians, funding agencies, and industry.

"The collaboration between NoNO Inc., the University of Calgary and investigators at 48 leading stroke hospitals around the world has shown how effective such an academic-industry partnership can be in running high-quality, foundational stroke trials that can lead to positive changes in clinical practice," says Dr. Michael Tymianski, MD, PhD, CEO of NoNO Inc. and the inventor of nerinetide.

The results in the current study, called the ESCAPE-NA1 Trial, build on the success of the ESCAPE trial, in which the Calgary Stroke Program proved that a clot retrieval procedure known as EVT can dramatically improve patient outcomes after an acute ischemic stroke. During the procedure, a catheter is inserted in the groin and guided through blood vessels into the brain. A tiny metal mesh device is used to grab the clot and pull it out. The current study investigates whether administering nerinetide in addition to clot retrieval improves the patient's ability to recover.

Source:

University of Calgary

Journal reference:

Hill, M.D, et al. (2020) Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial. The Lancet. doi.org/10.1016/S0140-6736(20)30258-0.

Using cutting-edge imaging technology, researchers at Massachusetts General Hospital (MGH) have shown that the brains of young men with autism spectrum disorder (ASD) have low levels of a protein that appears to play a role in inflammation and metabolism. This surprising discovery, which published online today in the journal Molecular Psychiatry provides an important new insight into the possible origins of ASD, which affects one in 59 children.

ASD is a developmental disorder that emerges in early childhood and is characterized by difficulty communicating and interacting with others. While the cause is unknown, growing evidence has linked ASD to inflammation of brain tissue, or neuroinflammation. One sign of neuroinflammation is elevated levels of a substance called translocator protein (TSPO), which can be measured and located in the brain using positron-emission tomography (PET) and anatomical magnetic resonance imaging (MRI). The MGH study, led by Nicole Zurcher, PhD, an investigator in MGH's Athinoula A. Martinos Center for Biomedical Imaging, was the first to use a new generation of PET "tracers," which more accurately detect TSPO, to examine the brains of people with ASD.

In the study, Zurcher and her colleagues scanned the brains of 15 young adult males (average age, 24) with ASD. The group included both high- and low-functioning subjects with varying degrees of intellectual abilities. For comparison, Zurcher's team scanned the brains of 18 healthy control subjects who were similar in age. The investigators hypothesized that the scans would show increased levels, or expression, of TSPO in subjects who have ASD.

"To our surprise, that's not what we saw," says Zurcher. Instead, the scans showed that the brains of males with ASD had lower levels of TSPO than those of the healthy subjects. In fact, the men with the most severe symptoms of ASD tended to have the lowest expression of TSPO. When the tests were repeated several months later, the pattern persisted. The brain regions found to have low expression of TSPO have previously been linked to ASD in earlier studies, and are believed to govern social and cognitive capacities such as processing of emotions, interpreting facial expressions, empathy, and relating to others. "We know these brain regions are involved in autism," says Zurcher.

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To understand this unexpected finding, Zurcher notes that TSPO does more than serve as a marker of inflammation. "It has multiple complex roles," she says, and some actually promote brain health. For example, adequate TSPO is necessary for normal functioning of mitochondria, which are the "power houses" in cells that produce energy. Earlier research has linked malfunctioning mitochondria in brain cells to ASD.

Zurcher and her colleagues next plan to study brains from deceased donors with the goal of determining which brain cells in people with ASD might experience mitochondrial dysfunction, which she says may well be occurring alongside neuroinflammation and other mechanisms to cause ASD.

Our study has generated new hypotheses that now need to be investigated. There's more work to be done."

Nicole Zurcher, PhD, investigator, MGH's Athinoula A. Martinos Center for Biomedical Imaging

Source:

Massachusetts General Hospital

Journal reference:

Zürcher, N.R., et al. (2020) [11C]PBR28 MR–PET imaging reveals lower regional brain expression of translocator protein (TSPO) in young adult males with autism spectrum disorder. Molecular Psychiatry. doi.org/10.1038/s41380-020-0682-z.