Hibernating Ground Squirrels Provide Clues to New Stroke Treatments

Wei Yang, PhD

Wei Yang, PhD

In the fight against brain damage caused by stroke, researchers have turned to an unlikely source of inspiration: hibernating ground squirrels.

While the animals’ brains experience dramatically reduced blood flow during hibernation, just like human patients after a certain type of stroke, the squirrels emerge from their extended naps suffering no ill effects. Now, a team of NIH-funded scientists has identified a potential drug that could grant the same resilience to the brains of ischemic stroke patients by mimicking the cellular changes that protect the brains of those animals. The study was published in The FASEB Journal, the official journal of the Foundation of American Societies for Experimental Biology.

“For decades scientists have been searching for an effective brain-protecting stroke therapy to no avail. If the compound identified in this study successfully reduces tissue death and improves recovery in further experiments, it could lead to new approaches for preserving brain cells after an ischemic stroke,” said Francesca Bosetti, Ph.D., Pharm.D., program director at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS).

An ischemic stroke occurs when a clot cuts off blood flow to part of the brain, depriving those cells of oxygen and nutrients like the blood sugar glucose that they need to survive. Nearly 800,000 Americans experience a stroke every year and 87 percent of those are ischemic strokes.

Currently, the only way to minimize stroke-induced cell death is to remove the clot as soon as possible. A treatment to help brain cells survive a stroke-induced lack of oxygen and glucose could dramatically improve patient outcomes, but no such neuroprotective agents for stroke patients exist.

Recently, researchers led by John Hallenbeck, M.D., an NINDS senior investigator and co-senior author of the study, found that a cellular process called SUMOylation goes into overdrive in a certain species of ground squirrel during hibernation. Dr. Hallenbeck suspected this was how the animals’ brains survived the reduced blood flow caused by hibernation, and subsequent experiments in cells and mice confirmed his suspicions.

“If we could only turn on the process hibernators appear to use to protect their brains, we could help protect the brain during a stroke and ultimately help people recover,” said Joshua Bernstock, a graduate student in Dr. Hallenbeck’s lab and the study’s first author.

SUMOylation occurs when an enzyme attaches a molecular tag called a Small Ubiquitin-like Modifier (SUMO) to a protein, altering its activity and location in the cell. Other enzymes called SUMO-specific proteases (SENPs) can then detach those tags, thereby decreasing SUMOylation. In the current study, Bernstock and his colleagues teamed up with researchers from the NIH’s National Center for Advancing Translational Sciences (NCATS) to examine whether any of over 4,000 molecules from the NCATS small molecule collections could boost SUMOylation by blocking a SENP called SENP2, which would theoretically protect cells from a shortage of life-sustaining substances.

The researchers first used an automated process to examine whether the compounds prevented SENP2 from severing the connection between a tiny metal bead and an artificial SUMO protein created in the lab of Wei Yang, Ph.D., the study’s other senior author and an associate professor at Duke University in Durham, NC. This system, along with computer modeling and further tests performed both in and outside of cells, whittled the thousands of candidate molecules down to eight that could bind to SENP2 in cells and were non-toxic. Two of those – ebselen and 6-thioguanine – were then found to both boost SUMOylation in rat cells and keep them alive in the absence of oxygen and glucose.

A final experiment showed that ebselen boosted SUMOylation in the brains of healthy mice more than a control injection. 6-thioguanine was not tested because it is a chemotherapy drug with side effects that make it unsuitable as a potential stroke treatment. The researchers now plan to test whether ebselen can protect the brains of animal models of stroke.

Because SUMOylation affects a variety of molecules, Bernstock believes his group’s approach could inspire similar attempts to treat neurological conditions by targeting pathways with wide-ranging effects. He also hopes it will prompt others to look to natural models, as he and Dr. Hallenbeck did with the ground squirrel.

“As a physician-scientist, I really like to work on projects that have clear relevance for patients,” Bernstock said. “I always want outcomes that can lend themselves to new therapeutics for people who are in need.”

The study was funded by the Intramural Research Programs of the NINDS and NCATS, NINDS grant NS099590, the NIH-OxCam Fellowship, and the American Heart Association.

References:

Bernstock et al. Quantitative high-throughput screening identifies cytoprotective molecules that enhance SUMO-conjugation via the inhibition of SUMO-specific protease (SENP)2. The FASEB Journal. November 16, 2017. doi: 10.1096/fj.201700711R.

Source: National Institute of Neurological Disorders and Stroke press release (November 17, 2017) 

Chris KeithHibernating Ground Squirrels Provide Clues to New Stroke Treatments
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Neural Discovery at Duke is the Newest Cover of Nature

New research from two Duke University labs in the departments of anesthesiology and cell biology finds that astrocytes and their unique architecture play a significant role in regulating the development and function of synapses in the brain. The manuscript, titled “Astrocytic neuroligins control astrocyte morphogenesis and synaptogenesis,” was published in the November 9, 2017 issue of Nature and featured as the journal’s cover story. Duke Anesthesiology authors include Dr. Ru-Rong Ji, chief of pain research, Dr. Yong-Ho Kim and Di Liu.

An astrocyte (blue) grown in a dish with neurons forms an intricate, star-shaped structure. Neurons’ synaptic proteins appear in green and purple. Overlapping proteins represent the locations of synapses. Credit: Jeff Stogsdill, Duke University

An astrocyte (blue) grown in a dish with neurons forms an intricate, star-shaped structure. Neurons’ synaptic proteins appear in green and purple. Overlapping proteins represent the locations of synapses. Credit: Jeff Stogsdill, Duke University

According to the article, titled “Star-Shaped Brain Cells Orchestrate Neural Connections,” published by Duke TODAY and featured on Duke University’s Med School Blog, this study highlights that the dysfunction of intricate astrocyte cells may underlie devastating diseases such as autism, schizophrenia and epilepsy. The article goes on to state that the Duke team identified a family of three proteins that control the web-like structure of each astrocyte as it grows and encases neuronal structures such as synapses. Switching off one of these proteins not only limited the complexity of the astrocytes, but also altered the nature of the synapses between neurons they touched, shifting the delicate balance between excitatory and inhibitory neural connections.

Dr. Cagla Eroglu, co-author and associate professor of cell biology and neurology at Duke adds that, “We found that astrocytes’ shape and their interactions with synapses are fundamentally important for brain function and can be linked to diseases in a way that people have neglected until now.”

A 3-D-printed model of a single astrocyte from a mouse brain shows the sponge-like structure of these cells. Photo credit: Katherine King, Duke University.

A 3-D-printed model of a single astrocyte from a mouse brain shows the sponge-like structure of these cells. Photo credit: Katherine King, Duke University.

Ben Barres, a professor of neurobiology at Stanford University, who was not involved with the study, praised the findings as “a profoundly important, revolutionary advance” for understanding how interactions between neurons and astrocytes can affect synapse formation.

Dr. Ji is a distinguished professor of anesthesiology in the Duke University School of Medicine, co-director of Duke Anesthesiology’s Center for Translational Pain Medicine and a member of the Duke Institute for Brain Sciences. His Sensory Plasticity and Pain Research Laboratory focuses on identifying molecular and cellular mechanisms that underlie the genesis of chronic pain and developing novel pain therapies that can target those mechanisms.

Chris KeithNeural Discovery at Duke is the Newest Cover of Nature
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