Promising Neuroprotection Strategy Published in Stroke

Translational stroke research is in a critical phase, according to Duke Anesthesiology’s Wulf Paschen, PhD, and Wei Yang, PhD, whose research was published in the June 2017 issue of the journal, Stroke, titled “XBP1 (X-Box-Binding Protein-1)-Dependent O-GlcNAcylation Is Neuroprotective in Ischemic Stroke in Young Mice and Its Impairment in Aged Mice Is Rescued by Thiamet-G.” Their study reveals a critical role for the IRE1/XBP1 unfolded protein response branch in stroke outcome, noting that boosting prosurvival pathways to counterbalance the age-related decline in the brain’s self-healing capacity could be a promising strategy to improve ischemic stroke outcome in aged brains.

Drs. Wulf Paschen and Wei Yang

Drs. Wulf Paschen and Wei Yang

As the co-authors of this manuscript report, positive outcomes from neuroprotection treatment strategies aimed to minimize stroke damage have been reported in many pre-clinical stroke studies, but could not be repeated in clinical stroke trials. Many factors that potentially contribute to this disparity in outcomes have been identified. Age has attracted little attention as a factor potentially contributing to unsuccessful translational stroke research, even though the neuroprotection strategies that failed in clinical trials on elderly stroke patients were developed in experimental stroke studies performed primarily in young animals.

Drs. Paschen and Yang’s Molecular Neurobiology Laboratory is working on understanding the mechanisms contributing to the effect of age on stroke outcome. The pathophysiology of acute ischemic stroke has been investigated extensively in animal models. Traditional neuroprotection strategies were designed to improve stroke outcome by interfering with pathological processes triggered by ischemia. However, stroke outcome is also dependent on the brain’s capacity to restore cellular functions impaired by ischemia, and this capacity declines with age. In acute ischemic stroke, irreversibly damaged tissue – the ischemic core – is surrounded by metabolically compromised but still viable and salvageable tissue – the penumbra. The penumbra is, therefore, the primary target for stroke therapy to block the expansion of the ischemic core into the penumbra.

We know that maintenance of protein homeostasis (proteostasis) is key to keep cells functional. We also know that proteostasis is impaired with increasing age,” says Dr. Paschen. “Our current focus of research is to understand the effect of age on maintenance of proteostasis in the stroke penumbra. We found that a cellular pathway playing a pivotal role in restoration of proteostasis impaired by stress is activated in neurons located in the stroke penumbra in young mice but impaired in aged mice (see Stroke manuscript).” Dr. Paschen adds that notably, the dysfunctional proteostasis in the stroke penumbra is associated with worse stroke outcome and can be rescued pharmacologically to improve stroke outcome. He says their pharmacologic strategy can also help neurons to better withstand ischemic stress conditions when provided several hours before the ischemic challenge. This team of investigators expects their observations to have a major impact on translational stroke research and also be of interest for perioperative organ protection.

Dr. Paschen is a professor in anesthesiology in the Basic Science Division and a research professor in neurobiology. Dr. Yang is an assistant professor in anesthesiology, also in the Basic Science Division within Duke Anesthesiology.

Chris KeithPromising Neuroprotection Strategy Published in Stroke
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Cancer-Pain Discovery at Duke Makes Headlines

Ru-Rong Ji, PhDOnce hailed as a breakthrough in cancer treatment, immunotherapies are now raising concerns as doctors note new side effects like severe allergic reactions, acute-onset diabetes and heart damage.

These drugs, which work by unleashing the immune system to fight cancer, are only effective in about a fifth of cases, prompting many patients to wonder if they are worth the risk.

But a new study from Duke University researchers, featured in Duke TODAY and The San Diego Union-Tribune, suggests there may be a quick and easy way to predict which cancer patients are likely to benefit from immunotherapy treatments.

The researchers showed that a molecule called PD-L1, which is blocked by the popular immunotherapy drug, nivolumab, acts not only on immune cells but also on the nerve cells that signal pain. That insight could lead to a simple test that measures subtle differences in pain sensitivity to gauge whether or not the body is responding to treatment.

The findings, published May 22 in the journal, Nature Neuroscience, underscore the surreptitious nature of cancer, which uses a variety of tricks to evade detection by the body’s natural defense mechanisms.

“Cancer cells are smart. We already knew that they produced PD-L1 to suppress the immune system,” said senior study author Ru-Rong Ji, Ph.D., professor of anesthesiology and neurobiology at Duke University School of Medicine. “But there’s another defense system at play as well, and that is pain. We showed that this well-known molecule can mask pain, so that cancers can grow without setting off any alarms before metastasis.”

In its early stages, when cancer cells are just starting to grow and multiply in a given tissue or organ, the disease is not usually painful. But as the cancer becomes more aggressive and spreads throughout the body, these cells secrete thousands of pain-inducing chemicals, which either trigger pain-sensing nerve fibers or, in the case of molecules like nerve growth factor, generate entirely new ones. The pain can become so unbearable that some cancer patients die from opioid overdoses.

Ji has been studying pain for over twenty years. Recently, his group noticed that mouse models of melanoma didn’t show the typical signs of pain that he observed in mice with other kinds of cancer, which would flinch or lick their hind paws whenever they were in discomfort.

Ji also knew that melanoma cells could produce a molecule called PD-L1, which latched onto a receptor called PD-1 on the surface of white blood cells, effectively putting the brakes on the immune response. Ji wondered whether there was a connection. So his team treated mice with nivolumab, a drug that prevents PD-L1 from binding to PD-1. Then they poked the animals’ hind paws with a calibrated filament and measured how much force it took for them to withdraw their hind paws. They found that the mice responded to much lower forces than before treatment, indicating they had become more sensitive to pain. In addition, they also found that nivolumab caused spontaneous pain in mice with melanoma, which made them tend to their affected hindpaws like never before.

Next, the researchers performed the opposite experiment. They injected PD-L1 — the pain-masking factor in this equation — into the hind paws or spinal cord of mouse models of three different kinds of pain — inflammatory, neuropathic and bone cancer pain. In every case, the injections of PD-L1 had an analgesic effect, deadening the mice’s sensitivity to pain.

“The effect was surprisingly fast,” said Ji. “We saw a reduction of pain in under half an hour.”

To figure out the mechanism behind this quick response, Ji’s team examined the sensory neurons of the dorsal root ganglion (DRG), a collection of nerves and neurons near the top of the spinal cord. They isolated these cells from mouse DRGs as well as human DRGs from donors and cultured them in a dish, with or without PD-L1, and then recorded their electrical activity. The researchers found that PD-L1 impaired the ability of sodium channels to fire neurons (action potentials) in response to pain.

Ji believes the finding could potentially lead to new treatments for pain, as well as new ways to predict the efficacy of already existing treatments based on PD-1 and PD-L1. “The response to cancer drugs can take a long time, weeks to months,” he said. “The response to pain happens in minutes to hours.”

Sensory neurons from human dorsal root ganglia, a collection of nerves and neurons near the top of the spinal cord, show red for PD-1, a binding site for immunotherapies against cancer. The blue stain shows cell nuclei. Photo credit: Ru-Rong Ji Lab, Duke Anesthesiology

Sensory neurons from human dorsal root ganglia, a collection of nerves and neurons near the top of the spinal cord, show red for PD-1, a binding site for immunotherapies against cancer. The blue stain shows cell nuclei. Photo credit: Ru-Rong Ji Lab, Duke Anesthesiology

In the future, Ji would like to explore whether the mechanism uncovered in this study also applies to other immunotherapy treatments. He is also interested in working with clinicians to measure changes in patients’ pain sensitivity after treatment, a first step toward developing a diagnostic test.

The study was a collaboration between Duke University and two Chinese universities, Fudan University and Nantong University. Professor Yu-Qiu Zhang from Fudan University, the co-senior author of the paper, is a well-known expert in cancer pain. The lead author, Dr. Gang Chen, was an Assistant Professor at Duke  and is now a Professor at Nantong.

The research was supported by the National Institutes of Health (NS87988, DE17794, and DE22743), the National Science Fund of China (31420103903), and the National Research Foundation of Korea (2013R1A6A3A04065858)

CITATION:  “PD-L1 inhibits acute and chronic pain by suppressing nociceptive neuron activity via PD-1,” Gang Chen, Yong Ho Kim, Hui Li, Hao Luo, Da-Lu Liu, Zhi-Jun Zhang, Mark Lay, Wonseok Chang, Yu-Qiu Zhang, and Ru-Rong Ji. Nature Neuroscience, May 22, 2017. DOI: doi:10.1038/nn.4571

Source: Duke University Office of News and Communications (Durham, N.C. – Tuesday, May 23, 2017)

Chris KeithCancer-Pain Discovery at Duke Makes Headlines
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Dr. Levy Co-Authors Manuscript in NEJM

Jerrold H. Levy, MD, FAHA, FCCMCardiac surgery with the use of cardiopulmonary bypass is a common procedure, with more than one million operations performed in the United States and Europe each year. Studies show that 3 to 14 percent of patients who undergo this type of procedure experience a complication known as the low cardiac output syndrome; prevention of this syndrome is an important therapeutic objective for the improvement of outcomes in this patient population.

Duke Anesthesiology’s Dr. Jerrold Levy co-authored an article published on March 19, 2017 in the New England Journal of Medicine, titled “Levosimendan in Patients with Left Ventricular Dysfunction Undergoing Cardiac Surgery.”

Levosimendan is an inotropic agent that has been shown in small studies to prevent or treat the low cardiac output syndrome after cardiac surgery. In a multicenter, randomized, placebo-controlled, phase 3 trial, investigators evaluated the efficacy and safety of levosimendan in patients with a left ventricular ejection fraction of 35 percent or less who were undergoing cardiac surgery with the use of cardiopulmonary bypass.

The authors concluded that prophylactic levosimendan did not result in a rate of the short-term composite end point of death, renal-replacement therapy, perioperative myocardial infarction, or use of a mechanical cardiac assist device that was lower than the rate with placebo among patients with a reduced left ventricular ejection fraction who were undergoing cardiac surgery with the use of cardiopulmonary bypass.

This study was presented at the Late Breaking Clinical Trials Session of the American College of Cardiology on March 19, 2017.

Chris KeithDr. Levy Co-Authors Manuscript in NEJM
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