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.
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.