Selectivity, efficacy and toxicity studies of UCCB01-144, a dimeric neuroprotective PSD-95 inhibitor

Inhibition of postsynaptic density protein-95 (PSD-95) decouples N-methyl-d-aspartate (NMDA) receptor downstream signaling and results in neuroprotection after focal cerebral ischemia. We have previously developed UCCB01-144, a dimeric PSD-95 inhibitor, which binds PSD-95 with high affinity and is neuroprotective in experimental stroke. Here, we investigate the selectivity, efficacy and toxicity of UCCB01-144 and compare with the monomeric drug candidate Tat-NR2B9c. Fluorescence polarization using purified proteins and pull-downs of mouse brain lysates showed that UCCB01-144 potently binds all four PSD-95-like membrane-associated guanylate kinases (MAGUKs). In addition, UCCB01-144 affected NMDA receptor signaling pathways in ischemic brain tissue. UCCB01-144 reduced infarct size in young and aged male mice at various doses when administered 30 min after permanent middle cerebral artery occlusion, but UCCB01-144 was not effective in young male mice when administered 1 h post-ischemia or in female mice. Furthermore, UCCB01-144 was neuroprotective in a transient stroke model in rats, and in contrast to Tat-NR2B9c, high dose of UCCB01-144 did not lead to significant changes in mean arterial blood pressure or heart rate. Overall, UCCB01-144 is a potent MAGUK inhibitor that reduces neurotoxic PSD-95-mediated signaling and improves neuronal survival following focal brain ischemia in rodents under various conditions and without causing cardiovascular side effects, which encourages further studies towards clinical stroke trials

The site of embolization related to infarct size, oedema and clinical outcome in a rat stroke model - further translational stroke research

<p>Abstract</p> <p>Background and purpose</p> <p>Reliable models are essential for translational stroke research to study the pathophysiology of ischaemic stroke in an effort to find therapies that may ultimately reduce oedema, infarction and mortality in the clinic. The purpose of this study was to investigate the relation between the site of arterial embolization and the subsequent oedema, infarction and clinical outcome in a rat embolic stroke model.</p> <p>Methods</p> <p>Thirty-six male Sprague-Dawley rats were thromboembolized into the internal carotid artery. The site of occlusion was demonstrated by arteriography. Following histological preparation and evaluation, the size of the hemispheres and the infarcts were measured by quantitative histology and planimetry. Another parallel stroke model study was subsequently examined to investigate if the conclusions from the first study could be applied to the second study.</p> <p>Results</p> <p>The median size of the infarct was 40% of the ipsilateral hemisphere in both the 19 animals with occlusion localised to the intracranial part of the internal carotid artery and in the 11 animals where the main trunk of the middle cerebral artery was occluded. In 5 animals, occlusion of the extracranial part of the internal carotid artery resulted in significantly smaller infarcts compared to other groups (p < 0.01). Another independent study re-confirmed these results. Furthermore, significant correlations (R > 0.76, p < 0.0001) were found between 1) cortical, subcortical, and total infarct volumes, 2) oedema in percent of the left hemisphere, 3) clinical score before termination and 4) postoperative weight loss.</p> <p>Conclusions</p> <p>Distal occlusions of the intracranial part of the internal carotid or middle cerebral arteries resulted in comparable large sized infarctions and oedema. This indicates that investigators do not need a similar number of such occlusions in each experimental group. Contrary to observations in the clinic, distal internal carotid artery occlusions did not result in worse outcome than middle cerebral stem occlusions, but this finding may be explained by the controlled emboli size in this experimental stroke model.</p

Meeting Paris agreement objectives will temper seabird winter distribution shifts in the North Atlantic Ocean

We explored the implications of reaching the Paris Agreement Objective of limiting global warming to <2°C for the future winter distribution of the North Atlantic seabird community. We predicted and quantified current and future winter habitats of five North Atlantic Ocean seabird species (Alle alle, Fratercula arctica, Uria aalge, Uria lomvia and Rissa tridactyla) using tracking data for ~1500 individuals through resource selection functions based on mechanistic modeling of seabird energy requirements, and a dynamic bioclimate envelope model of seabird prey. Future winter distributions were predicted to shift with climate change, especially when global warming exceed 2°C under a “no mitigation” scenario, modifying seabird wintering hotspots in the North Atlantic Ocean. Our findings suggest that meeting Paris agreement objectives will limit changes in seabird selected habitat location and size in the North Atlantic Ocean during the 21st century. We thereby provide key information for the design of adaptive marine‐protected areas in a changing ocean