The role for infarct volume as a surrogate measure of functional outcome following ischemic stroke.

The failed translation of proposed therapeutic agents for ischemic stroke from preclinical to clinical studies has led to increased scrutiny of preclinical studies, namely the model and outcome measures utilized. Preclinical studies routinely use infarct volume as an experimental endpoint or measure in studies employing young-adult, healthy male animals despite the fact that clinically, ischemic stroke is a disease of the elderly and improvements in functional outcome from pre- to post-intervention remains the most widely utilized assessment. The validity of infarct volume as a surrogate measure for functional outcome remains unclear in clinical studies as well as preclinical studies, particularly those utilizing a more clinically relevant aged thromboembolic model. In this work, we will address the relationship between acute and chronic functional outcome and infarct volume using a variety of functional assessments ranging from more simplistic, subjective measurements such as the modified Neurologic Severity Score (mNSS), to more complex, objective measurements such as grip strength and inclined plane.

Combination treatment of r-tPA and an optimized human apyrase reduces mortality rate and hemorrhagic transformation 6h after ischemic stroke in aged female rats.

Recombinant tissue plasminogen activator (r-tPA) is the only FDA-approved drug treatment for ischemic stroke and must be used within 4.5h. Thrombolytic treatment with r-tPA has deleterious effects on the neurovascular unit that substantially increases the risk of intracerebral hemorrhage if administered too late. These therapeutic shortcomings necessitate additional investigation into agents that can extend the therapeutic window for safe use of thrombolytics. In this study, combination of r-tPA and APT102, a novel form of human apyrase/ADPase, was investigated in a clinically-relevant aged-female rat embolic ischemic stroke model. We propose that successfully extending the therapeutic window of r-tPA administration would represent a significant advance in the treatment of ischemic stroke due to a significant increase in the number of patients eligible for treatment. Results of our study showed significantly reduced mortality from 47% with r-tPA alone to 16% with co-administration of APT102 and r-tPA. Co-administration decreased cortical (47 ± 5% vs. 29 ± 5%), striatal (50 ± 2%, vs. 40 ± 3%) and total (48 ± 3%vs. 33 ± 4%) hemispheric infarct volume compared to r-tPA alone. APT102 improved neurological outcome (8.9±0.6, vs. 6.8 ± 0.8) and decreased hemoglobin extravasation in cortical tissue (1.9 ± 0.1mg/dl vs. 1.4 ± 0.1mg/dl) striatal tissue (2.1 ± 0.3mg/dl vs. 1.4 ± 0.1mg/dl) and whole brain tissue (2.0 ± 0.2mg/dl vs. 1.4 ± 0.1mg/dl). These data suggest that APT102 can safely extend the therapeutic window for r-tPA mediated reperfusion to 6h following experimental stroke without increased hemorrhagic transformation. APT102 offers to be a viable adjunct therapeutic option to increase the number of clinical patients eligible for thrombolytic treatment after ischemic stroke.

Metabolic Syndrome and its Profound Effect on Prevalence of Ischemic Stroke.

Ischemic stroke represents a leading cause of death worldwide and the leading cause of disability in the United States. Greater than 8% of all deaths are attributed to ischemic stroke. This rate is consistent with the heightened burden of cardiovascular disease deaths. Treatments for acute ischemic stroke remain limited to tissue plasminogen activator and mechanical thrombolysis, both of which require significant medical expertise and can only be applied to a select number of patients based on time of presentation, imaging, and absence of contraindications. Over 1,000 compounds that were successful in treating ischemic stroke in animal models have failed to correlate to success in clinical trials. The search for alternative treatments is ongoing, drawing greater attention to the importance of preclinical models that more accurately represent the clinical population through incorporation of common risk factors. This work reviews the contribution of these commonly observed risk factors in the clinical population highlighting both the pathophysiology as well as current clinical diagnosis and treatment standards. We also highlight future potential therapeutic targets, areas requiring further investigation, and recent changes in best-practice clinical care.

Modeling clinically relevant blast parameters based on scaling principles produces functional & histological deficits in rats.

Blast-induced traumatic brain injury represents a leading cause of injury in modern warfare with injury pathogenesis poorly understood. Preclinical models of blast injury remain poorly standardized across laboratories and the clinical relevance unclear based upon pulmonary injury scaling laws. Models capable of high peak overpressures and of short duration may better replicate clinical exposure when scaling principles are considered. In this work we demonstrate a tabletop shock tube model capable of high peak overpressures and of short duration. By varying the thickness of the polyester membrane, peak overpressure can be controlled. We used membranes with a thickness of 0.003, 0.005, 0.007, and 0.010 in to generate peak reflected overpressures of 31.47, 50.72, 72.05, and 90.10 PSI, respectively. Blast exposure was shown to decrease total activity and produce neural degeneration as indicated by fluoro-jade B staining. Similarly, blast exposure resulted in increased glial activation as indicated by an increase in the number of glial fibrillary acidic protein expressing astrocytes compared to control within the corpus callosum, the region of greatest apparent injury following blast exposure. Similar findings were observed with regard to activated microglia, some of which displayed phagocytic-like morphology within the corpus callosum following blast exposure, particularly with higher peak overpressures. Furthermore, hematoxylin and eosin staining showed the presence of red blood cells within the parenchyma and red, swollen neurons following blast injury. Exposure to blast with 90.10 PSI peak reflected overpressure resulted in immediate mortality associated with extensive intracranial bleeding. This work demonstrates one of the first examples of blast-induced brain injury in the rodent when exposed to a blast wave scaled from human exposure based on scaling principles derived from pulmonary injury lethality curves.