Doyle, K. P. (2016). Unraveling the pathophysiology of chronic stroke lesions could yield treatments for stroke-related dementia. Future Neurology, 11(1), 1-4.
Han, J., Pollak, J., Yang, T., Siddiqui, M. R., Doyle, K. P., Taravosh-Lahn, K., Cekanaviciute, E., Han, A., Goodman, J. Z., Jones, B., Jing, D., Massa, S. M., Longo, F. M., & Buckwalter, M. S. (2012). Delayed administration of a small molecule tropomyosin-related kinase B ligand promotes recovery after hypoxic-ischemic stroke. Stroke; a journal of cerebral circulation, 43(7), 1918-24.
Stroke is the leading cause of long-term disability in the United States, yet no drugs are available that are proven to improve recovery. Brain-derived neurotrophic factor stimulates neurogenesis and plasticity, processes that are implicated in stroke recovery. It binds to both the tropomyosin-related kinase B and p75 neurotrophin receptors. However, brain-derived neurotrophic factor is not a feasible therapeutic agent, and no small molecule exists that can reproduce its binding to both receptors. We tested the hypothesis that a small molecule (LM22A-4) that selectively targets tropomyosin-related kinase B would promote neurogenesis and functional recovery after stroke.
Doyle, K. P., Nguyen, T. V., Mckay, B. S., Konhilas, J. P., Day, A. W., Figueroa, A., Hayes, M., Constantopoulos, E., Zbesko, J., Frye, J., & Chung, A. (2018). Liquefaction of the brain following stroke shares a similar molecular and morphological profile with atherosclerosis and mediates secondary neurodegeneration in an osteopontin dependent mechanism. eNeuro.
Doyle, K. P., Quach, L. N., Arceuil, H. E., & Buckwalter, M. S. (2015). Ferumoxytol administration does not alter infarct volume or the inflammatory response to stroke in mice. Neuroscience letters, 584, 236-40.
Ferumoxytol is an ultrasmall superparamagnetic iron oxide (USPIO) nanoparticle that is FDA-approved as an intravenous iron replacement therapy for the treatment of iron deficiency anemia in patients with chronic kidney disease. Ferumoxytol has also been used as a contrast agent for cerebral blood volume mapping by magnetic resonance imaging (MRI), which suggests it could be used for imaging hemodynamic abnormalities after stroke. However, circulating macrophages can internalize USPIOs, and recent data indicate that the accumulation of iron in macrophages can lead them to adopt the M1 pro-inflammatory phenotype. Therefore, the uptake of intravenously administered iron particles by circulating macrophages that home to the stroke core could potentially alter the inflammatory response to stroke. To test this possibility in vivo we administered a dose of ferumoxytol previously used to obtain cerebral blood volume maps in healthy humans by steady-state susceptibility contrast (SSC) MRI to BALB/cJ mice 48h after stroke and examined cytokine levels, microglial/macrophage activation, and lesion volume in the brain 5 days later. Treatment with ferumoxytol did not lead to any differences in these parameters. These data indicate that the use of ferumoxytol as a contrast agent for brain imaging after stroke does not alter the inflammatory response to stroke in mice, and is therefore unlikely to do so in human subjects.
West, G. A., Golshani, K. J., Doyle, K. P., Lessov, N. S., Hobbs, T. R., Kohama, S. G., Pike, M. M., Kroenke, C. D., Grafe, M. R., Spector, M. D., Tobar, E. T., Simon, R. P., & Stenzel-Poore, M. P. (2009). A new model of cortical stroke in the rhesus macaque. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 29(6), 1175-86.
Primate models are essential tools for translational research in stroke but are reportedly inconsistent in their ability to produce cortical infarcts of reproducible size. Here, we report a new stroke model using a transorbital, reversible, two-vessel occlusion approach in male rhesus macaques that produces consistent and reproducible cortical infarcts. The right middle cerebral artery (distal to the orbitofrontal branch) and both anterior cerebral arteries were occluded with vascular clips. Bilateral occlusion of the anterior cerebral artery was critical for reducing collateral flow to the ipsilateral cortex. Reversible ischemia was induced for 45, 60, or 90 mins (n=2/timepoint) and infarct volume and neurologic outcome were evaluated. The infarcts were located predominantly in the cortex and increased in size with extended duration of ischemia determined by T(2)-weighted magnetic resonance imaging . Infarct volume measured by 2,3,5-triphenyl tetrazolium chloride and cresyl violet staining corroborated magnetic resonance imaging results. Neurologic deficit scores worsened gradually with longer occlusion times. A subset of animals (n=5) underwent 60 mins of ischemia resulting in consistent infarct volumes primarily located to the cortex that correlated well with neurologic deficit scores. This approach offers promise for evaluating therapeutic interventions in stroke.
