Assistant Director, Research Ethics & Compliance
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Preclinical Research in Stroke and Cerebral Ischemia
We use the intraluminal thread model of middle cerebral artery occlusion (MCAO) in rats as an experimental model for
studying focal cerebral ischemia. The common carotid is isolated and a nylon monofilament suture is surgically inserted into the internal carotid artery and advanced into the circle of Willis at the base of the brain where it obstructs blood flow through the right or left middle cerebral artery (MCA). Such unilateral vascular occlusion can induce focal cerebral ischemia in brain areas perfused by the MCA. By altering the duration or temporal pattern of MCAO, we are able to model various ischemic states such as acute occlusive stroke, surgical ischemia due to occluded cerebral blood flow during lengthy neurosurgery, and transient ischemic attacks.
Neuroprotection during intermittent focal cerebral ischemia with a stable nitroxide antioxidant. We recently tested the neuroprotective efficacy of the stable nitroxide antioxidant Tempol in the intraluminal thread model of MCAO interspersed with repeated bouts of reperfusion in male Sprague Dawley rats. This occlusion schedule (140 min interspersed with five 10-min reperfusion periods) mimics what a neurosurgeon might use to avoid prolonged
ischemia during a lengthy surgery requiring occlusion of cerebral blood flow. However, such reperfusion of blood-starved tissue can lead to reperfusion injury, in part due to the generation of reactive oxygen species. Tempol infusion (10 mg/kg i.v.) during the first 20 min of experimental ischemia, reduced sub-cortical and total infarct volumes in response to intermittent transient focal ischemia after 6 hr of recovery/reperfusion. We continue to investigate the usefulness of Tempol as a therapy for acute stroke and as a neurosurgical adjuvant; in particular we are investigating the influence of this compound on ischemia-induced neurogenesis (Collaborators: Keith Kattner, Paul Garris & Susan Farner).
The role of dopamine in ischemia-induced neurodegeneration. The long-term objective of this research is to identify basic mechanisms underlying neurodegeneration associated with stroke. To this end, a novel approach, combining established animal models with state-of-the-art microsensor technology, is being developed for investigating the role of dopamine (DA) in ischemia-induced striatal degeneration. Several lines of evidence support an important role for DA in ischemia. Not only is DA massively released in the striatum during occlusion of cerebral blood flow, but the loss of striatal neurons is reduced by DA depletion, suggesting that released DA drives neurodegeneration. Currently, limitations of DA sampling techniques have precluded a more complete understanding of key issues, including the temporal profile of DA changes during ischemia, factors regulating DA, and the relationship between the onset and severity of ischemia, DA and neurodegeneration. In the present project, we monitor DA using fast-scan cyclic voltammetry (FSCV) at a carbon-fiber microelectrode (CFM). This microsensor technique will advance DA monitoring during ischemia by overcoming technical limitations related to temporal resolution, probe size and chemical specificity. Soon, we will couple DA monitoring with other neural measurements relevant to ischemia in order to obtain a more comprehensive understanding of the interactions between ischemia, DA and neurodegeneration. In particular we plan to monitor both DA and oxygen at the same CFM and develop a dual microsensor consisting of a CFM and a pH sensor. (Collaborators: Paul Garris & John Baur)