Targeting inflammation and neurogenesis in an animal model of small-vessel stroke
| dc.contributor.advisor | Walz, Wolfgang | en_US |
| dc.contributor.committeeMember | Schreyer, David | en_US |
| dc.contributor.committeeMember | Sulakhe, Prakash | en_US |
| dc.contributor.committeeMember | Fisher, Thomas E. | en_US |
| dc.contributor.committeeMember | Doucette, J. Ronald | en_US |
| dc.contributor.committeeMember | Desautels, Michel | en_US |
| dc.creator | Hua, Rui | en_US |
| dc.date.accessioned | 2007-06-30T16:32:01Z | en_US |
| dc.date.accessioned | 2013-01-04T04:41:24Z | |
| dc.date.available | 2008-07-03T08:00:00Z | en_US |
| dc.date.available | 2013-01-04T04:41:24Z | |
| dc.date.created | 2007 | en_US |
| dc.date.issued | 2007 | en_US |
| dc.date.submitted | 2007 | en_US |
| dc.description.abstract | Therapeutic strategies of stroke can take two directions: to prevent brain damage from stroke or aid in its repair after a stroke. In this thesis, a rat stroke model, which mimics the human small vessel stroke, was used. Two potential repair strategies were investigated with this model, reduction of inflammatory processes with the aid of minocycline treatment and replacing necrotic neurons with new ones with the aid of neurogenesis of endogenous progenitor cells. The stroke model is induced by disrupting the medium-size pial vessels within a 5mm-circular brain surface of adult Wistar rats. This leads to a cone-shaped cortical lesion. Therefore it mimics the clinical situation of lacunar infarction, the most frequent outcome of small vessel stroke. Minocycline, a second-generation tetracycline, prevented cavitation and facilitated the repopulation of the lesion by reactive astrocytes. However, I could not identify the molecular target as the number of activated microglia, infiltrating leukocytes and CD3+ lymphocytes as well as interleukin-1β expression were not significantly altered. Doublecortin (DCX) is a microtubule-associated protein expressed by migrating neuroblasts and immature neurons. After injury, DCX-positive cells appeared in the neocortex at the base of the lesion. These cells exhibit a morphology resembling differentiated post-migratory neurons with long branched processes. Some of the DCX-positive cells were also immunoreactive for βIII-tubulin, another marker of immature neurons. This might indicate a migratory pathway for developing neuroblasts from the subventricular zone (SVZ) through the corpus callosum to the lesion. SVZ cells were labeled with carboxyfluorescein diacetate, succinimidyl ester (CFSE) stereotaxical injections. Although rostral migratory stream and olfactory bulb were intensely labeled, no CFSE containing cells were found in the cortex underneath the lesion. These results suggest that the DCX-positive cells may not originate from neural precursors from the SVZ, but might be generated from local progenitor cells. In summary, using the PVD II model, which mimics the lacunar stroke, I found that neuroblasts appeared spontaneously near the lesion in the cerebral cortex and were attempting to upregulate neuronal properties. Reducing inflammation with post-stroke minocycline treatment prevented cavitation. I think both findings open up exciting new avenues for treatment of lacunar infarctions. | en_US |
| dc.identifier.uri | http://hdl.handle.net/10388/etd-06302007-163201 | en_US |
| dc.language.iso | en_US | en_US |
| dc.subject | minocycline | en_US |
| dc.subject | neuroblasts | en_US |
| dc.subject | reactive gliosis | en_US |
| dc.subject | cavitation | en_US |
| dc.subject | focal ischemia | en_US |
| dc.subject | doublecortin | en_US |
| dc.title | Targeting inflammation and neurogenesis in an animal model of small-vessel stroke | en_US |
| dc.type.genre | Thesis | en_US |
| dc.type.material | text | en_US |
| thesis.degree.department | Physiology | en_US |
| thesis.degree.discipline | Physiology | en_US |
| thesis.degree.grantor | University of Saskatchewan | en_US |
| thesis.degree.level | Doctoral | en_US |
| thesis.degree.name | Doctor of Philosophy (Ph.D.) | en_US |