Stroke increases neurogenesis (birth of new neurons) through upregulation of ciliary neurotrophic factor (CNTF), a potent neurogenic cytokine made almost exclusively in the central nervous system. Previous study found that CNTF is induced and needed to stimulate neurogenesis in the subventricular zone (SVZ) of mouse brain in a stroke model. CNTF also has a neuroprotective function. Focal adhesion kinase (FAK), protein tyrosine kinase 2, is ubiquitously expressed in various cell types and mediates cell adhesion and migration. We previously discovered that systemic inhibition of FAK upregulates CNTF expression in the SVZ, making FAK a pharmacological target to increase CNTF to promote neurogenesis and neuroprotection after stroke. This study examined whether systemic FAK inhibitor treatment after stroke regulates SVZ neurogenesis and neuroprotection using a middle cerebral artery occlusion (MCAO) to induce a stroke in adult male C57BL/6 mice. A filament was inserted in the external carotid artery and then fed through the carotid bifurcation into the internal carotid artery to the base of the middle cerebral artery. After 30 minutes of occlusion, the filament was removed to restore blood flow. Mice were randomly assigned to receive 3 daily doses of saline or FAK inhibitor (FAK14, i.p., 3 mg/kg) and treatment started at 6 hours, 12 days, or 58 days after MCAO. Because CNTF has a neuroprotective function, the amount of tissue damage was analyzed to compare treatment groups. The neuroprotective role of FAK14 was examined by measuring MCAO-induced infarction. The infarct size was measured using the absence of NeuN (neuronal cell marker) and GFAP (activated astrocytes) and presence of CD68 (activated microglia). FAK14 given at 6 hours post-stroke reduced the infarct size to 38% of the uninjured side of the brain compared to 46% with saline. Proliferating cells were labeled by injecting bromodeoxyuridine (BrdU, 50 mg/kg), the mice were processed 2 h after the last BrdU injection, and proliferated cells in the SVZ were counted with unbiased stereology. There were no significant differences in the total numbers of BrdU+ cells between saline and FAK14 at 3, 14 and 60 days. Future studies are needed to confirm the levels of CNTF at the various times of treatment. If there is no difference in CNTF expression or increased expression of counteracting cytokines, no difference in neurogenesis between groups would be expected. The neuroprotective effect of FAK14 during the acute phase following injury could provide novel pharmacological options to stroke patients extending the current therapeutic treatment window.
| Identifer | oai:union.ndltd.org:ETSU/oai:dc.etsu.edu:asrf-1395 |
| Date | 12 April 2019 |
| Creators | Malone, Hannah M, Jia, Cuihong, Phd, Hagg, Theo, MD, Phd |
| Publisher | Digital Commons @ East Tennessee State University |
| Source Sets | East Tennessee State University |
| Detected Language | English |
| Type | text |
| Source | Appalachian Student Research Forum |
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