After ischemic stroke, apoptosis of neurons is a primary factor in determining outcome. Wnt3a is a naturally occurring protein that has been shown to have protective effects in the brain for traumatic brain injury. Although wnt3a has been investigated in the phenomena of neurogenesis, anti-apoptosis, and anti-inflammation, it has never been investigated as a therapy for stroke. We hypothesized that the potential neuroprotective agent wnt3a would reduce infarction and improve behavior following ischemic stroke by attenuating neuronal apoptosis and promoting cell survival through the Frizzled-1/PIWI1a/FOXM1 pathway in MCAO rats. 229 Sprague-Dawley rats were assigned to male, female, and aged 9-month male MCAO or sham groups followed by reperfusion 2 hours after MCAO. Animals assigned to MCAO were either given wnt3a or its control. To explore the downstream signaling of wnt3a, the following interventions were given: Frizzled-1 siRNA, PIWI1a siRNA, and PIWI1a-CRISPR, along with the appropriate controls. Post-MCAO assessments included neurobehavioral tests, infarct volume, Western blot, and immunohistochemistry. Endogenous levels of wnt3a, Frizzled-1/PIWI1a/FOXM1, were lowered after MCAO. The administration of intranasal wnt3a, 1 h post MCAO, increased PIWIL1a and FOXM1 expression through Frizzled-1, reducing brain infarction and neurological deficits at 24 and 72 hours. Frizzled-1 and PIWI1a siRNAs reversed the protective effects of wnt3a post MCAO. Restoration of PIWIL1a after knockdown of Frizzled-1 increased FOXM1 survival protein and reduced Cleaved Caspase-3 levels. In summary, wnt3a decreases neuronal apoptosis and improves neurological deficits through Frizzled-1/PIWI1a/FOXM1 pathway after MCAO in rats. Therefore, wnt3a is a novel intranasal approach to decrease apoptosis after stroke.
School of Medicine
Zhang, John H.
Doctor of Philosophy (PhD)
Year Degree Awarded
Date (Title Page)
Library of Congress/MESH Subject Headings
Ischemic Attack, Transient; Cerebral Ischemia; Cerebrovascular Accident; Stroke - Therapy;
Subject - Local
Apoptosis; Traumatic Brain Injury; Neurogenesis
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Matei, Nathanael, "The Role of Wnt3a in Ischemic Stroke" (2018). Loma Linda University Electronic Theses, Dissertations & Projects. 496.
Loma Linda University Electronic Theses and Dissertations
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