The Role of Wnt3a in Ischemic Stroke

<p>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.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Basic Sciences

Year

2018

Author dc:creator

• Matei, Nathanael

Contributors dc:contributor

• Zhang, John H.
• Goyal, Ravi
• Khan, Salma
• Perry, Christopher
• Tang, Jiping

• Medical Biochemistry
• Medical Sciences
• Medicine and Health Sciences
• Ischemic Attack; Transient; Cerebral Ischemia; Cerebrovascular Accident; Stroke - Therapy;
• Apoptosis; Traumatic Brain Injury; Neurogenesis

Statement dc:rights

• This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Language dc:language

English

Repository record dc:identifier

https://scholarsrepository.llu.edu/etd/496

OAI identifier oai:identifier

oai:scholarsrepository.llu.edu:etd-1501