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Basic Science and Pathogenesis
Gilbert Charles Morgan1, Chengyun Tang1, Andrew Gregory1
1Augusta University, Augusta, GA, USA.
Background:
Genetic evidence ties EPHX2 (encoding sEH) and PTGS2 (encoding COX-2) to AD/ADRD. Both sEH and COX-2 were elevated in AD/ADRD patients and animal models, affecting pathways related to neurodegeneration, glial activation, vascular function, and inflammation. We previously showed that 3-month sEH inhibition with TPPU (1 mg/kg/day) improved cerebral hemodynamics and cognition in AD/ADRD. This study evaluates the effects of a novel dual COX-2 and sEH inhibitor on cerebral vascular function and cognition in AD.
Methods:
TgF344-AD rats were orally administered PTUPB. Cognitive function was evaluated using the Novel Object Recognition test. Cerebral vascular function was assessed through pressure myography to measure the myogenic responses of the middle cerebral arteries and penetrating arterioles. Additionally, a transcriptomic profile was generated from bulk RNA-seq analysis of primary VSMCs isolated from AD rats treated with either PTUPB or vehicle.
Results:
Body weights, plasma glucose, and HbA1c levels were unaltered in vehicle and drug-treated AD rats. Dual inhibition of COX-2 and sEH improved recognition memory in AD rats associated with enhanced myogenic responses of the freshly isolated middle cerebral arteries and penetrating arterioles. Transcriptomic analysis of primary cerebral vascular smooth muscle cells from AD rats treated with PTUPB revealed enhanced pathways related to cell contraction, alongside decreased oxidative stress and inflammation.
Conclusions:
These findings provide novel evidence that dual inhibition of COX-2 and sEH can reverse cerebrovascular dysfunction and cognitive impairments in AD, demonstrating greater potency than sEH inhibition alone. Our study presents a promising avenue for therapeutic development.
Financial Disclosure:
None.
Funding Resources:
This study was supported by grants AG079336, and AG057842, from the National Institutes of Health, TRIBA Faculty Startup Fund from Augusta University, and 25PRE1365157 from the American Heart Association.
Insights
Dual inhibition of COX-2 and soluble epoxide hydrolase (sEH) improved cognition and cerebral vascular function in Alzheimer's disease (AD) rats. This novel therapeutic approach shows promise for treating AD/ADRD.
Area of Science:
- Neuroscience
- Pharmacology
- Vascular Biology
Background:
- Genetic links between EPHX2 (sEH) and PTGS2 (COX-2) and Alzheimer's disease (AD/ADRD).
- Elevated sEH and COX-2 levels in AD/ADRD patients and models impact neurodegeneration, glial activation, vascular function, and inflammation.
- Previous studies showed sEH inhibition improved cerebral hemodynamics and cognition in AD/ADRD.
Purpose of the Study:
- To evaluate the effects of a novel dual COX-2 and sEH inhibitor on cerebral vascular function and cognition in AD.
- To assess the therapeutic potential of combined COX-2 and sEH inhibition for AD.
Main Methods:
- TgF344-AD rats were treated with the dual inhibitor PTUPB.
- Cognitive function was assessed using the Novel Object Recognition test.
- Cerebral vascular function was measured via pressure myography; transcriptomic profiling of vascular smooth muscle cells was performed.
Main Results:
- Dual COX-2 and sEH inhibition improved recognition memory in AD rats.
- Enhanced myogenic responses in middle cerebral arteries and penetrating arterioles were observed.
- Transcriptomic analysis revealed improved cell contraction pathways and reduced oxidative stress and inflammation.
Conclusions:
- Dual inhibition of COX-2 and sEH reverses cerebrovascular dysfunction and cognitive impairments in AD.
- This dual inhibition strategy demonstrates greater potency than sEH inhibition alone.
- The study presents a promising therapeutic avenue for Alzheimer's disease treatment.
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