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Basic Science and Pathogenesis.

Gilbert Charles Morgan1, Chengyun Tang1, Andrew Gregory1

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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.

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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.