Soluble epoxide hydrolase: a next-generation drug target for Alzheimer’s disease and related dementias

Andrew Gregory; Chengyun Tang; Fan Fan

doi:10.4103/nrr.nrr-d-24-00503

September 6, 2024Neural Regeneration ResearchOpen Access

Soluble epoxide hydrolase: a next-generation drug target for Alzheimer’s disease and related dementias

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Key Points

To evaluate the therapeutic potential of soluble epoxide hydrolase (sEH) inhibition for alleviating cerebrovascular dysfunction, neuroinflammation, and cognitive impairment in Alzheimer's disease and related dementias.
Reviewed mechanisms of sEH-mediated degradation of anti-inflammatory epoxyeicosatrienoic acids (EETs) and its downstream impact on neurovascular uncoupling and brain hypoperfusion.
Synthesized findings from preclinical trials of small-molecule sEH inhibitors (TPPU and EC5026) across rodent models of Alzheimer's disease (5xFAD, TgF344-AD) and diabetic dementia (T2DN).
Assessed clinical development data, including early-phase safety and pharmacokinetic trials of sEH inhibitors in human cohorts.
Chronic oral TPPU administration (1 mg/kg/day for 9 weeks) rescued spatial learning and short- and long-term memory deficits in both diabetic ADRD and TgF344-AD rats without altering systemic glucose or body weight.
Pharmacological sEH inhibition normalized middle cerebral artery myogenic reactivity, cerebral blood flow autoregulation, and vascular smooth muscle cell contractility impaired by amyloid-beta.
Inhibition of sEH markedly reduced cortical and hippocampal amyloid plaque burden, lowered neuroinflammatory markers, and increased hippocampal neuronal survival.

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Implication

Preclinical review reveals that soluble epoxide hydrolase inhibition rescues cerebral perfusion and memory in dementia models, highlighting a vascular approach to therapy.

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Gregory et al. (2024) studied this question.

synapsesocial.com/papers/6aaa40cbe8e9244134793ff1 https://doi.org/10.4103/nrr.nrr-d-24-00503

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Soluble epoxide hydrolase: a next-generation drug target for Alzheimer’s disease and related dementias

Key Points

No abstract yet

Implication

Discussion

Cite This Study

Soluble epoxide hydrolase: a next-generation drug target for Alzheimer’s disease and related dementias

Key Points

No abstract yet

Implication

Discussion

Cite This Study

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