Therapeutic assessment of a novel mitochondrial complex I inhibitor in in vitro and in vivo models of Alzheimer′s disease

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 17, 2025

Abstract Despite recent approval of monoclonal antibodies that reduce amyloid (Aβ) accumulation, the development disease-modifying strategies targeting underlying mechanisms Alzheimer’s disease (AD) is urgently needed. We demonstrate mitochondrial complex I (mtCI) represents a druggable target, where its weak inhibition activates neuroprotective signaling, benefiting AD mouse models with Aβ and p-Tau pathologies. Rational design structure‒activity relationship studies yielded novel mtCI inhibitors profiled in drug discovery funnel designed to address their safety, selectivity, efficacy. The new lead compound C458 highly protective against toxicity, has favorable pharmacokinetics, minimal off-target effects. exhibited excellent brain penetrance, activating pathways single dose. Preclinical APP/PS1 mice were conducted via functional tests, metabolic assessment, vivo 31 P- NMR spectroscopy, blood cytokine panels, ex electrophysiology, Western blotting. Chronic oral administration improved long-term potentiation, reduced oxidative stress inflammation, enhanced biogenesis, antioxidant cellular energetics. These provide further evidence restoration function energetics response mild energetic promising disease- modifying strategy for AD.

Language: Английский

Phenylpropanoids of Eleutherococcus senticosus (Rupr. & maxim.) maxim. Alleviate oxidative stress in Alzheimer's disease in vitro and in vivo models by regulating Mst1 and affecting the Nrf2/Sirt3 pathway

Bioorganic Chemistry, Journal Year: 2025, Volume and Issue: 159, P. 108347 - 108347

Published: March 8, 2025

Language: Английский