IDB

Postmenopausal osteoporosis (PMOP), driven by estrogen deficiency-induced osteoclast overactivation, poses a significant global health burden with limited therapeutic options. In this study, we investigated the potential of Idebenone (IDB) as a therapeutic agent for PMOP, focusing on its effects on osteoclast differentiation and underlying molecular mechanisms. Bone marrow-derived macrophages (BMMs) were cultured and stimulated to induce osteoclast differentiation, with or without IDB treatment. IDB's effects on osteoclast formation were assessed via TRAcP staining, F-actin ring visualization, resorption pit assays, and Western blotting. Network pharmacology highlighted the protein kinase B (AKT) as a key target, corroborated by molecular docking and CETSA showing IDB-AKT interaction. We found that IDB suppressed osteoclast differentiation and activity through reducing oxidative stress and inhibiting the AKT and mitogen-activated protein kinase (MAPK) signaling pathways. In vivo, ovariectomized (OVX) mice were treated with IDB (50 mg/kg) for six weeks, followed by micro-CT and histomorphometric analysis to evaluate bone microstructure and osteoclast activity. Notably, in OVX mice, IDB treatment significantly improved bone mass compared to controls. These findings suggested that IDB may serve as a promising therapeutic candidate for the treatment of postmenopausal osteoporosis by modulating osteoclast differentiation.

Ischemic stroke (IS) represents a substantial global health threat, but only a few effective medicines exist to treat IS, with a huge unmet clinical need. Idebenone (IDB), a coenzyme Q10 analogue, has multitarget effects, including enhancing mitochondrial energy metabolism, scavenging free radicals, and anti-inflammation, which is approved in Europe for treating Leber's hereditary optic neuropathy (LHON). However, IDB has poor water solubility and oral bioavailability, resulting in insufficient therapeutic plasma concentrations, even following high-dose oral administration, and limiting its use for brain diseases and acute-phase interventions. To address these challenges, we synthesized and identified novel water-soluble IDB prodrugs and found that compound I-7 could adopt intravenous delivery for treating acute IS (AIS) with excellent plasma and brain exposure in normal and IS rats. Besides, I-7 significantly alleviated brain infarct and edema and improved motor function and cerebral blood flow in acute and chronic IS rat models. Compound I-7 is currently undergoing comprehensive evaluation as a preclinical candidate for anti-AIS.