5-HT2c Receptor Mediated Neuroprotection in Postmenopausal Alzheimer's Disease

摘要

Objective: Alzheimer's disease(AD) is a neurodegenerative disorder with a high incidence in postmenopausal women, in which neuronal loss is one of the core pathological features. This report systematically explores the roles and mechanisms of the phytoestrogen Biochanin A(BCA) and a modified estrogen receptor β(ERβ) agonist MG01 in postmenopausal mouse model, with a focus on the regulation of mitochondrial homeostasis, ferroptosis, and targeted optimization strategies. Methods: ovariectomy operation(OVX) C57 and APP/PS1 mice were subjected to BCA and MG01 intervention and behavioral tests, followed by histological staining, immunofluorescence, western blot, and ELISA to assess neuronal morphology, mitochondrial function, lipid peroxidation, and ferroptosis. High-performance liquid chromatography(HPLC) was employed to determine the concentration of MG01 in mouse blood and cerebrospinal fluid, in order to evaluate its pharmacokinetic profile and brain penetration characteristics. Results: Its neuroprotective actions occur through multiple pathways: From one perspective, BCA regulates mitochondrial homeostasis by activating the peroxisome proliferator-activated receptor gamma coactivator-1α(PGC-1α) pathway to promote mitochondrial biogenesis, modulating the phosphorylation of dynamin-related protein 1(Drp1) to restore mitochondrial dynamics, and activating the PTEN-induced putative kinase 1(PINK1)/Parkin ubiquitin ligase pathway to enhance mitophagy and eliminate damaged mitochondria. On the other hand, BCA helps maintain redox balance, for example by upregulating glutathione peroxidase levels to facilitate the clearance of lipid peroxidation products, thereby protecting neurons from oxidative injury and ferroptosis, and ultimately improving cognitive function in ovariectomized AD mouse models. Compared with BCA, the novel optimized ERβ agonist MG01 demonstrates higher blood-brain barrier permeability and brain bioavailability, enabling more efficient activation of ERβ signaling. Consequently, MG01 shows stronger efficacy in regulating mitochondrial homeostasis, inhibiting ferroptosis, and improving cognition. Conclusion: Notably, estrogen deficiency can induce mitochondrial dysfunction and reactive oxygen species(ROS) accumulation even before cognitive impairment occurs; the generation of iron-dependent lipid peroxides further amplifies these damages, forming a vicious cycle of“ mitochondrial dysfunction-ferroptosis-neuronal loss.” Collectively, phytoestrogens and ERβ-targeted agonists MG01 disrupt this cycle and provide multi-targeted, highly specific potential therapeutic strategies for postmenopausal AD, offering both experimental evidence and theoretical support for the development of safe and effective treatments.

关键词

phytoestrogen / ovariectomy / pharmacokinetic / mitochondrial homeostasis / ferroptosis / cognitive function