Utility of 7, 8-dihydroxyflavone in preventing astrocytic and synaptic deficits in the hippocampus elicited by PTSD. (February 2022)

• Record Type: Journal Article
• Authors: Wang, Juan; Gao, Feng; Cui, Shuai; Yang, Shaojie; Gao, Fang; Wang, Xuncui; Zhu, Guoqi
• Is Part Of: Pharmacological research. Volume 176(2022)
• Publication Date: 2022-02
• Subjects: PTSD post-traumatic stress disorder -- 7, 8-DHF 7, 8-dihydroxyflavone -- SPS single-prolonged stress -- BDNF brain-derived neurotrophic factor -- TrkB tyrosine kinase receptor B -- GFAP glial fibrillary acidic protein -- PSD95 postsynaptic density protein 95 -- GluA1 AMPA receptor subunit GluR1 -- Akt phosphorylated protein kinase B -- mTOR mammalian target of rapamycin -- PTEN phosphatase and tension homolog; Post-traumatic stress disorder -- 7 -- 8-dihydroxyflavone -- Astrocyte -- Synaptic function; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2022.106079
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: Astrocytic functions and brain-derived neurotrophic factor (BDNF)-tyrosine kinase receptor B (TrkB) signaling pathways are impaired in stress-related neuropsychiatric diseases. Previous studies have reported neuroprotective effects of 7, 8-dihydroxyflavone (7, 8-DHF), a TrkB activator. Here, we investigated the molecular mechanisms underlying pathogenesis of post-traumatic stress disorder (PTSD) using a modified single-prolonged stress (SPS&S) model and the potential beneficial effects of 7, 8-DHF. SPS&S reduced the hippocampal expression of glial fibrillary acidic protein (GFAP), a marker of astrocytes, and induced morphological changes in astrocytes. From the perspective of synaptic function, the SPS&S model displayed reduced expression of BDNF, p-TrkB, postsynaptic density protein 95 (PSD95), AMPA receptor subunit GluR1 (GluA1), NMDA receptor subunit N2A/N2B ratio, calpain-1, phosphorylated protein kinase B (Akt) and phosphorylated mammalian target of rapamycin (mTOR) and conversely, higher phosphatase and tension homolog (PTEN) expression in the hippocampus. Acute or continuous intraperitoneal administration of 7, 8-DHF (5 mg/kg) after SPS&S procedures prevented SPS&S-induced fear memory generalization and anxiety-like behaviors as well as abnormalities of hippocampal oscillations. Most importantly, 7, 8-DHF attenuated SPS&S-induced abnormal BDNF-TrkB signaling and calpain-1-dependent cascade of synaptic deficits. Furthermore, treatment with a TrkB inhibitor completely blocked while an mTOR inhibitor partially blocked the effects of 7, 8-DHF on behavioral changes of SPS&S model mice. Our collective findings suggest that 7, 8-DHF effectively alleviates PTSD-like symptoms, including fear generalization and anxiety-like behavior, potentially by preventing astrocytic and synaptic deficits in the hippocampus through targeting of TrkB. Graphical Abstract: ga1