Dehydroevodiamine ameliorates neurological dysfunction after traumatic brain injury in mice via regulating the SIRT1/FOXO3a/Bim pathway

• Published in: Phytomedicine (Stuttgart) 2024-03, Vol.125, p.155321-155321, Article 155321
• Main Authors: Xu, Min, Zhao, Yalin, Gong, Mingjie, He, Ziyang, Wang, Wenhua, Li, Yunjuan, Zhai, Weiwei, Yu, Zhengquan
• Format: Article
• Language: English
• Subjects: Bim; Dehydroevodiamine; FOXO3a; Neuroprotection; SIRT1; Traumatic brain injury
• ISSN: 0944-7113; 1618-095X
• DOI: 10.1016/j.phymed.2023.155321

•DEDM inhibits oxidative stress and apoptosis, and ameliorates neurologic dysfunction and secondary brain injury after TBI.•DEDM promotes the deacetylation of FOXO3a by up-regulating the expression of SIRT1, thereby inhibiting the expression of Bim and attenuating the neurological damage after traumatic brain injury, resulting in the improvement of symptoms in mice.•SIRT1 plays a key mediating role in the activation of the SIRT1/FOXO3a/Bim pathway. Traumatic Brain Injury (TBI) poses a considerable public health challenge, resulting in mortality, disability, and economic strain. Dehydroevodiamine (DEDM) is a natural compound derived from a traditional Chinese herbal medicine. Prior studies have substantiated the neuroprotective attributes of this compound in the context of TBI. Nevertheless, a comprehensive comprehension of the exact mechanisms responsible for its neuroprotective effects remains elusive. It is imperative to elucidate the precise intrinsic mechanisms underlying the neuroprotective actions of DEDM. The aim of this investigation was to elucidate the mechanism underlying DEDM treatment in TBI utilizing both in vivo and in vitro models. Specifically, our focus was on comprehending the impact of DEDM on the Sirtuin1 (SIRT1) / Forkhead box O3 (FOXO3a) / Bcl-2-like protein 11 (Bim) pathway, a pivotal player in TBI-induced cell death attributed to oxidative stress. We established a TBI mouse model via the weight drop method. Following continuous intraperitoneal administration, we assessed the neurological dysfunction using the Modified Neurological Severity Score (mNSS) and behavioral assay, followed by sample collection. Secondary brain damage in mice was evaluated through Nissl staining, brain water content measurement, Evans blue detection, and Western blot assays. We scrutinized the expression levels of oxidative stress-related indicators and key proteins for apoptosis. The intricate mechanism of DEDM in TBI was further explored through immunofluorescence, Co-immunoprecipitation (Co-IP) assays, real-time quantitative PCR (RT-qPCR), dual-luciferase assays and western blotting. Additionally, we further investigated the specific therapeutic mechanism of DEDM in an oxidative stress cell model. The results indicated that DEDM effectively ameliorated oxidative stress and apoptosis post-TBI, mitigating neurological dysfunction and brain injury in mice. DEDM facilitated the deacetylation of FOXO3a by up-regulating the expression of the deacetylase SIRT1