17β-Estradiol Abrogates Oxidative Stress and Neuroinflammation after Cortical Stab Wound Injury

Abstract

Disruptions in brain energy metabolism, oxidative damage, and neuroinflammation are commonly seen in traumatic brain injury (TBI). Microglial activation is the hallmark of neuroinflammation. After brain injury, microglia also act as a double-edged sword with distinctive phenotypic changes. Therefore, therapeutic applications to potentiate microglia towards pro-inflammatory response following brain injury have become the focus of attention in recent years. Here, in the current study, we investigated the hypothesis that 17β-estradiol could rescue the mouse brain against apoptotic cell death and neurodegeneration by suppressing deleterious proinflammatory response probably by abrogating metabolic stress and oxidative damage after brain injury. Male C57BL/6N mice were used to establish a cortical stab wound injury (SWI) model. Immediately after brain injury, the mice were treated with 17β-estradiol (10 mg/kg, once every day via i.p. injection) for one week. Immunoblotting and immunohistochemical analysis was performed to examine the cortical and hippocampal brain regions. For the evaluation of reactive oxygen species (ROS), reduced glutathione (GSH), and oxidized glutathione (GSSG), we used specific kits. Our findings revealed that 17β-estradiol treatment significantly alleviated SWI-induced energy dyshomeostasis and oxidative stress by increasing the activity of phospho-AMPK (Thr172) and by regulating the expression of an antioxidant gene (Nrf2) and cytoprotective enzymes (HO-1 and GSH) to mitigate ROS. Importantly, 17β-estradiol treatment downregulated gliosis and proinflammatory markers (iNOS and CD64) while significantly augmenting an anti-inflammatory response as evidenced by the robust expression of TGF-β and IGF-1 after brain injury. The treatment with 17β-estradiol also reduced inflammatory mediators (Tnf-α, IL-1β, and COX-2) in the injured mouse. Moreover, 17β-estradiol administration rescued p53-associated apoptotic cell death in the SWI model by regulating the expression of Bcl-2 family proteins (Bax and Bcl-2) and caspase-3 activation. Finally, SWI + 17β-estradiol-treated mice illustrated reduced brain lesion volume and enhanced neurotrophic effect and the expression of synaptic proteins. These findings suggest that 17β-estradiol is an effective therapy against the brain secondary injury-induced pathological cascade following trauma, although further studies may be conducted to explore the exact mechanisms.

SENP5 deteriorates traumatic brain injury via SUMO2-dependent suppression of E2F1 SUMOylation

“…Similar to our findings, p53 was found to be activated in the ischemic areas of brain, which resulted in neuronal apoptosis [25] , and p53 loss or applications of p53 inhibitors significantly attenuated brain damage in several stroke models [26] . Furthermore, 17β-estradiol administration rescued p53-stimulated apoptotic cell death in the cortical stab wound injury model by modulating the expressions of Bax and Bcl-2 and caspase-3 activation [27] . However, the specific role of p53 in SENP5-mediated TBI progression needs to be further verified.…”

Neuroprotective Potential of Raloxifene via G-Protein-Coupled Estrogen Receptors in Aβ-Oligomer-Induced Neuronal Injury

“…However, considering the effects of GPER treatment on Aβo-induced changes in [Ca 2+ ] i , it is unlikely that the inhibitory effects of raloxifene and estradiol on Aβo-induced ROS production can be solely explained by mechanisms mediated by membrane GPER stimulation. It has been reported that raloxifene or estradiol increase the expression of Glutathione-SH, an antioxidant in cells [ 43 , 44 ]. Based on these previous studies, the increased expression of antioxidants, including Glutathione-SH, by raloxifene or estradiol may be caused by the stimulation of GPER, which is expressed in intracellular organelles such as mitochondria and the endoplasmic reticulum.…”

Neuroprotective Effects of Nicotinamide against MPTP-Induced Parkinson’s Disease in Mice: Impact on Oxidative Stress, Neuroinflammation, Nrf2/HO-1 and TLR4 Signaling Pathways

“…Nrf2 also regulates the expression several antioxidants defense genes through several mechanism, including HO-1, which removed the toxic heme, carbon monoxide, and iron ions. Additionally, HO-1 protects the cells against ROS and oxidative stress [ 72 , 73 ]. Furthermore, the natural bioactive supplements like vitamins play an important role against oxidative stress and neurodegeneration [ 74 ].…”