17β‐estradiol rescues damages following traumatic brain injury from molecule to behavior in mice

Abstract

Traumatic brain injury (TBI) is a public health concern, and causes cognitive dysfunction, emotional disorders, and neurodegeration, as well. The currently available treatments are all symptom-oriented with unsatifying efficacy. It is highly demanded to understand its underlying mechanisms. Controlled cortical impact (CCI) was used to induce TBI in aged female mice subjected to ovariectomy. Brain damages were assessed with neurological severity score, brain infarction and edema. Morris water maze and elevated plus maze were applied to evaluate the levels of anxiety. Apoptosis in the hippocampus was assayed with Fluoro-Jade B staining and TUNEL staining. Western blot was employed to measure the expression of NMDA receptor subunits and phosphorylation of ERK1/2, and biochemical assays were used to estimate oxidative stress. 17beta-Estradiol (E2) was intraperitoneally administered at 10-80 μg/kg once per day for 7 consecutive days before or after CCI. Chronic administration of E2 both before and immediately after CCI conferred neuroprotection, reducing neurological severity score, brain infarction, and edema in TBI mice. Additionally, E2 improved many aspects of deleterious effects of TBI on the hippocampus, including neuronal apoptosis, dysfunction in spatial memory, reduction in NR2B, enhancement of oxidative stress, and activation of ERK1/2 pathway. The present study provides clue for the notion that E2 has therapeutic potential for both prevention and intervention of TBI-induced brain damages.

Direct activation of tachykinin receptors within baroreflex afferent pathway and neurocontrol of blood pressure regulation

“…Taking functional and molecular findings together, the protective effect of estrogen‐specific expression of NKRs in baroreflex afferent pathway could be pinpointed. Consistently, recent animal study showing that intact female mice have a significant lesser damage after traumatic brain injury compared with male and OVX mice and the outcomes of OVX mice recover dramatically with estrogen treatment, suggesting a potential key role of estrogen‐dependent NKRs expression in the protection against neuroinflammation by down‐regulation of SP‐mediated cardiovascular responses, which further explains why the sensitivity to traumatic brain injury and caused brain damage are far less in females.…”

Molecular mechanisms and cellular events involved in the neuroprotective actions of estradiol. Analysis of sex differences

“…Estradiol has been shown to decrease oxidative damage and lipid peroxidation in neural cells in vitro (Nilsen, 2008;Liu et al, 2011;Guo et al, 2012;Rettberg et al, 2014;Sørvik et al, 2018; Table 1) and in rat models of hypoxia-ischemia, traumatic brain injury and Parkinson's disease (Zhang et al, 2009;Zhu et al, 2012;Aguirre-Vidal et al, 2017;Lu et al, 2018). The antioxidant effect of the hormone is mediated by the increase in the brain expression of oxidative stress response enzymes, such as catalase, glutathione peroxidase, superoxide dismutase (SOD), peroxiredoxin 5 and glutaredoxin (Nilsen, 2008;Rettberg et al, 2014).…”

“…3). Thus estradiol prevents apoptosis in neurons exposed to oxygen glucose deprivation (Chen et al, 2015;Guo et al, 2017), H 2 O 2 (Liu et al, 2011;De Marinis et al, 2013;Nuzzo et al, 2017), glutamate (Sribnick et al, 2009), β-amyloid (Yao et al, 2007) or neuroinflammatory molecules (Smith et al, 2009) and in animal models of cerebral ischemia (Ma et al, 2016), traumatic brain injury (Bao et al, 2011;Lu et al, 2018), spinal cord injury (Rong et al, 2012) and retinal degeneration (Nixon and Simpkins, 2012), among others. The protective action of estradiol not only involves the intrinsic apoptotic pathway, since the hormone reduces Fas ligand expression induced by transient global cerebral ischemia in the CA1 subfield of the hippocampus of male rats (Wang et al, 2006) and inhibits Fas-mediated apoptosis in the cerebral cortex of ovariectomized mice exposed to middle cerebral artery occlusion (Jia et al, 2009).…”

The Synthetic Steroid Tibolone Decreases Reactive Gliosis and Neuronal Death in the Cerebral Cortex of Female Mice After a Stab Wound Injury

“…Among these, estradiol exerts a variety of regulatory functions on neurons and glial cells and has neuroprotective properties [1][2][3][4]. In acute brain lesions, estradiol reduces tissue damage and neurological deficits [5,6]. The mechanisms involved in the neuroprotective actions of estradiol include the regulation of reactive gliosis [7][8][9][10][11] and the decrease in the inflammatory activity of astrocytes and microglia [12][13][14].…”