Abstract
Patients surviving traumatic brain injury (TBI) face numerous neurological and neuropsychological problems significantly affecting their quality of life. Extensive studies over the past decades have investigated pharmacological treatment options in different animal models, targeting various pathological consequences of TBI. Sex and gender are known to influence the outcome of TBI in animal models and in patients, respectively. Apart from its well-known effects on reproduction, 17β-estradiol (E2) has a neuroprotective role in brain injury. Hence, in this review, we focus on the effect of E2 in TBI in humans and animals. First, we discuss the clinical classification and pathomechanism of TBI, the research in animal models, and the neuroprotective role of E2. Based on the results of animal studies and clinical trials, we discuss possible E2 targets from early to late events in the pathomechanism of TBI, including neuroinflammation and possible disturbances of the endocrine system. Finally, the potential relevance of selective estrogenic compounds in the treatment of TBI will be discussed.
Highlights
Introduction diol in Traumatic Brain InjuryMech-Traumatic brain injury (TBI) is defined as an alteration in brain function or any other evidence of brain pathology caused by an external force [1]
E2 originates from a variety of sources, including the gonads, local conversion of circulating androgen precursors via aromatase, and direct synthesis from cholesterol in neurons and the glia [83]. During brain injuries such as TBI, aromatase expression is induced in astrocytes [84,85,86], representing a mechanism of neuroplasticity activated for repair [87]
In the CNS, astrocytes are believed to mediate the action of tibolone [236]: in an in vivo experiment, tibolone attenuated the reactive response of the microglia and astrocytes in the brain after a TBI in OVX female mice [237]
Summary
Traumatic brain injury (TBI) is defined as an alteration in brain function or any other evidence of brain pathology caused by an external force [1]. Several pharmacological treatment options have been tested in animal models, targeting the varied pathological consequences of TBI. More than 130 monotherapies seemed like promising neuroprotective agents in animal models [7] but failed in clinical trials. From these trials, 867 addressed different therapeutic options but only seven dealt with clinical testing of neuroprotective agents. Several clinical studies have demonstrated that males have higher mortality rates and higher incidence of complications than females [10,11,12], suggesting that gonadal steroids such as 17β-estradiol (E2) play a critical role in the outcome of TBI. Clinical trials have shown conflicting results regarding the effectiveness of female sexual hormones in TBI treatment [17,18]. We review the clinical aspects, pathomechanism of TBI, animal models, and E2-induced neuroprotective effects. Based on the findings of preclinical rodent and human clinical studies, the relevance and potential clinical application of E2 and estrogenic compounds in the treatment of TBI will be summarized
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