Neuroprotective effects of estrogen in CNS injuries: insights from animal models

Abstract

Among the estrogens that are biosynthesized in the human body, 17β-estradiol (estradiol or E2) is the most common and the best estrogen for neuroprotection in animal models of the central nervous system (CNS) injuries such as spinal cord injury (SCI), traumatic brain injury (TBI), and ischemic brain injury (IBI). These CNS injuries are not only serious health problems, but also enormous economic burden on the patients, their families, and the society at large. Studies from animal models of these CNS injuries provide insights into the multiple neuroprotective mechanisms of E2 and also suggest the possibility of translating the therapeutic efficacy of E2 in the treatment SCI, TBI, and IBI in humans in the near future. The pathophysiology of these injuries includes loss of motor function in the limbs, arms and their extremities, cognitive deficit, and many other serious consequences including life-threatening paralysis, infection, and even death. The potential application of E2 therapy to treat the CNS injuries may become a trend as the results are showing significant therapeutic benefits of E2 for neuroprotection when administered into the animal models of SCI, TBI, and IBI. This article describes the plausible mechanisms how E2 works with or without the involvement of estrogen receptors and provides an overview of the known neuroprotective effects of E2 in these three CNS injuries in different animal models. Because activation of estrogen receptors has profound implications in maintaining and also affecting normal physiology, there are notable impediments in translating E2 therapy to the clinics for neuroprotection in CNS injuries in humans. While E2 may not yet be the sole molecule for the treatment of CNS injuries due to the controversies surrounding it, the neuroprotective effects of its metabolite and derivative or combination of E2 with another therapeutic agent are showing significant impacts in animal models that can potentially shape the new treatment strategies for these CNS injuries in humans.

Changes in neurosteroidogenesis during demyelination and remyelination in cuprizone‐treated mice

“…Interestingly, MBP protein and mRNA was also recovered in the hippocampus and neocortex, suggesting possible myelin‐protective effects of endogenous steroids. Previous studies have conclusively demonstrated the promyelinating, neuroprotective and anti‐inflammatory effects of sex steroids in the CNS . In cuprizone demyelination, the combined treatment with progesterone and oestradiol of young mice counteracts myelin loss, whereas single progesterone treatment increases the number of mature oligodendrocytes, its precursors (OPCs) and myelin proteins .…”

17β-Estradiol as a Neuroprotective Agent

“…We argue that, despite profound dichotomy between basic science and clinical studies, E2 is ideally suited to be developed as a broad-spectrum neuroprotectant if its action can be restricted to the CNS, that is, to the site of action to avoid undesirable peripheral hormonal burdens. Since neurotrauma triggers a cascade of biochemical events leading to further damages decreasing thereby the chance of appreciable functional recovery [17,20,102,103], chronic pharmacotherapeutic interventions should be considered in the context of translational research. This, on the other hand, brings about critical considerations for safety and efficacy, which highlights the need for brain-selective (or in general CNS-selective) neurotherapy, considering both a preventative and a curative modality.…”

“…Among estrogens and estrogenic compounds, E2 also is the best-known estrogen to be used as a powerful neuroprotective agent in various in vitro and preclinical animal models of neurodegeneration impacting the central nervous system (CNS) [16][17][18][19][20]. It is important to emphasize, though, that E2 has a large array of other beneficial effects in the CNS, including regulating body temperature, enhancing cognition and memory and ameliorating neuropsychiatric conditions in both females and males [7,11,[21][22][23].…”

Examining estradiols neuroprotective abilities and mechanisms of action in cerebrovascular accidents and neurodegenerative conditions

“…Estrogen is a common steroidal sex hormone in women. Four natural estrogens are biosynthesized: estrone (E1), estradiol (E2), estriol (E3), and estetrol (E4) (4,5). E1 has a hydroxyl group at the C3 position, and a ketone group at the C17 position (5).…”

“…Four natural estrogens are biosynthesized: estrone (E1), estradiol (E2), estriol (E3), and estetrol (E4) (4,5). E1 has a hydroxyl group at the C3 position, and a ketone group at the C17 position (5). It is an agonist of the estrogen receptors ERα and ERβ but is considered to be a weak estrogen (4).…”