Estrogen as a Neuroprotectant in Both Sexes: Stories From the Bird Brain

10 posts on estrogen all the way back to Jan. 2012 just to show you how fucking incompetent your stroke medical world is.

 If your doctors and stroke hospital aren't getting human research going based on animal studies they don't belong in stroke at all. 

This line from rat testing should have immediately triggered human research;

Acute estrogen therapy during reperfusion improves tissue outcome from experimental stroke.

Estrogen as a Neuroprotectant in Both Sexes: Stories From the Bird Brain

Colin J. Saldanha^*

• Departments of Neuroscience, Biology, Psychology & The Center for Behavioral Neuroscience, American University, Washington, DC, United States

Estrogens such as estradiol (E2) are potent effectors of neural structure and function via peripheral and central synthesis. In the zebra finch (Taeniopygia guttata), neural E2 synthesis is among the highest reported in homeotherms due to the abundant constitutive expression of aromatase (E-synthase) in discrete neuronal pools across the forebrain. Following penetrating or concussive trauma, E2 synthesis increases even further via the induced expression of aromatase in reactive astrocytes around the site of damage. Injury-associated astrocytic aromatization occurs in the brains of both sexes regardless of the site of injury and can remain elevated for weeks following trauma. Interestingly, penetrating injury induces astrocytic aromatase more rapidly in females compared to males, but this sex difference is not detectable 24 h posttrauma. Indeed, unilateral penetrating injury can increase E2 content 4-fold relative to the contralateral uninjured hemisphere, suggesting that glial aromatization may be a powerful source of neural E2 available to circuits. Glial aromatization is neuroprotective as inhibition of injury-induced aromatase increases neuroinflammation, gliosis, necrosis, apoptosis, and infarct size. These effects are ameliorated upon replacement with E2, suggesting that the songbird may have evolved a rapidly responsive neurosteroidogenic system to protect vulnerable brain circuits. The precise signals that induce aromatase expression in astrocytes include elements of the inflammatory cascade and underscore the sentinel role of the innate immune system as a crucial effector of trauma-associated E2 provision in the vertebrate brain. This review will describe the inductive signals of astroglial aromatase and the neuroprotective role for glial E2 synthesis in the adult songbird brains of both sexes.

The effects of estrogens such as 17β-estradiol (E2) on the structure and function of the vertebrate central nervous system (CNS) are well known (1–6). These include organizational effects such as the masculinization and feminization of neural circuits perinatally (1, 5, 7), organizational and activational effects during adolescence [reviewed in (8)], and activational effects on a diverse set of physiological endpoints during adulthood including, but not limited to, reproductive and aggressive behaviors, cognition, mood, motor control, and mood [see (9)]. We have more recently learned that the influence of this steroid extends even further than the physiology of the normal brain and potently modulates many processes involved in pathological conditions such as traumatic brain injury (TBI).

Influence of E2 on the Injured Brain

Traumatic brain injury is defined in the clinical realm as a disruption in the normal function of the brain caused by percussive, concussive, or penetrating head injury. The incidence of TBI is strongly sexually dimorphic and male biased: a demographic characteristic attributed to higher rates of risky behavior in younger males [see (10) for review]. Following TBI, however, the predicted outcome and recovery of females are better than those of males (11). The underlying reason for this is hinted at by the observation that premenopausal women and those on hormone replacement have a lower risk of neurotraumatic events such as stroke, compared to the respective groups of age-matched men (12, 13). Following TBI in humans, both E2 and testosterone (T) decreased in the cerebrospinal fluid (CSF) over time. Importantly, a higher E2/T ratio was associated with lower mortality and better scores on the Glasgow Outcome Scale (GOS) 6 months after TBI (14). It is noteworthy that aromatase gene expression itself has been implicated in human TBI. More specifically, three single-nucleotide polymorphisms on the aromatase gene are associated with worse GOS-6 scores, suggesting that the expression of aromatase following TBI may be associated with differences in clinical outcomes post-TBI (14). The location of altered aromatase gene expression and the source of steroids in the CSF are unknown, but the pattern of data suggests the possibility that ovarian steroids may protect the brain from injury and/or damage and perhaps may even accelerate recovery.

Among the several steroids synthesized in the vertebrate ovary, E2 appears to be a powerful neuroprotectant as evidenced by multiple studies, using different types of TBI, in many vertebrate species. In rats, gerbils, and mice, females respond more favorably to medial carotid artery occlusion (MCAO) and other experimental inducers of ischemia (15–17). More recently, in mice subjected to controlled cortical impact, males demonstrated larger lesions compared to females (18). All these effects are apparently linked to circulating ovarian steroids because MCAO causes greater neural damage when it is conducted during metestrus compared to estrus, times of the rodent ovarian cycle when circulating E2 levels are low and high, respectively (15). In addition, infarct sizes increase following ovariectomy, and damage is exacerbated further the longer the animal is deprived of ovarian estrogens (19). The data demonstrate a neuroprotective effect of peripheral E2 across several species and types of damage. While it is true that all the aforementioned effects of E2 on the normal and injured brain reflect influences due to circulating levels of this steroid, there is excellent support for the notion that centrally synthesized E2 is a critical modifier of neurophysiological variables in both the normal and the injured CNS.