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

Already proven in rats in 1998, which just goes to show how incompetent stroke leadership is.

Estrogen-Mediated Neuroprotection After Experimental Stroke in Male Rats

Originally published August 1, 1998

https://www.dovepress.com/articles.php?article_id=33592

Authors Raghava N, Das BC, Ray SK
Received 5 November 2016
Accepted for publication 23 May 2017
Published 4 July 2017 Volume 2017:6 Pages 15—29
DOI https://doi.org/10.2147/NAN.S105134
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Akshita Wason
Peer reviewer comments 6
Editor who approved publication: Dr Annabel Chen

Narayan Raghava,¹ Bhaskar C Das,² Swapan K Ray<sup>1

1</sup>Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC, USA; ²Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA

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.

Testosterone increases neurotoxicity of glutamate in vitro and ischemia-reperfusion injury in an animal model

When will someone from that Great stroke association analyze all this about testosterone and create a stroke protocol? Do you really think every neurologist is up to studying this and coming to the same conclusion?
http://jap.physiology.org/content/92/1/195.short

Abstract

Increasing evidence has demonstrated striking sex differences in the outcome of neurological injury. Whereas estrogens contribute to these differences by attenuating neurotoxicity and ischemia-reperfusion injury, the effects of testosterone are unclear. The present study was undertaken to determine the effects of testosterone on neuronal injury in both a cell-culture model and a rodent ischemia-reperfusion model. Glutamate-induced HT-22 cell-death model was used to evaluate the effects of testosterone on cell survival. Testosterone was shown to significantly increase the toxicity of glutamate at a 10 μM concentration, whereas 17β-estradiol significantly attenuated the toxicity at the same concentration. In a rodent stroke model, ischemia-reperfusion injury was induced by temporal middle cerebral artery occlusion (MCAO) for 1 h and reperfusion for 24 h. To avoid the stress-related testosterone reduction, male rats were castrated and testosterone was replaced by testosterone pellet implantation. Testosterone pellets were removed at 1, 2, 4, or 6 h before MCAO to determine the duration of acute testosterone depletion effects on infarct volume. Ischemic lesion volume was significantly decreased from 239.6 ± 25.9 mm³ in control to 122.5 ± 28.6 mm³ when testosterone pellets were removed at 6 h before MCAO. Reduction of lesion volume was associated with amelioration of the hyperemia during reperfusion. Our in vitro and in vivo studies suggest that sex differences in response to brain injury are partly due to the consequence of damaging effects of testosterone.

Serum estradiol and risk of stroke in elderly men

You are on your own with your doctor on this.
http://www.neurology.org/content/68/8/563.short

Abstract

Objective: To determine if levels of serum estradiol and testosterone can predict stroke in a population-based sample of elderly men.

Methods: Serum 17β estradiol and testosterone were measured in 2,197 men aged 71 to 93 years who participated in the Honolulu-Asia Aging Study from 1991 to 1993. All were free of prevalent stroke, coronary heart disease, and cancer. Participants were followed to the end of 1998 for thromboembolic and hemorrhagic events.

Results: During the course of follow-up, 124 men developed a stroke (9.1/1,000 person-years). After age adjustment, men in the top quintile of serum estradiol (≥125 pmol/L [34.1 pg/mL]) experienced a twofold excess risk of stroke vs men whose estradiol levels were lower (14.8 vs 7.3/1,000 person-years, p < 0.001). Among the lower quintiles, there were little differences in the risk of stroke. Findings were also significant and comparable for bioavailable estradiol and for thromboembolic and hemorrhagic events. After additional adjustment for hypertension, diabetes, adiposity, cholesterol concentrations, atrial fibrillation, and other characteristics, men in the top quintile of serum estradiol continued to have a higher risk of stroke vs those whose estradiol levels were lower (relative hazards = 2.2; 95% CI = 1.5 to 3.4, p < 0.001). Testosterone was not related to the risk of stroke.

Conclusions: High levels of serum estradiol may be associated with an elevated risk of stroke in elderly men.

Estrogen-Mediated Neuroprotection After Experimental Stroke in Male Rats

If we don't know about testosterone then how about estrogen?  Your doctor should know  how to use this in your stroke protocol. Its only 14 years old so if your doctor hasn't figured out how to incorporate this into your protocol then you need to find an up-to-date doctor. We really need a Great stroke association, this luck of the draw in hoping your doctor is up-to-date is stupid. But don't listen to me, your medical gods are omnipotent.
http://stroke.ahajournals.org/content/29/8/1666.short

Abstract

Background and Purpose—We have previously shown that 17β-estradiol reduces infarction volume in female rats. The present study determined whether single injection or chronic implantation of estrogen confers neuroprotection in male animals with middle cerebral artery occlusion (MCAO) and whether there is an interaction with endogenous testosterone.

Methods—Male Wistar rats were treated with 2 hours of reversible MCAO. In protocol 1, acute versus chronic estrogen administration was examined in groups receiving the following: Premarin (USP) 1 mg/kg IV, immediately before MCAO (Acute, n=13, plasma estradiol=171±51 pg/mL); 7 days of 25 μg (E25, n=10, 10±3 pg/mL) or 100 μg 17β-estradiol (E100, n=12, 69±20 pg/mL) by subcutaneous implant; or saline (SAL, n=21, 3±1 pg/mL). Laser-Doppler flowmetry was used to monitor the ipsilateral parietal cortex throughout the ischemic period and early reperfusion. At 22 hours of reperfusion, infarction volume was determined by 0 2,3,5-triphenyltetrazolium chloride staining and image analysis. In protocol 2, rats were castrated to deplete endogenous testosterone and then treated with estradiol implants: castration only (CAST, n=13, estradiol=5±2 pg/mL), sham-operated (SHAM, n=10, 4±2 pg/mL), estradiol implant 25 μg (CAST+E25, n=16, 7±2 pg/mL) or 100 μg (CAST+E100, n=14, 77±14 pg/mL).

Results—Cortical infarct volumes were reduced in all estrogen-treated groups: Acute (21±4% of ipsilateral cortex), E25 (12±5%), and E100 (12±3%) relative to SAL (38±5%). Caudate infarction was similarly decreased: Acute (39±7% of ipsilateral striatum), E25 (25±7%), and E100 (34±6%) relative to SAL (63±4%). Castration did not alter ischemic outcome; cortical and caudate infarction (percentage of respective ipsilateral regions) were 37±5% and 59±5% in CAST and 39±7% and 57±5% in SHAM, respectively. Estrogen replacement reduced infarction volume in castrated animals in cortex (19±4% in CAST+E25 and 12±4% in CAST+E100) and in caudate (42±6% in CAST+25 and 20±7% in CAST+100). Laser-Doppler flowmetry results during ischemia and reperfusion was not different among groups.

Conclusions—Both acute and chronic 17β-estradiol treatments protect male brain in experimental stroke. Testosterone availability does not alter estradiol-mediated tissue salvage after MCAO.