The neuroprotective double-life of estrogen

January 25, 2022

Written by: Omer Zeliger

Around one in four people will suffer a stroke in their lifetime, which can lead to lifetime disability or even death1. While they are more common in the elderly, strokes can happen to anyone and often result in consequences such as paralysis, loss of speech, and difficulty focusing and remembering, all of which can severely impact quality of life and independence2.

The most common type of stroke, called an ischemic stroke, happens when a blood clot temporarily blocks blood flow to the brain3. While every stroke is different, common first symptoms include weakness in one half of the body, confusion, trouble speaking or understanding, and difficulty walking or maintaining balance2. When in doubt, remember FAST – Face drooping, Arm weakness, Speech difficulty, Time to call 9114 – catching a stroke in its early stages can save a life.

Quick treatment is essential for the most successful stroke recovery. If the stroke symptoms are caught in time, doctors can prescribe a tissue plasminogen activator, which breaks down the blood clot and lets blood flow resume. This treatment is associated with better recovery the earlier it is given5. Unfortunately, though, even the best stroke treatments have risks. Reperfusion, which happens when blood flow returns to brain regions that previously lost it, can itself cause damage to brain cells from harmful oxygen-containing molecules, and can even trigger cell death6.

Given these challenges with available treatments, researchers are always looking for ways to improve outcomes for stroke patients. Estradiol, a member of the estrogen hormone family, is capable of protecting against the negative effects of reperfusion, and is correlated with better recovery after a stroke7. Estradiol is neuroprotective, reducing damage from oxygen and stopping programmed cell death that can occur during reperfusion. Estradiol in the blood does this by activating estrogen receptors embedded in the cell’s outer membrane. Not all estrogen receptors are equal; they differ in their functions and their locations in the cell8.

Developing novel treatments requires maximizing benefits and minimizing risk. Though estradiol can help protect against neuron death after a stroke, estrogen-based treatments do come with downsides like increased risk of endometrial or breast cancer9. Crucially, it seems that estradiol’s neuroprotective properties come from its interactions with estrogen receptors on the cell membrane, while the side effects tend to come from estrogen receptors in the cell nucleus10. Therefore, an estrogen-mimicking drug called pathway preferential estrogen-1 (PaPE-1), which binds to membrane estrogen receptors but not nuclear receptors, might be a candidate to help stroke victims recover from reperfusion while minimizing negative side-effects.

Though it’s a promising drug candidate, until recently PaPE-1 still hadn’t been concretely shown to protect neurons against reperfusion damage after a stroke. To answer that question, scientists artificially induced stroke conditions in test-tube grown mouse neurons by depriving them of glucose and oxygen for six hours before mimicking reperfusion by returning oxygen and glucose levels to normal. Neurons that were treated with PaPE-1 during reperfusion were significantly less likely to undergo programmed cell death than the untreated neurons.

This is a promising study that shows how the drug mimics estradiol’s neuroprotective effects, and takes a first step towards refining treatments to help stroke patients. Nevertheless, further research has to be done to determine if PaPE-1 has fewer negative side-effects than estradiol. If in the future clinical trials show that PaPE-1 is safe and effective for humans, this research could make a different in the lives of stroke victims, minimizing the damage from reperfusion and helping them recover their quality of life.


  1. Global Burden of Disease 2016 Lifetime Risk of Stroke Collaborators. “Global, Regional, and Country-Specific Lifetime Risks of Stroke, 1990 and 2016”. The New England Journal of Medicine, 20 December 2018.
  2. National Center for Chronic Disease Prevention and Health Promotion, Division for Heart Disease and Stroke Prevention. “Stroke Signs and Symptoms.” Center for Disease Control and Prevention, 28 August 2020.
  3. National Center for Chronic Disease Prevention and Health Promotion, Division for Heart Disease and Stroke Prevention. “Types of Stroke.” Center for Disease Control and Prevention, 2 August 2021.
  4. American Heart Association. “Stroke Symptoms.” American Stroke Association.
  5. Alexandrov AV, Demchuk AM, Felberg RA, Christou I, Barber PA, Burgin WS, Malkoff M, Wojner AW, & Grotta JC. (2000). High rate of complete recanalization and dramatic clinical recovery during tPA infusion when continuously monitored with 2-MHz transcranial doppler monitoring. Stroke 31(3):610-614.
  6. Orellana-Urzúa S, Rojas I, Líbano L, & Rodrigo R. (2020). Pathophysiology of Ischemic Stroke: Role of Oxidative Stress. Current Pharmaceutical Design 26(34):4246-4260.
  7. Pabon M, Tamboli C, Tamboli S, Acosta S, De La Pena I, Sanberg PR, Tajiri N, Kaneko Y, & Borlongan CV. (2014). Estrogen replacement therapy for stroke. Cell Medicine 6(3):111-122.
  8. Fuentes N & Silveyra P. (2019). Estrogen receptor signaling mechanisms. Advances in Protein Chemistry and Structural Biology 116:135-170.
  9. Barrett-Connor E. (1992). Risks and benefits of replacement estrogen. Annual Review of Medicine 43:239-251.
  10. Wnuk A, Przepiórska K, Pietrzak BA, & Kajta M. (2021). Posttreatment Strategy Against Hypoxia and Ischemia Based on Selective Targeting of Nonnuclear Estrogen Receptors with PaPE-1. Neurotoxicity Research 39:2029-2041.

Cover image by pasja1000 via Pixabay.

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