Cytisine and estrogen: A promising duo for protecting brain cells in Parkinson’s

The smoking cessation drug cytisine has demonstrated the ability to protect brain cells in Parkinson’s disease, and new research highlights the critical role of estrogen in enhancing its neuroprotective properties. These findings suggest that cytisine could be a promising treatment for pre-menopausal women with Parkinson’s disease.

In 2021, Sara Zarate and Gauri Pandey, graduate students from the lab of Rahul Srinivasan, MBBS, PhD, assistant professor at the Texas A&M University College of Medicine, co-authored research published in the Journal of Neurochemistry. Their work identified cytisine’s neuroprotective potential, particularly for females with Parkinson’s disease.

Subsequent studies by Zarate, Pandey and Roger Garcia, an MD/PhD candidate, explored the role of estrogen in this effect. Their findings, published recently in npj Parkinson’s under the broader umbrella of Nature, demonstrated that reducing estrogen levels diminished the protective effects of cytisine, underscoring estrogen’s essential role in this process.

A surprising link between smoking and Parkinson’s disease sparked Srinivasan’s exploration of this area two decades ago.

“Our research revealed that tobacco, especially nicotine, reduces the risk of developing Parkinson’s by an impressive 50 percent,” Srinivasan said. “Digging deeper, we found that nicotine helps lower the endoplasmic reticulum (ER) stress response pathway in the cells. When this stress response is overactive, it can cause cell death and brain damage, both of which are key factors in Parkinson’s and other neurodegenerative diseases.”

Although nicotine demonstrates neuroprotective potential, it cannot be used in clinical trials due to significant side effects such as palpitations and fainting episodes. Given this limitation, researchers explored alternatives that retain nicotine’s beneficial effects without the harmful side effects.

Cytisine is a promising candidate because it works similarly to nicotine by targeting the same receptors in the brain. Like nicotine, cytisine helps reduce endoplasmic reticulum (ER) stress by alleviating the protein burden on ion channels. However, unlike nicotine, cytisine’s milder action doesn’t lead to the same cardiovascular side effects, making it a safer choice for potential treatments.

The researchers’ 2021 study investigated cytisine’s neuroprotective effects in models of Parkinson’s disease. Their findings suggest that cytisine could be a safer option for managing neurodegenerative diseases, offering the desired chaperone effect to support neuronal health but with fewer side effects.

In this most recent study, the researchers explored estrogen’s role by depleting its level, either through ovariectomy or by using letrozole, an aromatase inhibitor that blocks estrogen production.

“Interestingly, simply removing the ovaries also provided some protection on its own, but this effect was different from what was seen when estrogen was blocked,” Garcia said. “The neuroprotective effect was restored when estrogen was reintroduced, highlighting the complex interplay between estrogen and cytisine in promoting neuroprotection.”

Srinivasan said he looks forward to this paper’s impact on the broader landscape of medical research and discovery.

“Each paper takes on two crucial meanings. First, it contributes to the ever-growing body of scientific literature, providing lasting value for future generations. Second, it serves as a springboard for the upcoming scientists—like Roger and Gauri—who will build upon this work and carry the torch forward,” Srinivasan said.

These findings have significant implications, especially as the team seeks ways to extend the benefits of cytisine-based neuroprotection to both men and women. Parkinson’s disease exhibits a gender disparity, with men being diagnosed twice as often as women. However, if cytisine were brought to market now, it would be most effective for pre-menopausal women, limiting its broader use. The goal is to expand this therapy to benefit both sexes by finding ways to administer estrogen selectively to the brain without causing systemic feminization in men.

This research is also part of a larger effort to prevent neurodegeneration through early detection and disease-modifying treatments. The team ultimately aims to not only alleviate symptoms or slow disease progression, but also to find ways to detect and offer neuroprotection against the development of Parkinson’s disease.

After their research findings were published in 2021, the team received numerous emails from individuals with Parkinson’s disease, all expressing interest in cytisine and its potential benefits. Srinivasan explained that these messages have been more than just a source of encouragement—they have become a motivating force in the ongoing work.

“These personal connections are a reminder of why this work matters, and I am grateful to be part of this growing scientific community,” he said.

The emails have reinforced the significance of the team’s research, highlighting its potential to improve the lives of those affected by Parkinson’s disease. The team hopes their efforts are making meaningful progress toward positively impacting individuals living with the condition.

Srinivasan emphasized that this was a team effort, and the contributions of researchers like Zarate, Garcia and Pandey are invaluable. For Garcia, it was a major milestone—his first publication indexed in PubMed. For Pandey, this marked her second co-authored publication.

“The first co-author paper in 2021 was only the beginning, and each publication along the way feels like a precious addition to the broader narrative we are working to create in the world of scientific research,” Pandey said.