Estrogen enhances neuroprotective effects of cytisine in female mice
Drug-hormone combo found to help protect brain cells in Parkinson’s model
Estrogen, a female sex hormone, was found to enhance the neuroprotective effects of cytisine, a smoking cessation drug, in a female mouse model of Parkinson’s disease.
That’s according to a study conducted by researchers at Texas A&M University, which analyzed the effects of cytisine in female mice that had been depleted of estrogen. When these animals were treated with estrogen, the neuroprotective effects of cytisine — such as improved survival of nerve cells and better motor function — were restored.
The scientists say these results support the use of cytisine in female Parkinson’s patients who have not yet entered menopause, when menstrual periods permanently stop and the body’s levels of estrogen decline.
“Taken together, our findings suggest that the smoking cessation drug cytisine is a viable neuroprotective drug for premenopausal women with Parkinson’s disease,” the researchers wrote.
Their study, “Systemically circulating 17β-estradiol enhances the neuroprotective effect of the smoking cessation drug cytisine in female parkinsonian mice,” was published in the journal npj Parkinson’s Disease.
Texas A&M team builds on earlier work in Parkinson’s mice
Parkinson’s is caused by the progressive dysfunction of dopaminergic neurons, the nerve cells that produce dopamine, which is a brain chemical messenger important for muscle movement and coordination. Although the disease occurs across the sexes, men are diagnosed with Parkinson’s twice as often as women are.
Several studies have demonstrated that smokers and tobacco users have a lower risk of developing Parkinson’s. In particular, nicotine — the main addictive ingredient in tobacco — has been shown to reduce neuronal death and brain damage.
“Our research revealed that tobacco, especially nicotine, reduces the risk of developing Parkinson’s by an impressive 50 percent,” Rahul Srinivasan, PhD, an associate professor at Texas A&M and the study’s senior author, said in a university news story.
The team also uncovered another impact of nicotine — on the endoplasmic reticulum, or ER, an organelle found in cells that acts like a factory and transportation system for proteins and fats.
“Digging deeper, we found that nicotine helps lower the [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,” Srinivasan said.
Nicotine cannot be used in clinical trials due to its harmful side effects. As such, the scientists turned to cytisine, which was selected as a promising candidate because it binds to the same receptors in the brain, helps to reduce ER stress, and doesn’t lead to nicotine’s adverse effects.
In an earlier study, a Srinivasan team had demonstrated that cytisine attenuated the loss of dopaminergic neurons and improved motor function in a mouse model of Parkinson’s — particularly in females. When further exploring the underlying mechanisms underlying these effects, the researchers found that estrogen contributed to the reduction of neuronal death.
Smoking cessation drug cytisine may be neuroprotective in women
Now, in this new study, the researchers noted that their work highlights the key role of estrogen in enhancing the protective effects of cytisine in Parkinson’s mice.
When the scientists depleted estrogen in female mice, either through the surgical removal of the ovaries — the organs in females that produce estrogen — or using a medication that blocks estrogen production, it led to the loss of the neuroprotective effects of cytisine in dopaminergic neurons.
Specifically, in females where ovaries were removed, there was a loss of the beneficial effects of cytisine in improving motor function, as well as in reducing the activation of cells in the brain. This namely affected astrocytes and microglia, cells that are involved in Parkinson’s progression, by promoting brain inflammation.
However, the researchers noted that, in these animals, the removal of the ovaries by itself was somehow neuroprotective to an extent.
“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,” said Roger Garcia, an MD/PhD candidate and study coauthor.
The researchers hypothesize that this protective effect could be due to compensatory changes in the brain, specifically due to a decrease in the expression of certain dopamine receptors.
Loss of cytisine-mediated neuroprotection was specifically associated with the systemic reduction of estrogen, and not brain-derived estrogen, the team reported. They also noted that the effect of cytisine at preventing the loss of dopaminergic neurons was restored when female mice were treated with estrogen.
These results “[highlight] the complex interplay between estrogen and cytisine in promoting neuroprotection,” Garcia said.
The current study bolsters our view that the smoking cessation drug cytisine prevents … neurons loss … and can therefore be regarded as a potential neuroprotective drug for premenopausal women with [Parkinson’s].
According to the researchers, cytisine at this time would likely be most effective in women prior to menopause. The team’s goal, however, is to expand the potential use of the drug to men, by finding ways to deliver estrogen directly to the male brain while avoiding the feminizing effects that would come with a systemic administration.
Overall, the team concluded that “the current study bolsters our view that the smoking cessation drug cytisine prevents … neurons loss … and can therefore be regarded as a potential neuroprotective drug for premenopausal women with [Parkinson’s].”
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