Activating select estrogen receptor shows promise in lab models

Cianidanol may protect dopaminergic neurons via hormone's beta receptor

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Treatment with cianidanol, a plant molecule that can activate a specific estrogen receptor in the brain, showed neuroprotective potential in cell and animal models of Parkinson’s disease, a study reports.

The identification of cianidanol as a selective estrogen receptor beta agonist and evaluation of its neuroprotective effects on Parkinson’s disease models,” was published in Life Sciences.

Parkinson’s disease is marked by the progressive death and dysfunction of dopaminergic neurons — specialized nerve cells in the brain that are responsible for making the signaling molecule dopamine. While the exact mechanisms that drive Parkinson’s are not fully understood, toxic clumps of alpha-synuclein protein in the brain are thought to play a major role.

Parkinson’s affects men more often than women. The reasons for these gender-based differences are unclear, but one possible explanation has to do with estrogen, a hormone that is typically higher in women than men.

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Activating estrogen receptor beta affected nerve cells, alpha-synuclein

Studies have shown that estrogen exerts protective effects on dopaminergic neurons, which may help to shield these cells from Parkinson’s-driving damage. Theoretically, compounds that mimic estrogen’s nerve-protecting effects might be useful for treating Parkinson’s.

Estrogen works by binding to specific receptors on cells. There are several different estrogen receptors (ERs) in the brain, including ERalpha and ERbeta. Experimental data has shown that activating both of these receptors can help to protect dopaminergic neurons.

ERalpha, however, is the main receptor driving estrogen-related female development, such as breast growth, and a medication activating it could be a source of unwelcome side effects in men with Parkinson’s. ERalpha’s activation also could increase the risk of breast cancer and other health problems in people of all sexes.

Researchers in India set out to identify compounds that do not activate ERalpha, avoiding these potential side effects, but do activate estrogen receptor beta in order to trigger nerve-protecting effects.

They conducted computer-based analyses of more than 500,000 molecules and zeroed in on cianidanol — an antioxidant molecule made by certain woody plants — as a promising candidate.

“Through structure-based drug design we found cianidanol as a potential candidate for selective ER[beta] activation,” the scientists wrote.

The effects of cianidanol were tested in a cell model of Parkinson’s induced by rotenone, a chemical that’s toxic to dopaminergic neurons. Results showed that treatment with cianidanol lessened nerve cell death induced by rotenone, implying a nerve-protective effect. Cianidanol also lowered the expression of alpha-synuclein in the nerve cells.

Adding a chemical that blocks ERbeta prevented cianidanol from showing protective effects, implying that the compound’s benefits in this cell model are mediated by this specific estrogen receptor. Of note, these experiments used relatively low doses of cianidanol, since the researchers found that the compound at high doses could have toxic effects on the nerve cells.

Scientists next evaluated cianidanol’s effects in a rat model of Parkinson’s induced by rotenone. Results suggested that treatment with cianidanol led to improvements in measures of motor function, balance, and cognition.

Cianidanol-treated rats also showed a lesser loss of dopaminergic neurons in their brain. These cell and animal experiments are consistent with the idea that this molecule has nerve-protecting effects that may be of benefit in Parkinson’s disease, the researchers concluded.

More broadly, this work lends support to the idea that selectively activating the estrogen receptor beta might be a viable approach in treatment development for Parkinson’s, they added.