Estrogen Therapy Suggested to Help Treat Parkinson Symptoms Based on Mouse Model

Researchers aiming to better understand the role of estrogen in the development of Parkinson disease (PD) and its potential as a treatment found that brain-selective estrogen therapy resulted in motor improvements in male mice with PD-like symptoms.

The study, published in the Journal of Neuroscience, noted that prior research has found PD to be more common in men and postmenopausal women, who have lower levels of estrogen. Some studies have demonstrated that estrogen can mitigate the symptoms of PD in women, but the safety of therapeutic estrogen has been questioned due to its adverse effects, and some forms of estrogen have been associated with higher PD risk.

Researchers from Harvard Medical School used a mouse model of PD to simulate brain pathology resulting from the accumulation of α-synuclein (αS) seen in PD. The αS tetramer-abrogating model of PD produced motor deficits similar to the phenotype of PD in the male mice by 6 months of age, whereas female mice had less muscle rigor and more frequent limb extension than the males, as well as better endurance and balance in motor tests, suggesting less severe motor symptoms among females.

Further analysis showed that the female mice in the PD model had a higher ratio of αS tetramers to monomers (T:M ratio); tetramers are resistant to aggregation whereas monomers can accumulate into clusters and cause neuronal death.

The researchers found that male and female mice in the PD model that were given a brain-selective form of estrogen (estradiol) had increased αS tetramerization and a reduction in monomers. The T:M ratios showed that the treatment increased αS tetramerization in a stepwise pattern toward the levels seen in phenotypically normal mice.

The estradiol treatment was also found to increase the density of dopaminergic nerve fibers in males so that they were similar to the levels found in females; the treatment also increased the complexity of striatal fibers in male and female mice. After 90 days of treatment with estradiol, males had significantly improved motor performance in terms of their time to climb down a pole (P = .04) and endurance while balancing on an accelerating rotarod (P = .02) compared with their baseline performance.

The female mice did not see significant improvements between baseline and after treatment, although there were positive trends toward improvement in female mice that received the estrogen treatment versus worsening performance in female mice that received no treatment.

In mice of both sexes, there were significant associations between treatment and secure gait, as measured by analysis of fine paw patterns when running (P = .04).

The researchers wrote that selective increase of estrogen in symptomatic male mice alleviated the PD-like pathologies induced by the mouse model of PD, “suggesting action of this sex hormone in regulating the neuronal PD pathology.” Treatment with estradiol “decreased the αS monomer accumulation at membranes and the worsening of αS aggregation, restored vesicle and neurite fiber complexity, and improved the motor phenotypes,” which is consistent with a protective role of estrogen against the severity of PD symptoms.

“Our findings support…a role for estrogen in mitigating PD-like neuropathology in vivo,” they concluded. “Brain-selective estrogen therapy may be useful in delaying or reducing PD symptoms in men and postmenopausal women.”

Reference

Rajsombath MM, Nam AY, Ericsson M, Nuber S. Female sex and brain-selective estrogen benefit α-synuclein tetramerization and the PD-like motor syndrome in 3K transgenic mice [published online August 12, 2019]. J Neurosci. doi: 10.1523/JNEUROSCI.0313-19.2019.