Hormone cycles dictate how the brain absorbs neuroprotective drugs
A new study published in Genomic Psychiatry suggests that clinical trials for brain-targeting drugs often fail because they rely on broad averages that overlook the influence of biological sex and hormonal fluctuations. Researchers led by Professor Illana Gozes at Tel Aviv University found that the drug davunetide, designed to stabilize neuronal scaffolding, shows varying uptake levels in the brain depending on the estrous cycle in mice and sex-specific physiological differences in humans.
Did You Know? During the proestrus phase of the estrous cycle, when estrogen levels are at their peak, female mice demonstrated significantly higher uptake of davunetide in the head region compared to male mice, with a p-value of 0.00029.
How Hormonal Cycles Affect Drug Delivery
The research team utilized a fluorescent tag and live imaging to track how intranasal davunetide moved through the bodies of mice. They observed that the drug’s path to the brain is not uniform but is instead influenced by the subject’s hormonal state. When estrogen levels were highest during the proestrus and estrus phases, the drug reached the brain in greater concentrations than in males. As the cycle progressed to metestrus and estrogen levels declined, the disparity between sexes diminished.
According to the study, this suggests that the blood-brain barrier and the tone of blood vessels are regulated by estrogen, which in turn dictates how much of the drug successfully reaches its target. This mechanism may explain why previous large-scale clinical trials for davunetide in patients with progressive supranuclear palsy failed to show a consistent effect.
Evidence from Human Pharmacokinetic Data
To determine if these findings held relevance for humans, the researchers analyzed data from a previous study involving two men and six women. While the cohort was small, the results indicated that women tended to reach higher peak concentrations of the drug, with the highest female peak exceeding the highest male peak by more than double. Conversely, men appeared to retain the drug for longer periods, with a significant half-life difference (p-value of 0.0057).
Expert Insight: The findings suggest that by failing to account for sex-specific physiology, researchers risk discarding potentially effective treatments. For complex conditions like Alzheimer’s disease, which disproportionately affects women, the traditional “one-size-fits-all” dosing model may fundamentally miscalculate how a drug interacts with the patient’s brain.
What May Happen Next
Future clinical trials could incorporate sex and hormonal status as core variables to better understand drug efficacy. Because the current study indicates that a drug’s performance may depend on the timing of administration relative to biological cycles, researchers might explore “precision” dosing schedules. If subsequent, larger-scale research confirms these patterns, the pharmaceutical industry may need to adjust how it designs protocols for tauopathies, ensuring that biological sex is no longer averaged out of the final results.
Frequently Asked Questions
What is davunetide?
Davunetide, also known as NAP, is a short protein fragment that stabilizes microtubules—the microscopic scaffolding inside nerve cells—to protect the brain’s internal wiring.
Why did previous trials for this drug fail?
The study suggests that trials previously used broad averages that failed to account for biological sex and hormonal cycles, which influence how the drug travels through the body and into the brain.
How does estrogen influence the drug?
Estrogen influences blood-brain barrier integrity and the tone of blood vessels, which directly affects the uptake of intranasal davunetide in the brain region.
Could accounting for biological sex in future drug development lead to more effective treatments for neurological disorders?