An Inserm team has recently demonstrated the involvement of endogenous progesterone in brain protection following stroke. But not without touching on a thorny issue: the brains of male and female mice react differently. Evidence in favor not only of rethinking the monopoly of male animals used in research but also of envisioning new ways to treat stroke that take the patient's sex into account.
Deprived of blood, the nervous tissue begins to undergo necrosis very rapidly following a stroke. In Le Kremlin-Bicêtre, a research team* has spent several years studying the role of steroids in the protection of the central nervous system. With her team, Rachida Guennoun is particularly interested in the role and mechanisms of action of progesterone and its metabolites. Her recently published research contains two findings. The first is that women appear to be relatively well-protected from stroke during their fertile years. “A benefit that disappears after menopause,” warns the researcher. And the second is that the administration of exogenous progesterone plays a protective role in various experimental models of brain lesions. Does endogenous progesterone protect the brain following ischemia?
The team tested this hypothesis on male and female mice, both young and old. It began by measuring the brain and plasma levels of progesterone and its active metabolites – capable of binding to the progesterone receptor (PR). It was there that they encountered their first surprise: in normal situations, the brain’s levels of progesterone and 5 alpha-dihydroprogesterone (5alpha-DHP) are much higher in males than in females. However, the females have high levels of 20alpha-dihydroprogesterone (20alpha-DHP), a metabolite that is inactive but that can retransform into progesterone. Furthermore, during the first few hours following a stroke provoked by middle cerebral artery occlusion, cerebral levels of progesterone and 5alpha-DHP soar in males but not in females.
The researchers then studied the effect of cerebral ischemia in mice deprived of the progesterone receptor (PR) in the neural cells. The result? Following a stroke, the extent of necrosis, neuron loss and impact on behavior is much greater than in the control animals. An effect that is even more marked in males. Progesterone therefore protects the brain via its PR receptor, in both sexes. However, females appear to benefit from another protection mechanism, independent of PR. The same experiment performed in elderly animals shows that the protective mechanism involving PR is still in place.
The difference observed between the sexes is fundamentally interesting and also raises some practical questions. Indeed, as explains Guennoun: “the immense majority of experimental research is performed on male animals, for reasons of simplicity: we do not have to worry about the estrous cycle. Then we generalize the results to both sexes.” Therefore, in biomedical and public health research strategies, sex should be considered as a variable – an issue that is beginning to emerge in the scientific community, at Inserm and elsewhere.
In clinical terms, the researcher envisions an early use of progesterone in addition to thrombolysis and/or thrombectomy when treating stroke. “The central area of the infarction is irremediably lost. It is surrounded by a peripheral area of cells that are affected but not destroyed: this is the area that we need to preserve in order to minimize the consequences of stroke,” she explains.
The team will continue its research in three directions. One involves testing synthetic progesterone receptor agonists in male and female animals. Another involves continuing to investigate an intranasal method of progesterone administration by performing dose-response studies, again in both males and females. “The ultimate idea, if we have the means, is to look at what happens in humans, with the neurovascular unit in Bicêtre. First by measuring changes in post-stroke plasma levels of progesterone and its metabolites, and then possibly by conducting clinical trials involving the administration of progesterone or 5a-DHP or PR receptor agonists,” suggests the researcher.
*Neuroprotection and axonal regeneration team, Unit 1195 Inserm/Université Paris-Sud, Neuroprotective, neurogenerative and remyelinating small molecules, Le Kremlin Bicêtre.
Zhu X. et coll. (2017) A role of endogenous progesterone in stroke cerebroprotection revealed by the neural-specific deletion of its intracellular receptors. J. Neurosci. 10.1523/JNEUROSCI.3874-16.2017