Contraceptive drugs mitigate experimental stroke-induced brain injury.

Abstract

AIMS:

Effective stroke treatments beyond reperfusion remain scant. The natural steroid hormone progesterone has shown protective effects in experimental models of brain injury and cardiovascular disease. However, unfavourable bioavailability limits its clinical use. Desogestrel and drospirenone are new generation progestins with progesterone-like properties, developed as oral contraceptives with excellent bioavailability and safety profile. We investigated the neuroprotective properties of these progestins in vivo using transient middle cerebral artery occlusion (MCAO) and in vitro using an oxygen-glucose deprivation and reoxygenation (OGD/R) model in primary neuronal cells.

METHODS AND RESULTS:

MCAO was induced in female, female ovariectomized (modelling postmenopausal females) and male mice. Treatment with the progestins resulted in less severe strokes after MCAO and less neuronal death in OGD/R. Desogestrel and drospirenone induced higher expression levels of GABAAR α4 and delta subunits within the brain, suggesting changes in GABAAR configuration favouring tonic inhibition as potential mechanism of action. Treatment with the GABAAR blocker picrotoxin abolished the protection afforded by the progestins in vivo and in vitro.

CONCLUSION:

For the first time, here, we delineate a potential role of desogestrel and drospirenone, both clinically approved and safe drugs in mitigating the consequences of stroke. Contraception with desogestrel and drospirenone in progestin-only preparations may be particularly beneficial for women at risk of stroke.

• Authors: Mohamad El Amki, Nadine Binder, Riccardo Steffen, Hannah Schneider, Andreas R Luft, Michael Weller, Bruno Imthurn, Gabriele S Merki-Feld, Susanne Wegener
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 115 Issue 3 Pg. 637-646 (03 01 2019) ISSN: 1755-3245 [Electronic] England
• PMID: 30295757 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: [email protected].

Chemical References

• Androstenes
• Gabra4 protein, mouse
• Gabrd protein, mouse
• Neuroprotective Agents
• Progestins
• Receptors, GABA-A
• Desogestrel
• drospirenone

Topics

• Androstenes (pharmacology)
• Animals
• Behavior, Animal (drug effects)
• Brain (drug effects, metabolism, pathology, physiopathology)
• Cells, Cultured
• Desogestrel (pharmacology)
• Disease Models, Animal
• Female
• Infarction, Middle Cerebral Artery (drug therapy, metabolism, pathology, physiopathology)
• Male
• Mice, Inbred C57BL
• Neural Inhibition (drug effects)
• Neurons (drug effects, metabolism, pathology)
• Neuroprotective Agents (pharmacology)
• Ovariectomy
• Progestins (pharmacology)
• Receptors, GABA-A (metabolism)
• Sensory Gating (drug effects)