Selective Nonnuclear Estrogen Receptor Activation Decreases Stroke Severity and Promotes Functional Recovery in...

Area of Science:

• Neuroscience
• Pharmacology
• Endocrinology

Background:

• Estrogens offer neuroprotection in stroke models, but clinical use is limited by side effects like uterine stimulation and cancer risk.
• Non-nuclear estrogen receptors (ERs) mediate beneficial effects, including cardiometabolic improvements, without adverse uterine or cancer outcomes.
• Selective activation of non-nuclear ERs presents a potential therapeutic strategy for stroke treatment.

Purpose of the Study:

• To investigate the efficacy of pathway-preferential estrogen (PaPE)-1, a non-nuclear ER agonist, in a mouse model of ischemic stroke.
• To assess the impact of PaPE-1 on stroke outcome, neuroinflammation, and functional recovery.
• To compare the effects of PaPE-1 with estradiol (E2) and a vehicle control, evaluating for uterotrophic effects.

Main Methods:

• Ovariectomized female mice underwent transient middle cerebral artery occlusion (tMCAo) to induce stroke.
• Mice received vehicle, E2, or PaPE-1 before and after tMCAo.
• Stroke severity was evaluated using MRI, and motor function was assessed over two weeks.
• Leukocyte infiltration, neurogenesis, and angiogenesis were analyzed post-stroke.

Main Results:

• Both E2 and PaPE-1 reduced infarct volumes, but only PaPE-1 decreased leukocyte infiltration into the ischemic brain.
• PaPE-1 demonstrated no uterotrophic effects, unlike E2.
• Both treatments improved functional recovery starting from 6 days post-stroke, with PaPE-1 associated with reduced neuroinflammation.
• Long-term neuronal or vascular plasticity showed negligible effects from either intervention.

Conclusions:

• Selective non-nuclear ER activation with PaPE-1 effectively reduces stroke severity and enhances functional recovery in mice.
• PaPE-1 offers neuroprotection without the undesirable uterotrophic effects associated with traditional estrogen therapy.
• PaPE-1's anti-inflammatory action in the brain contributes to its beneficial effects, suggesting its potential as a safer therapeutic agent for stroke.