Molecular mechanisms and cellular events involved in the neuroprotective actions of estradiol. Analysis of sex differences

Abstract

Estradiol, either from peripheral or central origin, activates multiple molecular neuroprotective and neuroreparative responses that, being mediated by estrogen receptors or by estrogen receptor independent mechanisms, are initiated at the membrane, the cytoplasm or the cell nucleus of neural cells. Estrogen-dependent signaling regulates a variety of cellular events, such as intracellular Ca 2+ levels, mitochondrial respiratory capacity, ATP production, mitochondrial membrane potential, autophagy and apoptosis. In turn, these molecular and cellular actions of estradiol are integrated by neurons and non-neuronal cells to generate different tissue protective responses, decreasing blood-brain barrier permeability, oxidative stress, neuroinflammation and excitotoxicity and promoting synaptic plasticity, axonal growth, neurogenesis, remyelination and neuroregeneration. Recent findings indicate that the neuroprotective and neuroreparative actions of estradiol are different in males and females and further research is necessary to fully elucidate the causes for this sex difference.

Age‐related hearing loss: Why we need to think about sex as a biological variable

“…In the brain, there is much evidence that estrogen has a role in neuroprotection (Arevalo, Azcoitia, Azcoitia, & Garcia-Segura, 2015;Azcoitia, Barreto, Barreto, & Garcia-Segura, 2019;Cui, Shen, Shen, & Li, 2013;Genazzani, Pluchino, Pluchino, Luisi, & Luisi, 2007).…”

Sex and Gender Aspects for Patient Stratification in Allergy Prevention and Treatment

“…Furthermore, the X chromosome contains 10% of microRNA in the human genome as compared to 2 on the Y chromosome and the X linked microRNA leads to much higher immune responses in female participating in sex differentiated immunity [33]. Authophagy may be another of the dysregulated basic cellular processes [34] involved in the pathogenesis of allergies. Estradiol regulates autophagy in several cell types and may activate the phosphoinositide 3-kinase (PI3K)/Akt pathway [35,36].…”

Arx expansion mutation perturbs cortical development by augmenting apoptosis without activating innate immunity in a mouse model of X-linked infantile spasms syndrome

“…We next sought to determine whether pretreatment with 17β-Estradiol (E2), a multifaceted, estrogen receptor-dependent (and independent) neuroactive hormone (Azcoitia et al, 2019), might ameliorate the elevated CC3-mediated cortical apoptosis in Arx (GCG)10+7 , thus providing a mechanism for its early protective effect. Previously, we showed that E2 treatment reduces neonatal spasms and aberrant electrographic phenotypes including seizures and interictal discharge in adults when administered daily during the first week of life, but not later in adult Arx (GCG)10+7 mutants (Olivetti et al, 2014).…”