Neuroactive Steroids in Hypoxic–Ischemic Brain Injury: Overview and Future Directions

Abstract

Hypoxic–ischemic brain injury is a number one cause of long-term neurologic disability and death worldwide. This public health burden is mainly characterized by a decrease in oxygen concentration and blood flow to the tissues, which lead to an inefficient supply of nutrients to the brain. This condition induces cell death by energy depletion and increases free radical generation and inflammation. Hypoxic–ischemic brain injury may occur in ischemic-stroke and over perinatal asphyxia, being both leading causes of morbidity in adults and children, respectively. Currently, there are no effective pharmaceutical strategies to prevent the triggering of secondary injury cascades, including oxidative stress and metabolic dysfunction. Neuroactive steroids like selective estrogen receptor modulators, SERMs, and selective tissue estrogenic activity regulators, STEARs, exert several neuroprotective effects. These encompass mitochondrial survival, a decrease in reactive oxygen species, and maintenance of cell viability, among others. In this context, these neurosteroids constitute promising molecules, which could modify brain response to injury. Here we show an updated overview of the underlying mechanisms of hypoxic–ischemic brain injury. We also highlight the neuroprotective effects of neurosteroids and their future directions.

Raloxifene Protects Oxygen-glucose-deprived Astrocyte Cells Used To Mimic Hypoxic-ischemic Brain Injury

“…The mitochondrial role in cell death stands on the control of energy metabolism, ROS production, and the release of apoptotic factors into the cytoplasm. Cytochrome C is the most prominent pro-apoptotic factor (Toro-Urrego et al, 2020), and mitochondrial apoptosis-inducing proteins like endonuclease G, Smac/DIABLO, and Omi/HtrA have also been described to play a significant role in apoptosis regulation. These pro-apoptotic factors are not released necessarily through mitochondrial permeability transition pores (MPT).…”

“…PA affects not only glial and neural circuits in the corpus striatum and the hippocampus (Herrera et al, 2018;Udovin et al, 2020) and increases presynaptic terminal buttons density and striatal and cortical dendritic spines (G. E. Saraceno et al, 2016Saraceno et al, , 2018. It also leads to necrosis and Disclaimer/Publisher's Note: The statements, opinions, and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s).…”

“…MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions, or products referred to in the content. 2 apoptosis in these areas and the cortex (Perez-Lobos et al, 2017), and astrogliosis in the striatum and cerebellum (Barkhuizen et al, 2017;Udovin et al, 2020). It disrupts the dopaminergic, GABAergic, glutamatergic, and redox systems (Lespay-Rebolledo et al, 2018Perez-Lobos et al, 2017), leading to oxidative stress (Lespay-Rebolledo et al, 2018) and protein aggregation with ubiquitination (G. E. Saraceno et al, 2016), among other deleterious effects.…”

“…Mortality caused by PA has decreased in the last decades, while morbidity has increased (Holubiec et al, 2018). Many physical and mental disorders can be associated with PA (Herrera-Marschitz et al, 2014), including cognitive deficits (Ahearne, 2016;Barkhuizen et al, 2017;Galeano et al, 2015), seizures and/or epilepsy (Johne et al, 2021), schizophrenia (Pugliese et al, 2019), autism spectrum disorders (Modabbernia et al, 2016), attention-deficit/hyperactivity (Perna & Cooper, 2012), and neurodegenerative disorders (Toro-Urrego et al, 2020).…”