Posttreatment Strategy Against Hypoxia and Ischemia Based on Selective Targeting of Nonnuclear Estrogen Receptors with PaPE-1

A Wnuk,M Kajta,K Przepiórska,B A Pietrzak

doi:10.1007/s12640-021-00441-y

Abstract

Newly synthesized Pathway Preferential Estrogen-1 (PaPE-1) selectively activates membrane estrogen receptors (mERs), namely, mERα and mERβ, and has been shown to evoke neuroprotection; however, its effectiveness in protecting brain tissue against hypoxia and ischemia has not been verified in a posttreatment paradigm. This is the first study showing that a 6-h delayed posttreatment with PaPE-1 inhibited hypoxia/ischemia-induced neuronal death, as indicated by neutral red uptake in mouse primary cell cultures in vitro. The effect was accompanied by substantial decreases in neurotoxicity and neurodegeneration in terms of LDH release and Fluoro-Jade C staining of damaged cells, respectively. The mechanisms of the neuroprotective action of PaPE-1 also involved apoptosis inhibition demonstrated by normalization of both mitochondrial membrane potential and expression levels of apoptosis-related genes and proteins such as Fas, Fasl, Bcl2, FAS, FASL, BCL2, BAX, and GSK3β. Furthermore, PaPE-1-evoked neuroprotection was mediated through a reduction in ROS formation and restoration of cellular metabolic activity that had become dysregulated due to hypoxia and ischemia. These data provide evidence that targeting membrane non-GPER estrogen receptors with PaPE-1 is an effective therapy that protects brain neurons from hypoxic/ischemic damage, even when applied with a 6-h delay from injury onset.

Highlights

Acute stroke is a commonly used name for a cerebrovascular accident
Perinatal asphyxia is a condition characterized by fetal oxygen deprivation that leads to the death of approximately 1 million children and disability of another 1 million annually (Manandhar and Basnet 2019)
Since a posttreatment paradigm is the most relevant approach to improve hypoxia-/ischemia-based injuries, the present study aims to identify the neuroprotective potential and mechanisms of action of Pathway Preferential Estrogen-1 (PaPE-1) as a posttreatment therapy in cellular models of ischemic stroke and perinatal asphyxia

Summary

Introduction

Acute stroke is a commonly used name for a cerebrovascular accident. Cerebrovascular accidents are the 2 nd leading cause of death and a leading cause of disability worldwide. Research has been shown that up to 15 million people suffer from stroke annually, that more than 5 million of whom die, and that another 5 million of whom remain disabled for the rest of their lives (World Health Organisation (n.d.), Stroke, cerebrovascular accident). The 3 main types of stroke are ischemic stroke, hemorrhagic stroke, and Perinatal asphyxia is a condition characterized by fetal oxygen deprivation that leads to the death of approximately 1 million children and disability of another 1 million annually (Manandhar and Basnet 2019). It occurs during the antepartum, intrapartum, or perinatal period. The current therapy for perinatal asphyxia must occur within 6 h and is based on therapeutic hypothermia (selective head or systemic cooling)

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