Roles of Testosterone and Estradiol in Mediation of Acute Neuroendocrine and Electroencephalographic Effects of Sevoflurane During the Sensitive Period in Rats.

Ningtao Li,Lei Lei,Yunan Lin,Ling-Sha Ju,Anatoly E Martynyuk,Jiaqiang Zhang,Ning Xu,Nikolaus Gravenstein,Timothy E Morey

doi:10.3389/fendo.2020.545973

Abstract

Testosterone (T), predominantly acting through its derivative 17β-estradiol (E2), regulates the brain’s sexual differentiation in rodents during the perinatal sensitive period, which mirrors the window of vulnerability to the adverse effects of general anesthetics. The mechanisms of anesthesia’s adverse effects are poorly understood. We investigated whether sevoflurane alters T and E2 levels and whether they contribute to sevoflurane’s acute adverse effects in postnatal day 5 Sprague-Dawley rats. The rats underwent electroencephalography recordings for 2 h of baseline activity or for 1 h before and another hour during 2.1% sevoflurane exposure, followed by collection of trunk blood and brain tissue. Pharmacological agents, including the GABA type A receptor inhibitor bicuculline and the aromatase inhibitor formestane, were administered 30 min before sevoflurane anesthesia. Sevoflurane increased serum T levels in males only. All other effects of sevoflurane were similar in both sexes, including increases in serum levels of E2, hypothalamic mRNA levels of aromatase, estrogen receptor α (Erα) [not estrogen receptor β (Erβ)], Na+-K+-Cl− cotransporter (Nkcc1)/K+-Cl− cotransporter (Kcc2) mRNA ratio, electroencephalography-detectable seizures, and stress-like corticosterone secretion. Bicuculline and formestane alleviated these effects, except the T level increases. The ERα antagonist MPP, but not the ERβ antagonist PHTPP, reduced electroencephalography-detectable seizures and normalized the Nkcc1/Kcc2 mRNA ratio. Collectively, sevoflurane exacerbates levels of T in males and E2 in both sexes during the period of their organizational effects in rodents. Sevoflurane acts through GABAAR-mediated, systemic T-independent elevation of E2 to cause electroencephalography-detectable seizures, stress-like corticosterone secretion, and changes in the expression of genes critical for brain development.

Highlights

According to 2016 World Health Organization estimates, the number of surgeries performed globally rose from 226.4 million in 2004 to 312.9 million in 2012 [1]
In contrast to serum levels of T, both male and female pups anesthetized with sevoflurane had increased serum levels of E2 (Table 1, Figure 2D), serum levels of corticosterone (Table 1, Figure 2E), and hypothalamic mRNA levels of aromatase, estrogen receptor a (Era), Nkcc1, and the Nkcc1/Kcc2 mRNA ratio, while hypothalamic mRNA levels of Kcc2 were decreased in both sexes
The novel findings of this study are that during the sensitive period, when T/E2 are known to program permanent changes in the rodent brain, sevoflurane administered to neonatal rats increases the systemic levels of T in males, while it elevates the levels of E2 and upregulates crucial components of the E2 and GABA type A receptor (GABAAR) signaling pathways in both sexes

Summary

Introduction

According to 2016 World Health Organization estimates, the number of surgeries performed globally rose from 226.4 million in 2004 to 312.9 million in 2012 [1]. This progress would not be possible without modern general anesthesia, which can be viewed as a state of pharmacologically induced “reversible brain coma” [2]. Experimental evidence indicates that GABAergic anesthetic agents, such as propofol, isoflurane, or sevoflurane, administered to neonatal rats, acutely induce electroencephalography (EEG)-detectable seizures and increased systemic levels of the main stress hormone corticosterone [8,9,10]. The long-term effects of these anesthetics comprise an abnormal (increased) hypothalamic and hippocampal Na+-K+-Cl− cotransporter (Nkcc1)/K+-Cl− cotransporter (Kcc2) mRNA ratio, an exacerbated hypothalamic-pituitary-adrenal (HPA) axis responses to stress, and behavioral deficiencies [8, 9, 11,12,13]

Methods

Results

Conclusion