Androgens modulate chronic intermittent hypoxia effects on brain and behavior

Abstract

Sleep apnea is associated with testosterone dysregulation as well as increased risk of developing neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). A rodent model of the hypoxic events of sleep apnea, chronic intermittent hypoxia (CIH), has been previously documented to impair cognitive function and elevate oxidative stress in male rats, while simultaneously decreasing testosterone. Therefore, androgens may modulate neuronal function under CIH. To investigate the role of androgens during CIH, male rats were assigned to one of four hormone groups: 1) gonadally intact, 2) gonadectomized (GDX), 3) GDX + testosterone (T) supplemented, or 4) GDX + dihydrotestosterone (DHT) supplemented. Each group was exposed to either normal room air or CIH exposure for one week, followed by memory and motor task assessments. Brain regions associated with AD and PD (entorhinal cortex, dorsal hippocampus, and substantia nigra) were examined for oxidative stress and inflammatory markers, key characteristics of AD and PD. Gonadally intact rats exhibited elevated oxidative stress due to CIH, but no significant memory and motor impairments. GDX increased memory impairments, regardless of CIH exposure. T preserved memory function and prevented detrimental CIH-induced changes. In contrast, DHT was not protective, as evidenced by exacerbated oxidative stress under CIH. Further, CIH induced significant spatial memory impairment in rats administered DHT. These results indicate androgens can have both neuroprotective and detrimental effects under CIH, which may have clinical relevance for men with untreated sleep apnea.

Rat Strain and Housing Conditions Alter Oxidative Stress and Hormone Responses to Chronic Intermittent Hypoxia

“…Chronic intermittent hypoxia has been associated with cognitive impairments in rodent models of sleep apnea ( Xu et al, 2004 ; Cai et al, 2010 ; Smith et al, 2013 ; Sapin et al, 2015 ; Snyder et al, 2018 ). To determine if strain or housing impact brain regions involved in memory pathways, we assessed the presence of tau hyperphosphorylated at serine 202 (p-tau), an indicator of tau tangle accumulation.…”

“…Acclimation to the chambers was followed by CIH exposure for 7 days from 8 am to 4 pm during the light (sleep) phase. Our CIH protocol utilized 8-min cycles of low oxygen (10%) followed by reoxygenation (21%) for 8 h during the light phase to model an AHI 8 ( Epstein et al, 2009 ; Snyder et al, 2018 ; Wilson et al, 2018 ). Specifically, nitrogen was injected into the chamber over a period of 5 min to reach a low oxygen concentration of 10%, followed by injection of oxygen over 3 min to return to and maintain normal room air concentrations (21%).…”

“…Plasma oxidative stress was assayed using Cell Biolabs, Inc. OxiSelect Advanced Oxidative Protein Products assay kit, according to our previously published protocol ( Cunningham et al, 2011 ; Snyder et al, 2017 , 2018 ). This kit measures the amount (uM) of all oxidized proteins in the sample relative to a known standard.…”

“…In addition to differences in CIH protocols, prior studies have been conducted on various rat strains under different housing conditions. Our laboratory has exposed single-housed Sprague Dawley ( Snyder et al, 2017 ), pair-housed Brown Norway ( Wilson et al, 2018 ), and pair-housed Long-Evans ( Snyder et al, 2018 ) rat strains to CIH with varying oxidative stress responses. Most CIH protocols have been performed on either Sprague Dawley or Wistar rat strains, but not the Long-Evans or Brown Norway rat strains.…”

Chronic Testosterone Deprivation Sensitizes the Middle-Aged Rat Brain to Damaging Effects of Testosterone Replacement

“…Although T can have antioxidant actions in experimental stroke [24][25][26], T can also induce oxidative stress in the brain [27]. In addition, preexisting oxidative stress can result in toxic effects of T treatment in dopaminergic neurons [28] and male rat brains [29].…”