Preconditioning Underlies Testosterone’s Protective Effects Against Neurodegeneration

Purpose: The incidence of neurodegenerative diseases (ND) such as Alzheimer’s disease and Parkinson’s disease is expected to rise over the next 40 years. Diagnosis occurs at advanced stages, and there is no cure or treatment for ND. Early identification of risk factors for ND may provide effective therapy targets. Because ND arises differently between men and women, major sex hormones may play a role. Many studies have examined the effects of estrogen, but not testosterone (T). T has been shown to be protective or damaging depending on the oxidative stress (OS) environment in cells. Sleep apnea is a comorbidity of ND, occurs more frequently in men than women, and is associated with decreased T. Our lab has shown that a rodent model of mild sleep apnea, chronic intermittent hypoxia (CIH), elevates OS and inflammation in brain regions associated with early-stage ND. We propose that T will protect against CIH-induced damage. Methods: Male Long-Evans rats will be divided into 3 groups: gonadectomized with cholesterol (GDX+C) or physiological T (GDX+T); gonadally intact (Intact). Afterwards, rats were exposed to eight minute cycles of alternating 10% and 21% oxygen to mimic the hypoxemia experienced by patients with sleep apnea. This cycle ran continuously for eight hours a day during the light phase for seven days. Following 7 days of CIH, behaviors associated with memory and motor function were assessed: Morris Water Maze, the novel object task, and a modified open field assay. Plasma and tissue punches from the entorhinal cortex (ETC) and substantia nigra (SN) were collected and tested for levels of OS, T, and inflammation, using Advanced Oxidative Protein Products (AOPP), ELISA, and multiplex immunoassays, respectively. Results: GDX+T had significantly more T than Intact and GDX+C, due to the CIH-induced decline in endogenous T levels in Intact rats. CIH increased OS and inflammation in GDX+C and Intact rats, whereas there was no effect in GDX+T. Rats exposed to room air were not impaired, regardless of hormone status. Conclusions: Maintenance of T is protective against OS and inflammation, key markers of ND. T loss was associated with behavioral deficits following an OS insult.