Sex Differences in Oxidative Stress Model of Prodromal Parkinson's Disease

INTRODUCTION: Parkinson's disease (PD) is an incurable neurodegenerative disorder that causes deterioration in motor and cognitive function and occurs more commonly in men. Gross motor impairment occurs after 60% dopaminergic neurons are lost in the substantia nigra brain region. However, it is unknown if sex differences are present in the prodromal stage of PD in which no dopaminergic neuronal loss or gross motor dysfunction are observed. Prodromal PD is associated with increased oxidative stress (OS) and OS damage in the substantia nigra, along with cognitive and fine motor skill dysfunction. To examine if sex differences are present in prodromal PD, we will use an animal model, chronic intermittent hypoxia (CIH), that recapitulates many prodromal PD characteristics. Our prior studies using male rats found that CIH induced global OS, OS damage in the substantia nigra, and cognitive dysfunction, which are all consistent with prodromal PD. METHODS: Adult male and female Sprague Dawley rats were exposed CIH to induce a prodromal PD phenotype. The CIH protocol consisted of 10 episodes of hypoxia (12% O2)/hour for a total of 8 hours/day over a 2-week period. Control rats were exposed to room air (normoxia). Rats were behaviorally tested for the following indexes during the last week of CIH exposure: 1) cognitive function (novel object recognition, Morris Water Maze), 2) fine motor behavior (modified open field with an elevated wire mesh), and 3) anxiety (marble test). At the conclusion of behavior testing, rats were sacrificed. Plasma and brain tissue was collected to examine oxidative stress. RESULTS: CIH increased circulating oxidized proteins in both male and female rats compared to control rats. No sex difference was observed in CIH induced circulating oxidative stress. Preliminary analysis indicate that sex differences are present in behavioral tests, especially cognitive function. CONCLUSIONS: These studies indicate sex differences in response to OS. CIH induced OS was consistent across both sexes, as evidenced by similar circulating OS levels. However, each sex responded (behaviorally) differently in response to CIH induced OS. These studies indicate that sex differences may be involved in prodromal PD. Knowledge of these sex differences could lead to earlier detection of PD and possibly the ability to slow conversion of prodromal PD to later stage PD that is exemplified by gross motor loss.