PROBLEM: Parkinson's disease (PD) has a higher prevalence in the human male population. PD is characterized by motor dysfunction, rigidity, and bradykinesia. Current research suggests that gender plays a role in this condition, since males have a greater incidence of PD. It is believed that the underlying mechanism of PD involves oxidative stress leading to cellular apoptosis. In many peripheral cells and some neuronal cells, androgens have been shown to increase apoptosis. PURPOSE: The goal of these studies is to determine androgen's effects on dopaminergic cells following oxidative stress by using both in vitro and in vivo methods. The central hypothesis of this proposal is that androgens increase cellular vulnerability to oxidative stress-induced neurotoxicity in dopaminergic neurons. RESEARCH QUESTIONS: The first specific aim of this proposal is to determine the apoptotic signaling pathways activated by androgens in dopaminergic N27 cells following oxidative stress (hydrogen peroxide). The second specific aim is designed to evaluate the effects of androgens on estrogen-mediated neuroprotection in dopaminergic N27 neurons following oxidative stress.
These aims will be accomplished through in vitro molecular studies with and without the presence of astroglia cells and the androgen receptor antagonist, hydroxyflutamide. Lastly, the third specific aim will characterize the in vivo effects of androgens on tyrosine hydroxylase expression, neuronal death, and motor behavior in aged male rats exposed to 6-OHDA, which induces oxidative stress and apoptosis in the substantia nigra and striatum. In vivo hormone treatment groups will consist of gonadectomized aged males, gonadally intact aged males, and gonadectomized aged males plus replacement androgen (testosterone or dihydrotestosterone) for either a chronic (3 months) or acute (1 week) treatment time length prior to 6-OHDA lesion. Immunocytochemical and behavioral techniques will be used to accomplish this aim. OUTCOMES: This study will provide basic knowledge on how androgens modulate dopaminergic cellular vulnerability to oxidative stress. Ultimately, this knowledge can be used to provide a foundation to understanding the mechanisms underlying sex differences in neurodegenerative disorders. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32NS061417-01
Application #
7408186
Study Section
Special Emphasis Panel (ZRG1-F03A-M (20))
Program Officer
Sutherland, Margaret L
Project Start
2008-03-01
Project End
2011-02-28
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
1
Fiscal Year
2007
Total Cost
$44,846
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Pharmacology
Type
Other Domestic Higher Education
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
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Cunningham, Rebecca L; Lumia, Augustus R; McGinnis, Marilyn Y (2012) Androgen receptors, sex behavior, and aggression. Neuroendocrinology 96:131-40
Su, Chang; Rybalchenko, Nataliya; Schreihofer, Derek A et al. (2012) Cell Models for the Study of Sex Steroid Hormone Neurobiology. J Steroids Horm Sci S2:
Cunningham, Rebecca L; Macheda, Teresa; Watts, Lora Talley et al. (2011) Androgens exacerbate motor asymmetry in male rats with unilateral 6-hydroxydopamine lesion. Horm Behav 60:617-24
Cunningham, Rebecca L; Giuffrida, Andrea; Roberts, James L (2009) Androgens induce dopaminergic neurotoxicity via caspase-3-dependent activation of protein kinase Cdelta. Endocrinology 150:5539-48