title: Effects of Oxidative Stress and Testosterone on Pro-Inflammatory Signaling in a Female Rat Dopaminergic Neuronal Cell Line.
abstract: Parkinson's disease, a progressive neurodegenerative disorder, is associated with oxidative stress and neuroinflammation. These pathological markers can contribute to the loss of dopamine neurons in the midbrain. Interestingly, men have a 2-fold increased incidence for Parkinson's disease than women. Although the mechanisms underlying this sex difference remain elusive, we propose that the primary male sex hormone, testosterone, is involved. Our previous studies show that testosterone, through a putative membrane androgen receptor, can increase oxidative stress-induced neurotoxicity in dopamine neurons. Based on these results, this study examines the role of nuclear factor κ B (NF-κB), cyclooxygenase-2 (COX2), and apoptosis in the deleterious effects of androgens in an oxidative stress environment. We hypothesize, under oxidative stress environment, testosterone via a putative membrane androgen receptor will exacerbate oxidative stress-induced NF-κB/COX2 signaling in N27 dopaminergic neurons, leading to apoptosis. Our data show that testosterone increased the expression of COX2 and apoptosis in dopamine neurons. Inhibiting the NF-κB and COX2 pathway with CAPE and ibuprofen, respectively, blocked testosterone's negative effects on cell viability, indicating that NF-κB/COX2 cascade plays a role in the negative interaction between testosterone and oxidative stress on neuroinflammation. These data further support the role of testosterone mediating the loss of dopamine neurons under oxidative stress conditions, which may be a key mechanism contributing to the increased incidence of Parkinson's disease in men compared with women.
authors.affiliation: Department of Pharmacology and Neuroscience, Institute for Aging and Alzheimer's Disease Research, University of North Texas Health Science Center, Fort Worth, Texas 76107.
authors.forename: Shaletha
authors.initials: S
authors.lastname: Holmes
authors.affiliation: Department of Pharmacology and Neuroscience, Institute for Aging and Alzheimer's Disease Research, University of North Texas Health Science Center, Fort Worth, Texas 76107.
authors.forename: Meharvan
authors.initials: M
authors.lastname: Singh
authors.affiliation: Department of Pharmacology and Neuroscience, Institute for Aging and Alzheimer's Disease Research, University of North Texas Health Science Center, Fort Worth, Texas 76107.
authors.forename: Chang
authors.initials: C
authors.lastname: Su
authors.affiliation: Department of Pharmacology and Neuroscience, Institute for Aging and Alzheimer's Disease Research, University of North Texas Health Science Center, Fort Worth, Texas 76107.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Cunningham
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002109:Caffeic Acids / Q000494:pharmacology; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D007052:Ibuprofen / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013739:Testosterone / Q000494:pharmacology*
chemical_list: D002109:Caffeic Acids; D016861:Cyclooxygenase Inhibitors; D016328:NF-kappa B; D013739:Testosterone; D051546:Cyclooxygenase 2; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol; D007052:Ibuprofen