title: 5α-reduced progestogens ameliorate mood-related behavioral pathology, neurotoxicity, and microgliosis associated with exposure to HIV-1 Tat.
abstract: Human immunodeficiency virus (HIV) is associated with motor and mood disorders, likely influenced by reactive microgliosis and subsequent neural damage. We have recapitulated aspects of this pathology in mice that conditionally express the neurotoxic HIV-1 regulatory protein, trans-activator of transcription (Tat). Progestogens may attenuate Tat-related behavioral impairments and reduce neurotoxicity in vitro, perhaps via progesterone's 5α-reductase-dependent metabolism to the neuroprotective steroid, allopregnanolone. To test this, ovariectomized female mice that conditionally expressed (or did not express) central HIV-1 Tat were administered vehicle or progesterone (4mg/kg), with or without pretreatment of a 5α-reductase inhibitor (finasteride, 50mg/kg). Tat induction significantly increased anxiety-like behavior in an open field, elevated plus maze and a marble burying task concomitant with elevated protein oxidation in striatum. Progesterone administration attenuated anxiety-like effects in the open field and elevated plus maze, but not in conjunction with finasteride pretreatment. Progesterone also attenuated Tat-promoted protein oxidation in striatum, independent of finasteride pretreatment. Concurrent experiments in vitro revealed Tat (50nM)-mediated reductions in neuronal cell survival over 60h, as well as increased neuronal and microglial intracellular calcium, as assessed via fura-2 AM fluorescence. Co-treatment with allopregnanolone (100nM) attenuated neuronal death in time-lapse imaging and blocked the Tat-induced exacerbation of intracellular calcium in neurons and microglia. Lastly, neuronal-glial co-cultures were labeled for Iba-1 to reveal that Tat increased microglial numbers in vitro and co-treatment with allopregnanolone attenuated this effect. Together, these data support the notion that 5α-reduced pregnane steroids exert protection over the neurotoxic effects of HIV-1 Tat.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Medical College of Virginia (MCV) Campus, Richmond, VA 23298-0613, USA. Electronic address: jason.paris@vcuhealth.org.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Paris
authors.affiliation: Department of Anatomy and Neurobiology, Virginia Commonwealth University, MCV Campus, Richmond, VA 23298-0709, USA.
authors.forename: ShiPing
authors.initials: S
authors.lastname: Zou
authors.affiliation: Department of Anatomy and Neurobiology, Virginia Commonwealth University, MCV Campus, Richmond, VA 23298-0709, USA.
authors.forename: Yun K
authors.initials: YK
authors.lastname: Hahn
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Medical College of Virginia (MCV) Campus, Richmond, VA 23298-0613, USA; Department of Anatomy and Neurobiology, Virginia Commonwealth University, MCV Campus, Richmond, VA 23298-0709, USA; Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Pamela E
authors.initials: PE
authors.lastname: Knapp
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Medical College of Virginia (MCV) Campus, Richmond, VA 23298-0613, USA; Department of Anatomy and Neurobiology, Virginia Commonwealth University, MCV Campus, Richmond, VA 23298-0709, USA; Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA, USA. Electronic address: kurt.hauser@vcuhealth.org.
authors.forename: Kurt F
authors.initials: KF
authors.lastname: Hauser
mesh_terms: D058891:5-alpha Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001007:Anxiety / Q000139:chemically induced / Q000503:physiopathology*; D001522:Behavior, Animal / Q000187:drug effects*; D042944:Cholestenone 5 alpha-Reductase / Q000378:metabolism*; D018920:Coculture Techniques; D005260:Female; D018120:Finasteride / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010052:Ovariectomy; D011280:Pregnanolone / Q000008:administration & dosage / Q000494:pharmacology*; D011374:Progesterone / Q000008:administration & dosage / Q000494:pharmacology*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000187:drug effects / Q000378:metabolism*
chemical_list: D058891:5-alpha Reductase Inhibitors; D054322:tat Gene Products, Human Immunodeficiency Virus; D011374:Progesterone; D018120:Finasteride; D011280:Pregnanolone; D042944:Cholestenone 5 alpha-Reductase
keywords: 5α-reductase; Allopregnanolone; Finasteride; HIV/AIDS; Iba-1; Intracellular calcium; Neurosteroid; Neurotoxicity; Oxidative stress; Progesterone