title: Increased vulnerability of ApoE4 neurons to HIV proteins and opiates: protection by diosgenin and L-deprenyl.
abstract: Human immunodeficiency virus (HIV) infection continues to rise in drug-abusing populations and causes a dementing illness in a subset of individuals. Factors contributing to the development of dementia in this population remain unknown. We found that HIV-infected individuals with the E4 allele of Apolipoprotein E (ApoE) or history of intravenous drug abuse had increased oxidative stress in the CNS. In vitro studies showed that HIV proteins, gp120 and Tat, Tat + morphine but not tumor necrosis factor-alpha (TNF-alpha), caused increased neurotoxicity in human neuronal cultures with ApoE4 allele. Microarray analysis showed a differential alteration of transcripts involved in energy metabolism in cultures of ApoE3 and 4 neurons upon treatment with Tat + morphine. This was confirmed using assays of mitochondrial function and exposure of the neurons to Tat + morphine. Using this in vitro model, we screened a number of novel antioxidants and found that only L-deprenyl and diosgenin protected against the neurotoxicity of Tat + morphine. Furthermore, Tat-induced oxidative stress impaired morphine metabolism which could also be prevented by diosgenin. In conclusion, opiate abusers with HIV infection and the ApoE4 allele may be at increased risk of developing dementia. L-deprenyl and a plant estrogen, diosgenin, may have therapeutic potential in this population.
authors.affiliation: Departments of Anatomy and Neurobiology, University of Kentucky, Lexington, KY 40546, USA.
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Turchan-Cholewo
authors.forename: Yiling
authors.initials: Y
authors.lastname: Liu
authors.forename: Suzanne
authors.initials: S
authors.lastname: Gartner
authors.forename: Rollie
authors.initials: R
authors.lastname: Reid
authors.forename: Chunfa
authors.initials: C
authors.lastname: Jie
authors.forename: Xuejun
authors.initials: X
authors.lastname: Peng
authors.forename: Kuey Chu C
authors.initials: KC
authors.lastname: Chen
authors.forename: Ashok
authors.initials: A
authors.lastname: Chauhan
authors.forename: Norman
authors.initials: N
authors.lastname: Haughey
authors.forename: Roy
authors.initials: R
authors.lastname: Cutler
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
authors.forename: Carlos
authors.initials: C
authors.lastname: Pardo
authors.forename: Katherine
authors.initials: K
authors.lastname: Conant
authors.forename: Ned
authors.initials: N
authors.lastname: Sacktor
authors.forename: Justin C
authors.initials: JC
authors.lastname: McArthur
authors.forename: Kurt F
authors.initials: KF
authors.lastname: Hauser
authors.forename: Chandra
authors.initials: C
authors.lastname: Gairola
authors.forename: Avindra
authors.initials: A
authors.lastname: Nath
mesh_terms: D015526:AIDS Dementia Complex / Q000188:drug therapy / Q000235:genetics; D000328:Adult; D000975:Antioxidants / Q000494:pharmacology; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000235:genetics*; D002478:Cells, Cultured; D018920:Coculture Techniques; D004144:Diosgenin / Q000494:pharmacology; D015870:Gene Expression; D015696:Gene Products, tat / Q000633:toxicity; D020022:Genetic Predisposition to Disease; D006678:HIV / Q000187:drug effects; D015699:HIV Envelope Protein gp120 / Q000633:toxicity; D015658:HIV Infections / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009020:Morphine / Q000378:metabolism / Q000633:toxicity; D009294:Narcotics / Q000378:metabolism / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects* / Q000473:pathology / Q000821:virology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000187:drug effects; D016133:Polymerase Chain Reaction; D017382:Reactive Oxygen Species; D012642:Selegiline / Q000494:pharmacology; D014764:Viral Proteins / Q000187:drug effects*; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: D000975:Antioxidants; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D015696:Gene Products, tat; D015699:HIV Envelope Protein gp120; D009294:Narcotics; D018696:Neuroprotective Agents; D009498:Neurotoxins; D017382:Reactive Oxygen Species; D014764:Viral Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; D012642:Selegiline; D009020:Morphine; D004144:Diosgenin