Increased vulnerability of ApoE4 neurons to HIV proteins and opiates: protection by diosgenin and L-deprenyl.
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.
Turchan-Cholewo
Jadwiga
J
Departments of Anatomy and Neurobiology, University of Kentucky, Lexington, KY 40546, USA.
Liu
Yiling
Y
Gartner
Suzanne
S
Reid
Rollie
R
Jie
Chunfa
C
Peng
Xuejun
X
Chen
Kuey Chu C
KC
Chauhan
Ashok
A
Haughey
Norman
N
Cutler
Roy
R
Mattson
Mark P
MP
Pardo
Carlos
C
Conant
Katherine
K
Sacktor
Ned
N
McArthur
Justin C
JC
Hauser
Kurt F
KF
Gairola
Chandra
C
Nath
Avindra
A
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
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