Oxidative stress in HIV demented patients and protection ex vivo with novel antioxidants.
OBJECTIVE
To determine the role of oxidative stress in mediating HIV dementia and to identify novel therapeutic compounds that may block this oxidative stress.


METHODS
Brain tissue from patients with HIV encephalitis and macaques with simian immune deficiency virus encephalitis was immunostained for lipid peroxidation. Oxidized proteins in CSF of patients with various stages of HIV dementia were quantitated and we determined whether CSF from these patients could alter mitochondrial function. Several novel compounds with antioxidant effects were screened to determine their relative efficacy in protecting against CSF-induced neurotoxicity.


RESULTS
Evidence for oxidative stress was present both in brain and in CSF. The presence of oxidized proteins in the CSF and CSF-induced progressive decrease in mitochondrial activity correlated with the severity of cognitive impairment, but only the group of patients with moderate to severe dementia reached statistical significance. L-deprenyl, didox, imidate, diosgenin, and ebselen blocked the CSF-induced toxicity. No effect of trimidox, ruthenium red, or Quercetin was seen.


CONCLUSIONS
Increased oxidative stress is present in brain and CSF of HIV-infected patients. There is also an accumulation of toxic substances in the CSF that are capable of inducing oxidative stress. The authors have identified several novel compounds that are capable of blocking the CSF-induced toxicity, the therapeutic potential of which is worthy of further exploration.
Turchan
J
J
Department of Neurology, Pharmaceutical Sciences, University of Kentucky, Lexington, USA.
Pocernich
C B
CB
Gairola
C
C
Chauhan
A
A
Schifitto
G
G
Butterfield
D A
DA
Buch
S
S
Narayan
O
O
Sinai
A
A
Geiger
J
J
Berger
J R
JR
Elford
H
H
Nath
A
A
D015526:AIDS Dementia Complex / Q000473:pathology / Q000503:physiopathology*; D000447:Aldehydes / Q000032:analysis / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D002555:Cerebrospinal Fluid / Q000737:chemistry / Q000378:metabolism; D002556:Cerebrospinal Fluid Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism; D005456:Fluorescent Dyes; D006801:Humans; D007659:Ketones / Q000032:analysis; D050356:Lipid Metabolism; D008251:Macaca; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D015302:Simian Immunodeficiency Virus
D000447:Aldehydes; D000975:Antioxidants; D002556:Cerebrospinal Fluid Proteins; D003574:Cytochrome c Group; D005456:Fluorescent Dyes; D007659:Ketones; C027576:4-hydroxy-2-nonenal