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Oxidative stress in HIV demented patients and protection ex vivo with novel antioxidants

From the Departments of Neurology (Drs. Berger and Nath), Microbiology and Immunology (Dr. Sinai), Chemistry (C.B. Pocernich and Dr. Butterfield), and Pharmaceutical Sciences (Dr. Gairola), University of Kentucky, Lexington; Department of Neurology (Dr. Schifitto), University of Rochester, NY; Department of Microbiology (Drs. Buch and Narayan), University of Kansas, KS; Department of Pharmacology and Therapeutics (Dr. Geiger), University of Manitoba, Canada; Molecules for Health (Dr. Elford), Richmond, VA; and Department of Neurology (Drs. Turchan, Chauhan, and Nath), Johns Hopkins University, Baltimore, MD.

Address correspondence and reprint requests to Dr. A. Nath, Department of Neurology, KY Clinic-L-445, University of Kentucky, Lexington, KY 40536-0284; e-mail: anath1{at}jhmc.edu

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.

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