Protective effect of glutathione in HIV-1 lytic peptide 1-induced cell death in human neuronal cells.
To elucidate the pathogenic mechanisms involved in neurodegeneration in AIDS patients with cognitive deficits, we have examined the toxic effect of the lentivirus lytic peptide 1 (LLP-1) corresponding to the carboxyl terminus of HIV-1 transmembrane glycoprotein gp41 on human neuronal and glial cell lines. LLP-1 induced a significant lactate dehydrogenase (LDH, a marker of cell death) release from these cells in a concentration- and time-dependent manner, while the noncytolytic LLP-1 analog 2 had little effect. Application of LLP-1 to SH-SY5Y, a well-characterized human neuronal cell line, caused the decline of intracellular glutathione (GSH) content that appeared to occur before a significant LDH release. Furthermore, LLP-1 elicited a significant loss of mitochondrial function as measured by mitochondrial transmembrane potential (MTP). Among the reducing agents and antioxidants tested, GSH and a GSH prodrug N-acetylcysteine (NAC) provided protection against LLP-1-induced neuronal cell death, evidently by restoring the intracellular GSH levels and blocking the disruption of mitochondrial integrity. Thus, gp41-derived LLP-1 may be a potential neurotoxic agent capable of causing the intracellular GSH depletion and disturbing the mitochondrial function, possibly contributing to the neurodegenerative cascade as seen in HIV-1-associated dementia. Our data indicate that restoring both GSH concentration and mitochondrial function may hold promise as possible therapeutic strategies for slowing disease progression of dementia in AIDS patients.
Sung
J H
JH
Department of Microbiology, College of Medicine, Division of Molecular Biology and Neuroscience, Medical Research Center, Ewha Womans University, Yangcheonku, Seoul, Korea.
Shin
S A
SA
Park
H K
HK
Montelaro
R C
RC
Chong
Y H
YH
D015526:AIDS Dementia Complex / Q000188:drug therapy; D000111:Acetylcysteine / Q000494:pharmacology; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D005978:Glutathione / Q000032:analysis / Q000494:pharmacology*; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000633:toxicity*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology; D008969:Molecular Sequence Data; D009410:Nerve Degeneration; D009447:Neuroblastoma / Q000473:pathology; D009474:Neurons / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000737:chemistry / Q000633:toxicity*; D011355:Prodrugs / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000975:Antioxidants; D015700:HIV Envelope Protein gp41; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D011355:Prodrugs; C116049:lentiviral lytic peptide type 1, Human immunodeficiency virus 1; D005978:Glutathione; D000111:Acetylcysteine