Kynostatin and 17β-estradiol prevent the apoptotic death of human neuroblastoma cells exposed to HIV-1 protease

Abstract

A significant number of adult male patients with acquired immunodeficiency syndrome develop cerebral atrophy and progressive brain disorders such as dementia complex and neuropsychiatric problems. Upon entering the brain via activated macrophages or microglias, the human immunodeficiency type 1 virus (HIV-1) may produce cytotoxic factors such as HIV-1 envelope protein (gp120) and protease. Owing to significant proteolysis of nonviral proteins, the protease derived from HIV-1 may be detrimental to brain cells and neurons. Our results revealed that HIV-1 protease, at nanomolar concentrations, was as potent as gp120 in causing neurotoxicity in human neuroblastoma neurotypic SH-SY5Y cells. As shown by the Oncor ApopTag staining procedure, HIV-1 protease significantly increased the number of apoptotic cells over the serum-free controls. Moreover, HIV-1 protease-induced neurotoxicity was blocked by a selective protease inhibitor, kynostatin (KNI-272). Antioxidants such as 17beta-estradiol, melatonin, and S-nitrosoglutathione also prevented protease-induced neurotoxicity. These findings indicate that oxidative proteolysis may mediate HIV-1 protease-induced apoptosis and the degeneration of neurons and other brain cells. Centrally active protease inhibitors and antioxidants may play an important role in preventing cerebral atrophy and associated dementia complex caused by HIV-1.

Melatonin, A Natural Programmed Cell Death Inducer in Cancer

“…10-500 CM [172] SH-SY5Y HIV-1 protease-induced cyto-and neurotoxicity were prevented by melatonin. 60 CM [173] N2a PC12 Melatonin was remarkably effective in preventing death of cultured neuroblastoma cells as well as oxidative damage and intracellular Ca2+ increases induced by a cytotoxic fragment of A .…”

Role of the transcription factor E2F1 in CXCR4-mediated neurotoxicity and HIV neuropathology

“…Before treatment with gp120 IIIB , SH-SY5Y cells were differentiated with retinoic acid (10 μM) in order to induce their neuronal phenotype-as previously described (Pahlman et al, 1984). Both differentiated and undifferentiated cells express CXCR4 and are sensitive to the toxic action of gp120 IIIB (Hawkins et al, 1999).…”

Review: The potential for estrogens in preventing Alzheimer's disease and vascular dementia

“…In HIV-related in vitro models, E2 protects against gp120, the coat protein of HIV, HIV regulatory protein (TAT), and exposure to HIV-1 protease [Howard et al, 2001; Kendall et al, 2005; Hawkins et al, 1999; Turchan et al, 2001; Russo et al, 2005; Corasaniti et al, 2005; Wallace et al, 2006; Bruce-Keller et al, 2001]. Estrogens also attenuate gp120-induced cell death in an animal model of HIV [Corasaniti et al, 2005].…”