The Tat antagonist neomycin B hexa-arginine conjugate inhibits gp-120-induced death of human neuroblastoma cells.
Several patients with acquired immunodeficiency syndrome (AIDS) develop neurological complications, which are referred to as human immunodeficiency virus (HIV)-associated dementia (HAD). The HIV-1 coat glycoprotein gp-120 has been proposed as the major etiologic agent for neuronal loss reported postmortem in the brain of AIDS patients. Chemokine receptors may play a role in gp-120-triggered neurotoxicity, both in vitro and in vivo, thus being an intriguing target for developing therapeutic strategies aimed to prevent or reduce neuronal damage occurring during HIV infection. We have previously shown that human CHP100 neuroblastoma cells express CXCR4 and CCR5 chemokine receptors and that interaction between gp-120 and these receptors contributes to cytotoxicity elicited by the protein. Here, we examined the neuroprotective potential of neomycin B hexa-arginine conjugate (NeoR), a recently synthesized compound with anti-HIV activity. We found that gp-120-triggered death is significantly reduced by NeoR, and this protective effect seems related to the ability of NeoR to interact with CXCR4 receptors. The ability of NeoR to cross the blood-brain barrier, as demonstrated in mice by systemic administration of the fluorescein conjugate drug, makes this compound a powerful and attractive therapeutic agent.
Catani
Maria Valeria
MV
Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy.
Corasaniti
Maria Tiziana
MT
Ranalli
Marco
M
Amantea
Diana
D
Litovchick
Alexander
A
Lapidot
Aviva
A
Melino
Gerry
G
D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D005456:Fluorescent Dyes / Q000737:chemistry; D005601:Framycetin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D015696:Gene Products, tat / Q000037:antagonists & inhibitors*; D015699:HIV Envelope Protein gp120 / Q000633:toxicity*; D006801:Humans; D051379:Mice; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism*; D019713:Receptors, CCR5 / Q000187:drug effects / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured
D019380:Anti-HIV Agents; D005456:Fluorescent Dyes; D015696:Gene Products, tat; D015699:HIV Envelope Protein gp120; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; C444521:neomycin B-arginine conjugate NeoR; D005601:Framycetin