title: Sigma-1 receptor agonists provide neuroprotection against gp120 via a change in bcl-2 expression in mouse neuronal cultures.
abstract: Although combined antiretroviral therapy has significantly improved the prognosis of HIV-1 infected patients and decreased the incidence of HIV-1 associated dementia, the cumulative prevalence of this disease, in particular, mild or asymptomatic neurocognitive impairment, has not decreased. Thus, in addition to active antiretroviral therapy, the search for an effective neuroprotective approach is very important. Sigma-1 receptors are widely distributed in the central nervous system. Sigma-1 receptor agonists are robustly neuroprotective in many neuropathy and neurotoxicity in vivo and in vitro studies. This study aims to investigate possible neuroprotective effects of sigma-1 receptor agonist, 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) against HIV-1 protein gp120. Primary cortical neuronal cultures were exposed to gp120 in different concentrations; to investigate neuroprotective effects of sigma-1 receptor agonist, cells were pre-treated with PPBP (10μM) in the presence or absence of pre-incubated sigma-1 receptor antagonist rimcazole (5μM). Cell apoptosis was confirmed with calcein/PI uptake test, lactate dehydrogenase (LDH) leakage assay or TUNEL assay and neurite degeneration was evaluated with morphometry via MAP-2 stained immunofluorescence. The mRNA and protein levels of apoptosis associated bax and bcl-2 were determined with real-time qPCR and Western blot. The results showed that gp120 could induce neuronal apoptosis and neurite degeneration in a concentration dependent manner and PPBP could attenuate the neurotoxicity of gp120. Simultaneously, gp120 could induce low expression of bcl-2 and bax, but only low expression of bcl-2 could be reversed by PPBP. The present data suggest that PPBP, at least, in part protects the neuron against gp120 by regulating bcl-2 expression.
authors: STD/AIDS Research Center, Department of Infectious Diseases, Beijing You An Hospital, Capital Medical University, Beijing 100069, China.
authors: Yulin
authors: Y
authors: Zhang
authors: Ying
authors: Y
authors: Shi
authors: Luxin
authors: L
authors: Qiao
authors: Yu
authors: Y
authors: Sun
authors: Wei
authors: W
authors: Ding
authors: Honghai
authors: H
authors: Zhang
authors: Ning
authors: N
authors: Li
authors: Dexi
authors: D
authors: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000166:cytology; D002227:Carbazoles / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000187:drug effects*; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology*; D006220:Haloperidol / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D016501:Neurites / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger; D017480:Receptors, sigma / Q000819:agonists*; D018709:Statistics, Nonparametric; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism; D000097605:Sigma-1 Receptor
chemical_list: D002227:Carbazoles; D015699:HIV Envelope Protein gp120; D006220:Haloperidol; D008869:Microtubule-Associated Proteins; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D017480:Receptors, sigma; D051028:bcl-2-Associated X Protein; D000097605:Sigma-1 Receptor; C094850:4-phenyl-1-(4-phenylbutyl)piperidine; C034931:rimcazole