Protection against Human Immunodeficiency Virus Type 1 Tat Neurotoxicity by Ginkgo biloba Extract EGb 761 Involving Glial Fibrillary Acidic Protein

Abstract

Human immunodeficiency virus (HIV)-1 Tat protein isan important pathogenic factor in HIV-associated neuropathogenesis. Despite recent progress, the molecular mechanisms underlying Tat neurotoxicity are still not completely understood. However, few therapeutics have been developed to specifically target HIV infection in the brain. Recent development of an inducible brain-specific Tat transgenic mouse model has made it possible to define the mechanisms of Tat neurotoxicity and evaluate anti-neuroAIDS therapeutic candidates in the context of a whole organism. Herein, we demonstrate that administration of EGb 761, a standardized formulation of Ginkgo biloba extract, markedly protected Tat transgenic mice from Tat-induced developmental retardation, inflammation, death, astrocytosis, and neuron loss. EGb 761 directly down-regulated glial fibrillary acidic protein (GFAP) expression at both protein and mRNA levels. This down-regulation was, at least in part, attributable to direct effects of EGb 761 on the interactions of the AP1 and NF-B transcription factors with the GFAP promoter. Most strikingly, Tat-induced neuropathological phenotypes including macrophage/microglia activation, central nervous system infiltration of T lymphocytes, and oxidative stress were significantly alleviated in GFAP-null/Tat transgenic mice. Taken together, these results provide the first evidence to support the potential for clinical use of EGb 761 to treat HIV-associated neurological diseases. Moreover, these findings suggest for the first time that GFAP activation is directly involved in Tat neurotoxicity, supporting the notion that astrocyte activation or astrocytosis may directly contribute to HIV-associated neurological disorders.

Exposure to HIV-1 Tat in brain impairs sensorimotor gating and activates microglia in limbic and extralimbic brain regions of male mice

“…Findings are broadly consistent with demonstrations of Tat-induced neuroinflammation in vivo , including biomarkers of neuroinflammation in the cortex of GT-tg bigenic mice [34], activation of astrocytes and elevated immunoreactive microglial markers in the striatum of Tat-induced mice that are co-administered morphine [35], and demonstrated microgliosis in the cortex of CX3CR1GFP/+ mice [36]. Moreover, a single exogenous administration of Tat protein to the hippocampus produced microgliosis within 24 h that lasted for 28 days in chimeric C57BL/6 mice genetically marked to distinguish infiltrating- from resident-immune cells [37].…”

Brain Invasion by CD4+ T Cells Infected with a Transmitted/Founder HIV-1BJZS7 During Acute Stage in Humanized Mice

“…This notion is in consistence with previous studies that virus, Tat and gp120 may directly contribute to HAND (Paris et al 2015;Podhaizer et al 2012;Zou et al 2007). Because gp120 glycoproteins can be taken up by brain microvessels and transported across the BBB (Banks et al 2005), it is possible that higher brain P24 antgenemia in HIV-1 JR-FL -infected mice contribute to severer neuron damages as compared with HIV-1 BJZS7 -infected animals.…”

“…Immunodeficient NOD.Cg-Prkdc scid Il2rgtm1Wjl/SzJ (NSG) mice were purchased from the Jackson Laboratory. NSG-HuPBL mice were generated as described previously (Nakata et al 2005). Briefly, 2x10 7 PBMCs, which were freshly isolated from healthy blood donors, were injected intraperitoneally (i.p.)…”

HIV-1 Tat Promotes Lysosomal Exocytosis in Astrocytes and Contributes to Astrocyte-mediated Tat Neurotoxicity

“…GFAP-null mice were generously provided by Dr. Albee Messing of University of Wisconsin (Madison, WI) (78). iTat/GFAP-null (iTat/GFAPϪ) mice were obtained by cross-breeding iTat mice with GFAP-null mice and characterized as described previously (79).…”