Neuroprotective effects of the drug GVT (monosodium luminol) are mediated by the stabilization of Nrf2 in astrocytes.
Oxidative stress is implicated in various kinds of neurological disorders, including human immunodeficiency virus (HIV) associated dementia (HAD). Our laboratory has been studying the murine retrovirus ts1, a pathogenic mutant of the Moloney murine leukemia virus (MoMuLV), as a model for HAD. Like HIV in humans, ts1 induces oxidative stress and progressive neurodegeneration in mice. We have shown previously that an antioxidant and anti-inflammatory drug GVT or MSL (monosodium luminol) suppresses ts1-induced oxidative stress, attenuates the development of spongiform encephalopathy, and delays hind limb paralysis in infected mice. It is known that upregulation of the nuclear transcription factor NF-E2-related factor 2 (Nrf2) is involved in upregulating cellular antioxidant defenses. Since Nrf2 is associated with elevation of antioxidant defenses in general, and since GVT suppresses ts1-induced neurodegeneration, our aim in this study was to determine whether GVT neuroprotection is linked to Nrf2 upregulation in the brain. We report here that GVT upregulates the levels of Nrf2, both in primary astrocyte cultures and in brainstem of ts1-infected mice. Significant upregulation of Nrf2 expression by GVT occurs in both the cytosolic and nuclear fractions of cultured astrocytes and brainstem cells. Notably, although GVT treatment increases Nrf2 protein levels in cultured astrocytes and brainstem tissues, Nrf2 mRNA levels are not altered. This suggests that the neuroprotective effects of GVT may be mediated by the stabilization of the Nrf2 protein, allowing continuous upregulation of Nrf2 levels in the astrocytes.
Reddy
Pichili Vijaya Bhaskar
PV
Department of Carcinogenesis, The University of Texas, MD Anderson Cancer Center, Science Park-Research Division, Smithville, TX 78957, USA.
Lungu
Gina
G
Kuang
Xianghong
X
Stoica
George
G
Wong
Paul K Y
PK
D000818:Animals; D001253:Astrocytes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D001933:Brain Stem / Q000737:chemistry / Q000378:metabolism; D002461:Cell Line, Transformed; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D007976:Leupeptins / Q000494:pharmacology; D008165:Luminol / Q000494:pharmacology*; D051379:Mice; D008979:Moloney murine leukemia virus / Q000235:genetics; D009154:Mutation; D051267:NF-E2-Related Factor 2 / Q000032:analysis / Q000187:drug effects* / Q000378:metabolism*; D009457:Neuroglia / Q000737:chemistry / Q000187:drug effects / Q000648:ultrastructure; D009474:Neurons / Q000737:chemistry / Q000187:drug effects / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D012192:Retroviridae Infections / Q000378:metabolism; D014412:Tumor Virus Infections / Q000378:metabolism
D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; D008165:Luminol; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde