Attenuation of oxidative stress, inflammation and apoptosis by minocycline prevents retrovirus-induced neurodegeneration in mice

Abstract

The ts1 mutant of the Moloney murine leukemia virus (MoMuLV) causes neurodegeneration in infected mice that resembles HIV-associated dementia. We have shown previously that ts1 infects glial cells in the brain, but not neurons. The most likely mechanism for ts1-mediated neurodegeneration is loss of glial redox support and glial cell toxicity to neurons. Minocycline has been shown to have neuroprotective effects in various models of neurodegeneration. This study was designed to determine whether and how minocycline prevents paralysis and death in ts1-infected mice. We show here that minocycline delays neurodegeneration in ts1 -infected mice, and that it prevents death of cultured astrocyte infected by ts1 through attenuating oxidative stress, inflammation and apoptosis. Although minocycline reduces virus titers in the CNS of infected mice, it does not affect virus titers in infected mice thymi, spleens or infected C1 astrocytes. In addition, minocycline prevents death of primary neurons when they are cocultured with ts1 -infected astrocytes, through mechanisms involving both inhibition of oxidative stress and upregulation of the transcription factor NF-E2-related factor 2 (Nrf2), which confers the cell the antioxidant defense. We conclude that minocycline delays retrovirus ts1 -induced neurodegeneration involving antioxidant, anti-inflammation and anti-apoptotic mechanisms.

Persistent retroviral infection with MoMuLV influences neuropathological signature and phenotype of prion disease

“…In vivo, neurons are the prime target for prion infection and play a crucial role for development of clinical prion disease [2,37,52]. As post-mitotic cells, neurons are not the prime target for retroviral infection [38,47,49,83]. In cell culture experiments, either fibroblasts or microglia cells were super-infected with retroviruses and prions [39,73].…”

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

“…Advanced clinical trials for the treatment of Huntington's disease are under development with minocycline, an antibiotic that has demonstrated neuroprotective properties due to NRF2 activation (Kuang et al, 2009). Another NRF2 inducer in phase I clinical study for the treatment of acute kidney disease is CXA-10, a nitro fatty acid with anti-inflammatory properties through the activation of NRF2 (Batthyany and Lopez, 2015).…”

Minocycline Blocks Asthma-associated Inflammation in Part by Interfering with the T Cell Receptor-Nuclear Factor κB-GATA-3-IL-4 Axis without a Prominent Effect on Poly(ADP-ribose) Polymerase

“…Additional groups of mice received 10 mg/kg minocycline (SigmaAldrich) or saline intraperitoneally 1 h prior to the OVA challenge. This dose of minocycline was selected on the basis of studies that demonstrated its protective effect in a variety of models of inflammation (17)(18)(19). Mice were then left to recover and were sacrificed 24 h or 48 h later for bronchio-alveolar lavage (BAL) or lung fixation and processing for histological analysis.…”