Pereira, E. F. R. | bioRxiv Science

bioRxiv2020

HIV-1 Vpr-induced Proinflammatory Response and Apoptosis are Mediated through the Sur1-Trpm4 Channel in Astrocytes

There are about 38 million people currently living with HIV/AIDS worldwide. Successful treatment with combinational antiretroviral therapies (cART) can eliminate active replicating viruses and prolong lives to nearly normal lifespans. However, the new challenge faced by more than half of those HIV-infected and aging patients is chronic CNS neuroinflammation, which leads to HIV-associated neurocognitive disorders (HAND). While severe and progressive HAND has decreased significantly due to cART, chronic HAND often persists, resulting in high rates of delirium, dementia and depression that could lead to suicide. Indeed, the risk of suicide mortality in HIV-infected persons is significantly higher than in HIV-uninfected counterparts. Nevertheless, the mechanism of neuropathogenesis underlying HAND is not well understood. HAND is typically characterized by HIV-mediated glial neuroinflammation and neurotoxicity. Interestingly, the severity of some HAND does not always correlate with the levels of HIV, but rather with glial activation, suggesting other HIV-associated factors, not the whole virus per se, contribute to those HAND. HIV-1 viral protein R (Vpr) might be one of those viral factors, because Vpr induces neuroinflammation and causes neuronal apoptosis. The objective of this study was to delineate the specific role(s) of Vpr in activation of host neuroinflammation and neurotoxicity, as well as its contribution to HAND. In this report, we show correlations between HIV expression and activation of proinflammatory markers (TLR4, TNF, and NF{kappa}B) and the Sur1-Trpm4 channel in astrocytes of HIV-infected postmortem human and transgenic mouse brain tissues. We further show that Vpr alone activate the same set of proinflammatory markers in an astrocytic cell line SNB19. Vpr-induced host cell proinflammatory responses result in apoptotic cell death. Together, our data suggest that HIV-1 Vpr-induced proinflammatory response and apoptotic cell death are mediated through the Sur1-Trpm4 channel in astrocytes.

neuroscience↗

bioRxiv2020

Oral Pretreatment with Galantamine Effectively Mitigates the Acute Toxicity of a Supra-Lethal Dose of Soman in Cynomolgus Monkeys Post-treated with Conventional Antidotes

The present study was designed to evaluate the effectiveness of galantamine administered orally as a pre-treatment to mitigate the acute toxicity of 4.0xLD50 soman in Cynomolgus monkeys post-treated with atropine, 2-PAM, and midazolam. Pharmacokinetic experiments revealed that the oral doses of 1.5 and 3.0 mg/kg galantamine HBr were quickly absorbed and produced plasma concentrations of galantamine that generated approximately 20% to 40% reversible inhibition of blood acetylcholinesterase (AChE) activity. This degree of reversible AChE inhibition has been shown to be safe and sufficient to protect AChE from the irreversible inhibition by nerve agents, and, thereby, suppress the acute toxicity of these agents. Thus, in subsequent experiments, adult male Cynomolgus monkeys were pretreated orally with 1.5 or 3.0 mg/kg galantamine, challenged intramuscularly with 4.0xLD50, and post-treated with intramuscular injections of 0.4 mg/kg atropine, 30 mg/kg 2-PAM, and 0.32 mg/kg midazolam. All animals subjected to these treatments survived the soman. By contrast, none of the animals that were pretreated with saline and only 40% of the animals that were pretreated with pyridostigmine survived the soman challenge when post-treated with the same conventional antidotal therapy as that delivered to the galantamine-pretreated, soman-challenged monkeys. In addition, large numbers of degenerating neurons were visualized in the hippocampi of soman-challenged monkeys that had been pretreated with pyridostigmine or saline, but not in the hippocampi of animals that had been pretreated with galantamine. To our knowledge, this is the first study to demonstrate the effectiveness of clinically relevant oral doses of galantamine to prevent the acute toxicity of supra-lethal doses of soman in non-human primates.

pharmacology and toxicology↗