Authors: Giovanni Sarnelli, Luisa Seguella, Marcella Pesce, Jie Lu, Stefano Gigli, Eugenia Bruzzese, Roberta Lattanzi, Alessandra D?Alessandro, Rosario Cuomo, Luca Steardo & Giuseppe Esposito

Institutions:

  • Department of Clinical Medicine and Surgery, ?Federico II? University of Naples, 80131, Naples, Italy
  • Department of Physiology and Pharmacology, ?Vittorio Erspamer?, La Sapienza University of Rome, 00185, Rome, Italy
  • Department of Anatomy, China Medical University, Shenyang, Liaoning Province, 110122, People?s Republic of China
  • Department of Physiology and Pharmacology, ?Vittorio Erspamer?, La Sapienza University of Rome, 00185, Rome, Italy
  • Department of Translational Medical Science, Section of Pediatrics, University Federico II, 80131, Naples, Italy

Publication: Journal of Neuroinflammation

Date: March 2018

Full paper:?https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-018-1126-4

Abstract:

Background
Diarrhea is a severe complication in HIV-1-infected patients with Trans-activator of transcription (HIV-1 Tat) protein being recognized as a major underlying cause. Beside its direct enterotoxic effects, Tat protein has been recently shown to affect enteric glial cell (EGC) activity. EGCs regulate intestinal inflammatory responses by secreting pro-inflammatory molecules; nonetheless, they might also release immune-regulatory factors, as palmytoilethanolamide (PEA), which exerts anti-inflammatory effects by activating PPAR? receptors. We aimed at clarifying whether EGCs are involved in HIV-1 Tat-induced diarrhea and if PEA exerts antidiarrheal activity.

Methods
Diarrhea was induced by intracolonic administration of HIV-1 Tat protein in rats at day 1. PEA alone or in the presence of peroxisome proliferator-activated receptor (PPAR) antagonists was given intraperitoneally from day 2 to day 7. S100B, iNOS, NF-kappaB, TLR4 and GFAP expression were evaluated in submucosal plexi, while S100B and NO levels were measured in EGC submucosal plexi lysates, respectively. To verify whether PEA effects were PPAR?-mediated, PPAR??/? mice were also used. After 7 days from diarrhea induction, endogenous PEA levels were measured in submucosal plexi homogenates deriving from rats and PPAR??/? mice.

Results
HIV-1 Tat protein induced rapid onset diarrhea alongside with a significant activation of EGCs. Tat administration significantly increased all hallmarks of neuroinflammation by triggering TLR4 and NF-kappaB activation and S100B and iNOS expression. Endogenous PEA levels were increased following HIV-1 Tat exposure in both wildtype and knockout animals. In PPAR??/? mice, PEA displayed no effects. In wildtype rats, PEA, via PPAR?-dependent mechanism, resulted in a significant antidiarrheal activity in parallel with marked reduction of EGC-sustained neuroinflammation.