title: In vitro downregulation of matrix metalloproteinase-9 in rat glial cells by CCR5 antagonist maraviroc: therapeutic implication for HIV brain infection.
abstract: BACKGROUND
  Matrix metalloproteinases (MMPs) released by glial cells are important mediators of neuroinflammation and neurologic damage in HIV infection. The use of antiretroviral drugs able to combat the detrimental effect of chronic inflammation and target the exaggerated MMP activity might represent an attractive therapeutic challenge. Recent studies suggest that CCR5 antagonist maraviroc (MVC) exerts immunomodulant and anti-inflammatory activity beyond its anti-HIV properties. We investigated the in vitro effect of MVC on the activity of MMPs in astrocyte and microglia cultures.
  
  
  RESULTS
  Primary cultures of rat astrocytes and microglia were activated by exposure to phorbol myristate acetate (PMA) or lypopolysaccharide (LPS) and treated in vitro with MVC. Culture supernatants were subjected to gelatin zymography and quantitative determination of MMP-9 and MMP-2 was done by computerized scanning densitometry. MMP-9 levels were significantly elevated in culture supernatants from both LPS- and PMA-activated astrocytes and microglia in comparison to controls. The treatment with MVC significantly inhibited in a dose-dependent manner the levels and expression of MMP-9 in PMA-activated astrocytes (p<0,05) and, to a lesser extent, in PMA-activated microglia. By contrast, levels of MMP-2 did not significantly change, although a tendency to decrease was seen in PMA-activated astrocytes after treatment with MVC. The inhibition of levels and expression of MMP-9 in PMA-activated glial cells did not depend on cytotoxic effects of MVC. No inhibition of MMP-9 and MMP-2 were found in both LPS-activated astrocytes and microglia.
  
  
  CONCLUSIONS
  The present in vitro study suggests that CCR5 antagonist compounds, through their ability to inhibit MMP-9 expression and levels, might have a great potential for the treatment of HIV-associated neurologic damage.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Bari, Bari, Italy.
authors.forename: Pasqua
authors.initials: P
authors.lastname: Gramegna
authors.forename: Tiziana
authors.initials: T
authors.lastname: Latronico
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Branà
authors.forename: Gaetano
authors.initials: G
authors.lastname: Di Bari
authors.forename: Fabio
authors.initials: F
authors.lastname: Mengoni
authors.forename: Valeria
authors.initials: V
authors.lastname: Belvisi
authors.forename: Maria T
authors.initials: MT
authors.lastname: Mascellino
authors.forename: Miriam
authors.initials: M
authors.lastname: Lichtner
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Vullo
authors.forename: Claudio M
authors.initials: CM
authors.lastname: Mastroianni
authors.forename: Grazia M
authors.initials: GM
authors.lastname: Liuzzi
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000821:virology*; D065100:CCR5 Receptor Antagonists; D016923:Cell Death / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003510:Cyclohexanes / Q000494:pharmacology* / Q000627:therapeutic use; D015536:Down-Regulation / Q000187:drug effects*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015658:HIV Infections / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D000077592:Maraviroc; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D009457:Neuroglia / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D019713:Receptors, CCR5 / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D008070:Lipopolysaccharides; D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger; D019713:Receptors, CCR5; D014230:Triazoles; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D000077592:Maraviroc; D013755:Tetradecanoylphorbol Acetate