Brain Advance Access originally published online on December 8, 2003
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Brain, Vol. 127, No. 2, 398-407, 2004
© 2004 Guarantors of Brain
doi: 10.1093/brain/awh049
Anti-HIV drugs decrease the expression of matrix metalloproteinases in astrocytes and microglia
1 Department of Biochemistry and Molecular Biology, University of Bari, Bari, 2 Department of Infectious and Tropical Diseases, La Sapienza University, Rome, and 3 Department of Biology D.B.A.F., University of Basilicata, Potenza, Italy
Correspondence to: Dr Grazia Maria Liuzzi, Department of Biochemistry and Molecular Biology, University of Bari, Via Orabona 4, 70126 Bari, Italy E-mail: m.g.liuzzi{at}biologia.uniba.it
The introduction of potent antiretroviral drugs for the treatment of patients with human immunodeficiency virus (HIV) infection has dramatically reduced the prevalence of HIV-associated neurological disorders. Such diseases can be mediated by proteolytic enzymes, i.e. matrix metalloproteinases (MMPs) and, in particular gelatinases, released from glial cells. The aim of this study was to investigate whether the antiretroviral drugs commonly used for the treatment of HIV-infected patients modulate the activity of MMPs in astrocyte and microglial cultures. Primary cultures of rat astrocyte and microglia were treated with different doses of zidovudine (AZT) or indinavir (IDV) for 20 h and simultaneously activated by exposure to lipopolysaccharide (LPS). Culture supernatants collected from astrocytes and microglia after 24 h incubation were subjected to gelatin zymography and western blot analysis for the assessment of MMP-2 (gelatinase A) and MMP-9 (gelatinase B) protein levels. Total RNA was extracted from glial cells and used for reverse transcriptase–polymerase chain reaction for the assessment of mRNA expression. Our results indicate that both astrocyte and microglial cells constitutively express MMP-2 mRNA and protein. LPS treatment increased MMP-2 mRNA and protein expression in astrocytes, but not in microglial cells. The treatment with both AZT and IDV dose-dependently inhibited the expression of MMP-2 in astrocytes, whereas it had no effect on microglial cells. The expression of MMP-9 in both astrocytes and microglia was induced by LPS treatment and was dose-dependently inhibited by AZT and IDV treatment in LPS-stimulated astrocytes and microglia. These results raise the possibility that AZT and IDV interfere directly with MMP production in glial cells and independently from their antiviral activity, thus suggesting the possible therapeutical use in neurological diseases associated with MMPs involvement.
Key Words: matrix metalloproteinases; antiretroviral drugs; HIV dementia; microglia; astrocytes
Abbreviations: AZT = zidovudine; BBB = blood brain barrier; DMEM= Dulbecco’s modified Eagle’s medium; GFAP = glial fibrillary acidic protein; HIV = human immunodeficiency virus; HIVD = HIV-associated dementia; IDV = indinavir; LPS = lipopolysaccharide; MMP = matrix metalloproteinase; MBP = myelin basic protein; PA = 1,10 phenanthroline; RT–PCR = reverse transcriptase polymerase chain reaction; TIMP = tissue inhibitors of matrix metalloproteinase.
Received July 25, 2003. Revised September 29, 2003. Accepted October 1, 2003.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  N. L. Webster and S. M. Crowe Matrix metalloproteinases, their production by monocytes and macrophages and their potential role in HIV-related diseases J. Leukoc. Biol., November 1, 2006; 80(5): 1052 - 1066. [Abstract] [Full Text] [PDF]
|
|