Abstract
Anti-inflammatory properties of pentoxifylline (PTX) have recently been described. Spontaneously hypertensive stroke-prone rats (SHRSP) constitute an animal model that develops an inflammatory condition that precedes the appearance of brain abnormalities. The aim of the present investigation was to assess: 1) the efficacy of PTX treatment in protecting the neural system in SHRSP, and 2) how its anti-inflammatory properties might be involved in this effect. Male SHRSP fed with a permissive diet received no drug or PTX (100 or 200 mg/kg/day). Brain abnormalities detected by magnetic resonance imaging developed spontaneously in control rats after 42 ± 3 days, whereas in rats treated with 100 mg/kg/day PTX, abnormalities developed in only 80% of the animals and only after 70 to 80 days. Treatment with a higher dose of PTX (200 mg/kg/day) completely protected the brain from abnormal development. The drug treatment prevented the accumulation of macrophages or CD4+ positive cells, the activation of glia in brain tissues, and the appearance of inflammatory proteins and thiobarbituric acid-reactive substances in body fluids. PTX treatment did induce a greater increase of serum tumor necrosis factor-α (TNF-α), but not of interleukin (IL)-1β and IL-6 induced by in vivo administration of lipopolysaccharide (LPS), which suggests a protective role for TNF-α. PTX also exerted protective effects when it was administered after the first occurrence of proteinuria (>40 mg/day). These data indicate that PTX treatment dose-dependently prevents the occurrence of spontaneous brain damage by reducing inflammatory events. We also hypothesize that the increase of TNF-α by PTX treatment represents a protective mechanism in SHRSP.
Footnotes
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This work was supported by a grant from the University of Milan and Italian Ministry of Education, University and Research (FIRB 2001: Project no. RBNE01BNFK).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.104.067090.
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ABBREVIATIONS: PTX, pentoxifylline; SHRSP, spontaneously hypertensive stroke-prone rats; MRI, magnetic resonance imaging; MPO, myeloperoxidase; TBA, thiobarbituric acid; TBARS, TBA reacting substances; MDA, malondialdehyde; TNF-α, tumor necrosis factor-α; IL, interleukin; LPS, lipopolysaccharide.
- Received February 17, 2004.
- Accepted June 15, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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