Pentoxifylline prevents spontaneous brain ischemia in stroke-prone rats.
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-alpha (TNF-alpha), but not of interleukin (IL)-1beta and IL-6 induced by in vivo administration of lipopolysaccharide (LPS), which suggests a protective role for TNF-alpha. 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-alpha by PTX treatment represents a protective mechanism in SHRSP.
Banfi
Cristina
C
Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy.
Sironi
Luigi
L
De Simoni
Grazia
G
Gelosa
Paolo
P
Barcella
Simona
S
Perego
Carlo
C
Gianazza
Elisabetta
E
Guerrini
Uliano
U
Tremoli
Elena
E
Mussoni
Luciana
L
D000818:Animals; D002545:Brain Ischemia / Q000150:complications* / Q000209:etiology / Q000517:prevention & control*; D004195:Disease Models, Animal; D007249:Inflammation / Q000209:etiology; D008297:Male; D010431:Pentoxifylline / Q000627:therapeutic use*; D011507:Proteinuria / Q000209:etiology / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D020521:Stroke / Q000150:complications*; D014665:Vasodilator Agents
D014665:Vasodilator Agents; D010431:Pentoxifylline