Banfi Cristina, Sironi Luigi, De Simoni Grazia, Gelosa Paolo, Barcella Simona, Perego Carlo, Gianazza Elisabetta, Guerrini Uliano, Tremoli Elena, Mussoni Luciana
Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy.
J Pharmacol Exp Ther. 2004 Sep;310(3):890-5. doi: 10.1124/jpet.104.067090. Epub 2004 Jun 16.
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.
己酮可可碱（PTX）的抗炎特性最近已被描述。自发性高血压易中风大鼠（SHRSP）构成了一种动物模型，该模型会发展出一种在脑部异常出现之前的炎症状态。本研究的目的是评估：1）PTX治疗对SHRSP神经系统的保护效果，以及2）其抗炎特性如何参与这一作用。喂食许可饮食的雄性SHRSP未接受药物或PTX（100或200毫克/千克/天）治疗。对照组大鼠在42±3天后磁共振成像检测到的脑部异常是自发出现的，而在接受100毫克/千克/天PTX治疗的大鼠中，只有80%的动物出现异常，且仅在70至80天后出现。更高剂量的PTX（200毫克/千克/天）治疗可完全保护大脑不出现异常发育。药物治疗可防止巨噬细胞或CD4 +阳性细胞的积累、脑组织中胶质细胞的激活以及体液中炎症蛋白和硫代巴比妥酸反应性物质的出现。PTX治疗确实导致血清肿瘤坏死因子-α（TNF-α）有更大程度的增加，但体内给予脂多糖（LPS）诱导的白细胞介素（IL）-1β和IL-6并未增加，这表明TNF-α具有保护作用。当在首次出现蛋白尿（>40毫克/天）后给予PTX时，它也发挥了保护作用。这些数据表明，PTX治疗通过减少炎症事件剂量依赖性地预防自发性脑损伤的发生。我们还推测，PTX治疗导致的TNF-α增加代表了SHRSP中的一种保护机制。
