Quan N, Mhlanga J D, Whiteside M B, Kristensson K, Herkenham M
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Neuroscience. 2000;96(1):181-94. doi: 10.1016/s0306-4522(99)00492-3.
We have reported previously that axonal degeneration in specific brain regions occurs in rats infected with the parasite Trypanosoma brucei. These degenerative changes occur in spatiotemporal association with over-expression of pro-inflammatory cytokine messenger RNAs in the brain. To test how aspirin-like anti-inflammatory drugs might alter the disease process, we fed trypanosome-infected rats with 200mg/kg of sodium salicylate (the first metabolite of aspirin) daily in their drinking water. Sodium salicylate treatment in uninfected rats did not cause any neural damage. However, sodium salicylate treatment greatly exacerbated neurodegeneration in trypanosome-infected rats, resulting in extensive terminal and neuronal cell body degeneration in the cortex, hippocampus, striatum, thalamus, and anterior olfactory nucleus. The exaggerated neurodegeneration, which occurred in late stages of infection, was temporally and somewhat spatially associated with a late-appearing enhancement of messenger RNA expression of interleukin-1beta, interleukin-1beta converting enzyme, tumor necrosis factor-alpha, and inhibitory factor kappaBalpha in the brain parenchyma. Restricted areas showed elevations in messenger RNA expression of interleukin-1 receptor antagonist, interleukin-6, inducible nitric oxide synthase, interferon-gamma, and inducible cyclooxygenase. The association suggests that increased production of pro-inflammatory cytokines in the brain may be an underlying mechanism for neural damage induced by the chronic sodium salicylate treatment. Furthermore, the results reveal a serious complication in using aspirin-like drugs for the treatment of trypanosome infection.
我们之前报道过，感染寄生虫布氏锥虫的大鼠特定脑区会发生轴突退化。这些退化性变化与脑中促炎细胞因子信使核糖核酸的过度表达在时空上相关联。为了测试阿司匹林样抗炎药物如何改变疾病进程，我们给感染锥虫的大鼠在饮水中每日喂食200毫克/千克的水杨酸钠（阿司匹林的首个代谢产物）。水杨酸钠对未感染大鼠的治疗未造成任何神经损伤。然而，水杨酸钠治疗极大地加剧了感染锥虫大鼠的神经退化，导致皮质、海马体、纹状体、丘脑和前嗅核出现广泛的终末和神经元细胞体退化。这种在感染后期出现的过度神经退化在时间上且在一定程度上在空间上与脑实质中白细胞介素-1β、白细胞介素-1β转换酶、肿瘤坏死因子-α和抑制因子κBα信使核糖核酸表达的后期增强相关。受限区域显示白细胞介素-1受体拮抗剂、白细胞介素-6、诱导型一氧化氮合酶、干扰素-γ和诱导型环氧化酶的信使核糖核酸表达升高。这种关联表明脑中促炎细胞因子产生增加可能是慢性水杨酸钠治疗诱导神经损伤的潜在机制。此外，结果揭示了使用阿司匹林样药物治疗锥虫感染的一个严重并发症。
