Trinity College Institute of Neuroscience and School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Republic of Ireland.
J Neurosci. 2013 Sep 18;33(38):15248-58. doi: 10.1523/JNEUROSCI.6361-11.2013.
Systemic inflammatory events often precipitate acute cognitive dysfunction in elderly and demented populations. Delirium is a highly prevalent neuropsychiatric syndrome that is characterized by acute inattention and cognitive dysfunction, for which prior dementia is the major predisposing factor and systemic inflammation is a frequent trigger. Inflammatory mechanisms of delirium remain unclear. We have modeled aspects of delirium during dementia by exploiting progressive neurodegeneration in the ME7 mouse model of prion disease and by superimposing systemic inflammation induced by the bacterial endotoxin lipopolysaccharide (LPS). Here, we have used this model to demonstrate that the progression of underlying disease increases the incidence, severity, and duration of acute cognitive dysfunction. This increasing susceptibility is associated with increased CNS expression of cyclooxygenase (COX)-1 in microglia and perivascular macrophages. The COX-1-specific inhibitor SC-560 provided significant protection against LPS-induced cognitive deficits, and attenuated the disease-induced increase in hippocampal and thalamic prostaglandin E2, while the COX-2-specific inhibitor NS-398 was ineffective. SC-560 treatment did not alter levels of the proinflammatory cytokines interleukin (IL)-1β, tumor necrosis factor-α, IL-6, or C-X-C chemokine ligand 1 in blood or brain, but systemic IL-1RA blocked LPS-induced cognitive deficits, and systemic IL-1β was sufficient to induce similar deficits in the absence of LPS. Furthermore, the well tolerated COX inhibitor ibuprofen was protective against IL-1β-induced deficits. These data demonstrate that progressive microglial COX-1 expression and prostaglandin synthesis can underpin susceptibility to cognitive deficits, which can be triggered by systemic LPS-induced IL-1β. These data contribute to our understanding of how systemic inflammation and ongoing neurodegeneration interact to induce cognitive dysfunction and episodes of delirium.
系统性炎症事件常可引发老年和痴呆人群的急性认知功能障碍。谵妄是一种常见的神经精神综合征，其特征为急性注意力不集中和认知功能障碍，先前的痴呆是主要的诱发因素，系统性炎症是常见的触发因素。谵妄的炎症机制仍不清楚。我们通过利用朊病毒病的 ME7 小鼠模型中的进行性神经退行性变以及通过叠加细菌内毒素脂多糖 (LPS) 诱导的全身炎症，来模拟痴呆期间的谵妄的各个方面。在这里，我们使用该模型表明，基础疾病的进展增加了急性认知功能障碍的发生率、严重程度和持续时间。这种易感性的增加与小胶质细胞和血管周围巨噬细胞中中枢神经系统环氧化酶 (COX)-1 的表达增加有关。COX-1 特异性抑制剂 SC-560 对 LPS 诱导的认知缺陷提供了显著的保护作用，并减轻了疾病诱导的海马体和丘脑前列腺素 E2 的增加，而 COX-2 特异性抑制剂 NS-398 则无效。SC-560 治疗不会改变血液或大脑中促炎细胞因子白细胞介素 (IL)-1β、肿瘤坏死因子-α、IL-6 或 C-X-C 趋化因子配体 1 的水平，但全身性 IL-1RA 可阻断 LPS 诱导的认知缺陷，并且在没有 LPS 的情况下，全身性 IL-1β 足以引起类似的缺陷。此外，耐受性良好的 COX 抑制剂布洛芬对 IL-1β 诱导的缺陷具有保护作用。这些数据表明，进行性小胶质细胞 COX-1 表达和前列腺素合成可以为认知缺陷的易感性提供基础，而这种易感性可以通过全身 LPS 诱导的 IL-1β 触发。这些数据有助于我们理解系统性炎症和进行性神经退行性变如何相互作用，引发认知功能障碍和谵妄发作。
