Cyclooxygenase-1-Dependent Prostaglandins Mediate Susceptibility to Systemic Inflammation-Induced Acute Cognitive Dysfunction
Cyclooxygenase-1-Dependent Prostaglandins Mediate Susceptibility to Systemic Inflammation-Induced Acute Cognitive Dysfunction
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DOI：
10.1523/jneurosci.6361-11.2013
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发表时间：
2013-09-18
影响因子：
5.3
通讯作者：
Cunningham, Colm
中科院分区：
文献类型：
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作者：
Griffin, Eadaoin W.;Skelly, Donal T.;Cunningham, Colm
全身性炎症事件经常在老年人和痴呆人群中引起急性认知功能障碍。谵妄是一种高度流行的神经精神综合征，其特征在于急性注意力不集中和认知功能障碍，其中先前的痴呆是主要的诱发因素，全身炎症是常见的触发因素。谵妄的炎症机制尚不清楚。我们已经模拟了痴呆期间谵妄的方面，利用进行性神经变性的ME 7小鼠模型朊病毒疾病和叠加全身炎症引起的细菌内毒素脂多糖（LPS）。在这里，我们使用这个模型来证明基础疾病的进展会增加急性认知功能障碍的发生率、严重程度和持续时间。这种增加的易感性与小胶质细胞和血管周围巨噬细胞中环氧合酶（考克斯）-1的CNS表达增加有关。考克斯-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，并减弱了疾病诱导的海马和丘脑前列腺素E-2的增加，而考克斯-2特异性抑制剂NS-398则无效。SC-560治疗未改变血液或脑中促炎细胞因子白细胞介素（IL）-1 β、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-1 RA可阻断LPS诱导的认知缺陷，而全身性IL-1 β足以在不存在LPS的情况下诱导类似的缺陷。此外，耐受性良好的考克斯抑制剂布洛芬对IL-1 β诱导的缺陷具有保护作用。这些数据表明，进行性小胶质细胞考克斯-1表达和前列腺素合成可以支持认知缺陷的易感性，这可以由全身性LPS诱导的IL-1 β触发。这些数据有助于我们了解全身炎症和持续的神经退行性变如何相互作用，以诱导认知功能障碍和谵妄发作。
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 E-2, while the COX-2-specific inhibitor NS-398 was ineffective. SC-560 treatment did not alter levels of the proinflammatory cytokines interleukin (IL)-1 beta, tumor necrosis factor-alpha, 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-1 beta was sufficient to induce similar deficits in the absence of LPS. Furthermore, the well tolerated COX inhibitor ibuprofen was protective against IL-1 beta-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-1 beta. These data contribute to our understanding of how systemic inflammation and ongoing neurodegeneration interact to induce cognitive dysfunction and episodes of delirium.