Nemeth Christina L, Miller Andrew H, Tansey Malú G, Neigh Gretchen N
Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, United States; Department of Physiology, Emory University, Atlanta, GA, United States.
Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, United States.
Behav Brain Res. 2016 Apr 15;303:160-7. doi: 10.1016/j.bbr.2016.01.057. Epub 2016 Jan 28.
Poor vascular health, atherosclerosis, or cardiac procedures in the elderly result in clinically silent microvascular infarcts that increase susceptibility to larger ischemic episodes and can precipitate changes in mood and cognition. Although the mechanisms that underlie ischemia-induced behavioral changes have not been fully elucidated, chronic inflammation has been implicated in the pathogenesis. Independent of brain injury, elevated levels of inflammatory cytokines can lead to sickness behaviors and symptoms of depression. Furthermore, in the presence of brain injury, inflammatory activation may serve as the linchpin that precipitates dysregulation of biological systems leading to changes to behavior. In the current study, we tested the hypothesis that cerebral inflammation caused by diffuse ischemia is necessary for the expression of post-injury anxiety- and depressive- like behavior. Using a microsphere embolism (ME) rodent model, we demonstrate prolonged elevations in expression of inflammatory genes in the hippocampus ipsilateral to the injury which are reflected in the contralateral hemisphere by two weeks following injury. Prophylactic administration of meloxicam, a preferential inhibitor of COX-2 activity, prevented both central inflammation and deficits in affective-like behaviors. Furthermore, meloxicam was more efficacious than the selective serotonin reuptake inhibitor fluoxetine in prevention of microembolism-induced changes in inflammation and behavior. These data demonstrate that inflammatory activation is necessary for microembolism-induced behavioral changes and suggest that anti-inflammatory treatments may be an effective therapeutic strategy in patients with risk factors for vascular depression or prior to invasive cardiac procedures.
老年人血管健康状况不佳、动脉粥样硬化或心脏手术会导致临床上无症状的微血管梗死，增加对较大缺血性发作的易感性，并可能引发情绪和认知变化。尽管缺血诱导行为改变的潜在机制尚未完全阐明，但慢性炎症已被认为与发病机制有关。独立于脑损伤，炎症细胞因子水平升高可导致疾病行为和抑郁症状。此外，在存在脑损伤的情况下，炎症激活可能是导致生物系统失调进而引起行为改变的关键因素。在本研究中，我们检验了这样一个假设，即弥漫性缺血引起的脑部炎症是损伤后焦虑样和抑郁样行为表达所必需的。使用微球栓塞（ME）啮齿动物模型，我们证明损伤同侧海马中炎症基因表达持续升高，损伤后两周在对侧半球也有体现。预防性给予美洛昔康（一种COX-2活性的优先抑制剂）可预防中枢炎症和情感样行为缺陷。此外，在预防微栓塞诱导的炎症和行为变化方面，美洛昔康比选择性5-羟色胺再摄取抑制剂氟西汀更有效。这些数据表明炎症激活是微栓塞诱导行为改变所必需的，并提示抗炎治疗可能是血管性抑郁危险因素患者或侵入性心脏手术前患者的一种有效治疗策略。
