A noradrenergic lesion aggravates the effects of systemic inflammation on the hippocampus of aged rats.
A noradrenergic lesion aggravates the effects of systemic inflammation on the hippocampus of aged rats.
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DOI：
10.1371/journal.pone.0189821
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Ledreux A
中科院分区：
文献类型：
--
作者：
Bharani KL;Derex R;Granholm AC;Ledreux A
蓝斑去甲肾上腺素通路(LC-NE)的早期变性会加剧神经炎症，这种通路在阿尔茨海默病和帕金森病等与衰老相关的神经退行性疾病中常见。在动物模型中，脂多糖(LPS)诱导强烈的外周免疫反应，可导致继发于神经炎症的认知改变。外周免疫反应对认知的影响可能会因LC-NE变性而加剧，但这一点以前还没有得到很好的描述。在这项研究中，我们研究了全身炎症对LC-NE递质系统正常或受损的老年大鼠的神经炎症和认知功能的影响。用选择性去甲肾上腺素(NE)神经毒素N-(2-氯乙基)-N-乙基-2-溴苯甲胺(DSP4)诱导大鼠中枢NE通路变性。两周后，这些大鼠接受了低剂量的内毒素。结果3个处理组(对照组、内毒素处理组和DSP4+内毒素处理组)分别在注射内毒素后4h(短期亚组)和7d(长期亚组)进行研究。与对照组和脂多糖处理组大鼠相比，DSP4+脂多糖处理组大鼠血清中几种致炎细胞因子水平升高，海马区星形胶质细胞和小胶质细胞激活程度增加，在新对象识别任务(NORT)中的表现较差。此外，与其他两组相比，DSP4+LPS组的血清和脑组织脑源性神经营养因子(BDNF)水平随着时间的推移而发生变化。短期亚组大鼠海马区脑源性神经营养因子水平(~25%)低于对照组和内毒素组大鼠，与海马星形胶质细胞增生呈负相关，与IL-1β水平呈正相关。长期亚组DSP4+脂多糖处理组大鼠血清和海马区BDNF水平恢复到与对照组相似的水平。这些结果表明，与LC-NE正常大鼠相比，LC-NE损伤老年大鼠的全身炎症反应和中枢炎症反应加剧，并改变了BDNF水平，表明这一神经递质系统在神经炎症反应中起着重要作用。
Neuroinflammation is potentiated by early degeneration of the locus coeruleus noradrenergic pathway (LC-NE) commonly seen in aging-related neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. In animal models, lipopolysaccharide (LPS) induces strong peripheral immune responses that can cause cognitive changes secondary to neuroinflammation. The influence of the peripheral immune response on cognition might be exacerbated by LC-NE degeneration, but this has not been well characterized previously. In this study, we investigated how systemic inflammation affects neuroinflammation and cognition in aged rats that have had either normal or damaged LC-NE transmitter systems. Rats were first exposed to the selective noradrenergic (NE) neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) to induce degeneration of central NE pathways. Two weeks later, the rats received a low dose of LPS. This resulted in 3 treatment groups (Control, LPS-, and DSP4+LPS-treated rats) studied at 4 hours (short-term subgroup) and 7 days (long-term subgroup) following the LPS injection. DSP4+LPS-treated rats exhibited increased serum levels of several pro-inflammatory cytokines, increased astroglial and microglial activation in the hippocampus, and poorer performance in the novel object recognition task (NORT) compared to controls and LPS-treated rats. Additionally, serum and brain tissue levels of brain-derived neurotrophic factor (BDNF) were modulated over time in the DSP4+LPS group compared to the other two groups. Specifically, DSP4+LPS-treated rats in the short-term subgroup had lower hippocampal BDNF levels (~25%) than controls and LPS-treated rats, which negatively correlated with hippocampal astrogliosis and positively correlated with hippocampal IL-1β levels. Serum and hippocampal BDNF levels in the DSP4+LPS-treated rats in the long-term subgroup returned to levels similar to the control group. These results show that systemic inflammation in LC-NE-lesioned aged rats promotes an exacerbated systemic and central inflammatory response compared to LC-NE-intact rats and alters BDNF levels, indicating the important role of this neurotransmitter system in response to neuroinflammation.
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影响因子：
4.2
作者：
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