Liechti F D, Grandgirard D, Leib S L
Neuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, Friedbühlstrasse 51, CH-3010 Bern, Switzerland.
Neuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, Friedbühlstrasse 51, CH-3010 Bern, Switzerland; Biology Division, Spiez Laboratory, Swiss Federal Office for Civil Protection, Austrasse, Spiez CH-3700, Switzerland.
Neuroscience. 2015 Jun 25;297:89-94. doi: 10.1016/j.neuroscience.2015.03.056. Epub 2015 Apr 1.
High mortality and morbidity rates are observed in patients with bacterial meningitis (BM) and urge for new adjuvant treatments in addition to standard antibiotic therapies. In BM the hippocampal dentate gyrus is injured by apoptosis while in cortical areas ischemic necrosis occurs. Experimental therapies aimed at reducing the inflammatory response and brain damage have successfully been evaluated in animal models of BM. Fluoxetine (FLX) is an anti-depressant of the selective serotonin reuptake inhibitors (SSRI) and was previously shown to be neuroprotective in vitro and in vivo. We therefore assessed the neuroprotective effect of FLX in experimental pneumococcal meningitis.
Infant rats were infected intracisternally with live Streptococcus pneumoniae. Intraperitoneal treatment with FLX (10mgkg(-1)d(-1)) or an equal volume of NaCl was initiated 15min later. 18, 27, and 42h after infection, the animals were clinically (weight, clinical score, mortality) evaluated and subject to a cisternal puncture and inflammatory parameters (i.e., cyto-/chemokines, myeloperoxidase activity, matrix metalloproteinase concentrations) were measured in cerebrospinal fluid (CSF) samples. At 42h after infection, animals were sacrificed and the brains collected for histomorphometrical analysis of brain damage.
A significant lower number of animals treated with FLX showed relevant hippocampal apoptosis when compared to littermates (9/19 animals vs 18/23, P=0.038). A trend for less damage in cortical areas was observed in FLX-treated animals compared to controls (13/19 vs 13/23, P=ns). Clinical and inflammatory parameters were not affected by FLX treatment.
A significant neuroprotective effect of FLX on the hippocampus was observed in acute pneumococcal meningitis in infant rats.
细菌性脑膜炎（BM）患者的死亡率和发病率很高，除了标准抗生素治疗外，迫切需要新的辅助治疗方法。在BM中，海马齿状回通过凋亡受到损伤，而在皮质区域则发生缺血性坏死。旨在减少炎症反应和脑损伤的实验性疗法已在BM动物模型中得到成功评估。氟西汀（FLX）是一种选择性5-羟色胺再摄取抑制剂（SSRI）类抗抑郁药，先前已证明其在体外和体内具有神经保护作用。因此，我们评估了FLX在实验性肺炎球菌性脑膜炎中的神经保护作用。
幼鼠经脑池内注射活的肺炎链球菌进行感染。15分钟后开始腹腔注射FLX（10mgkg⁻¹d⁻¹）或等体积的NaCl。感染后18、27和42小时，对动物进行临床评估（体重、临床评分、死亡率），并进行脑池穿刺，测量脑脊液（CSF）样本中的炎症参数（即细胞因子/趋化因子、髓过氧化物酶活性、基质金属蛋白酶浓度）。感染后42小时，处死动物并收集大脑进行脑损伤的组织形态计量分析。
与同窝幼崽相比，接受FLX治疗的动物出现相关海马凋亡的数量显著减少（9/19只动物 vs 18/23只，P = 0.038）。与对照组相比，接受FLX治疗的动物在皮质区域的损伤有减少趋势（13/19 vs 13/23，P =无显著性差异）。FLX治疗对临床和炎症参数没有影响。
在幼鼠急性肺炎球菌性脑膜炎中观察到FLX对海马具有显著的神经保护作用。
