Bally Lia, Grandgirard Denis, Leib Stephen L
Neuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, Bern, Switzerland.
Neuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, Bern, Switzerland
Antimicrob Agents Chemother. 2016 Jan 11;60(3):1841-6. doi: 10.1128/AAC.02429-15.
Pneumococcal meningitis (PM) causes neurological sequelae in up to half of surviving patients. Neuronal damage associated with poor outcome is largely mediated by the inflammatory host response. Dexamethasone (DXM) is used as an adjuvant therapy in adult PM, but its efficacy in the treatment of pneumococcal meningitis in children is controversially discussed. While DXM has previously been shown to enhance hippocampal apoptosis in experimental PM, its impact on hippocampal cell proliferation is not known. This study investigated the impact of DXM on hippocampal proliferation in infant rat PM. Eleven-day-old nursing Wistar rats (n = 90) were intracisternally infected with Streptococcus pneumoniae to induce experimental meningitis. Treatment with DXM or vehicle was started 18 h after infection, concomitantly with antibiotics (ceftriaxone 100 mg/kg of body weight twice a day [b.i.d.]). Clinical parameters were monitored, and the amount of cells with proliferating activity was assessed using in vivo incorporation of bromodeoxyuridine (BrdU) and an in vitro neurosphere culture system at 3 and 4 d postinfection. DXM significantly worsened weight loss and survival. Density of BrdU-positive cells, as an index of cells with proliferating activity, was significantly lower in DXM-treated animals compared to vehicle controls (P < 0.0001). In parallel, DXM reduced neurosphere formation as an index for stem/progenitor cell density compared to vehicle treatment (P = 0.01). Our findings provide clear evidence that DXM exerts an antiproliferative effect on the hippocampus in infant rat PM. We conclude that an impairment of regenerative hippocampal capacity should be taken into account when considering adjuvant DXM in the therapeutic regimen for PM in children.
肺炎球菌性脑膜炎（PM）在多达一半的存活患者中会导致神经后遗症。与不良预后相关的神经元损伤很大程度上由宿主炎症反应介导。地塞米松（DXM）在成人PM中用作辅助治疗，但其在儿童肺炎球菌性脑膜炎治疗中的疗效存在争议。虽然此前已证明DXM会增强实验性PM中的海马细胞凋亡，但其对海马细胞增殖的影响尚不清楚。本研究调查了DXM对幼鼠PM中海马增殖的影响。11日龄的哺乳期Wistar大鼠（n = 90）经脑池内感染肺炎链球菌以诱导实验性脑膜炎。感染后18小时开始用DXM或赋形剂治疗，同时使用抗生素（头孢曲松100 mg/kg体重，每日两次[b.i.d.]）。监测临床参数，并在感染后3天和4天使用体内溴脱氧尿苷（BrdU）掺入和体外神经球培养系统评估具有增殖活性的细胞数量。DXM显著加重了体重减轻和死亡率。与赋形剂对照组相比，接受DXM治疗的动物中作为增殖活性细胞指标的BrdU阳性细胞密度显著降低（P < 0.0001）。同时，与赋形剂治疗相比，DXM减少了神经球形成，作为干细胞/祖细胞密度的指标（P = 0.03）。我们的研究结果提供了明确的证据，表明DXM对幼鼠PM中的海马具有抗增殖作用。我们得出结论，在考虑儿童PM治疗方案中的辅助DXM时，应考虑到海马再生能力的损害。
