PMID- 28778220 OWN - NLM STAT- MEDLINE DCOM- 20180503 LR - 20200930 IS - 1742-2094 (Electronic) IS - 1742-2094 (Linking) VI - 14 IP - 1 DP - 2017 Aug 4 TI - Brain-derived neurotrophic factor reduces inflammation and hippocampal apoptosis in experimental Streptococcus pneumoniae meningitis. PG - 156 LID - 10.1186/s12974-017-0930-6 [doi] LID - 156 AB - BACKGROUND: Streptococcus pneumoniae meningitis is a serious inflammatory disease of the central nervous system (CNS) and is associated with high morbidity and mortality rates. The inflammatory processes initiated by recognition of bacterial components contribute to apoptosis in the hippocampal dentate gyrus. Brain-derived neurotrophic factor (BDNF) has long been recommended for the treatment of CNS diseases due to its powerful neuro-survival properties, as well as its recently reported anti-inflammatory and anti-apoptotic effects in vitro and in vivo. METHODS: In this study, we investigated the effects of BDNF-related signaling on the inflammatory response and hippocampal apoptosis in experimental models of pneumococcal meningitis. Pretreatment with exogenous BDNF or the tropomyosin-receptor kinase B (TrkB) inhibitor k252a was performed to assess the activation or inhibition of the BDNF/TrkB-signaling axis prior to intracisternal infection with live S. pneumoniae. At 24 h post-infection, rats were assessed for clinical severity and sacrificed to harvest the brains. Paraffin-embedded brain sections underwent hematoxylin and eosin staining to evaluate pathological severity, and cytokine and chemokine levels in the hippocampus and cortex were evaluated by enzyme-linked immunosorbent assay. Additionally, apoptotic neurons were detected in the hippocampal dentate gyrus by terminal deoxynucleotidyl transferase dUTP-nick-end labeling, key molecules associated with the related signaling pathway were analyzed by real-time polymerase chain reaction and western blot, and the DNA-binding activity of nuclear factor kappa B (NF-kappaB) was measured by electrophoretic mobility shift assay. RESULTS: Rats administered BDNF exhibited reduced clinical impairment, pathological severity, and hippocampal apoptosis. Furthermore, BDNF pretreatment suppressed the expression of inflammatory factors, including tumor necrosis factor alpha, interleukin (IL)-1beta, and IL-6, and increased the expression of the anti-inflammatory factor IL-10. Moreover, BDNF pretreatment increased TrkB expression, activated downstream phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling, and inhibited the myeloid differentiation primary response gene 88 (MyD88)/NF-kappaB-signaling pathway. CONCLUSIONS: These data suggested that BDNF administration exerted anti-inflammatory and anti-apoptotic effects on an experimental pneumococcal meningitis model via modulation of MyD88/NF-kappaB- and PI3K/AKT-signaling pathways. Our results indicated that treatment with exogenous BDNF might constitute a potential therapeutic strategy for the treatment of bacterial meningitis. FAU - Xu, Danfeng AU - Xu D AD - Department of Pediatric Neurology, Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine, Kongjiang Rd 1665, Shanghai, 200092, People's Republic of China. FAU - Lian, Di AU - Lian D AD - Department of Pediatric Neurology, Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine, Kongjiang Rd 1665, Shanghai, 200092, People's Republic of China. FAU - Wu, Jing AU - Wu J AD - Department of Pediatric Neurology, Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine, Kongjiang Rd 1665, Shanghai, 200092, People's Republic of China. FAU - Liu, Ying AU - Liu Y AD - Department of Clinical Laboratory, Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, People's Republic of China. FAU - Zhu, Mingjie AU - Zhu M AD - Department of Pathology, Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, People's Republic of China. FAU - Sun, Jiaming AU - Sun J AD - Department of Pathology, Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, People's Republic of China. FAU - He, Dake AU - He D AD - Department of Pediatric Neurology, Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine, Kongjiang Rd 1665, Shanghai, 200092, People's Republic of China. FAU - Li, Ling AU - Li L AD - Department of Pediatric Neurology, Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine, Kongjiang Rd 1665, Shanghai, 200092, People's Republic of China. linglidoctor@163.com. LA - eng PT - Journal Article DEP - 20170804 PL - England TA - J Neuroinflammation JT - Journal of neuroinflammation JID - 101222974 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Carbazoles) RN - 0 (Cytokines) RN - 0 (Enzyme Inhibitors) RN - 0 (Indole Alkaloids) RN - 97161-97-2 (staurosporine aglycone) RN - EC 2.7.10.1 (Ntrk2 protein, rat) RN - EC 2.7.10.1 (Receptor, trkB) RN - MYD88 Deficiency SB - IM MH - Animals MH - Apoptosis/*drug effects MH - Brain-Derived Neurotrophic Factor/*therapeutic use MH - Carbazoles/pharmacology MH - Cytokines/metabolism MH - Disease Models, Animal MH - Encephalitis/*drug therapy/*etiology MH - Enzyme Inhibitors/pharmacology MH - Female MH - Hippocampus/*pathology MH - Immunologic Deficiency Syndromes/metabolism MH - In Situ Nick-End Labeling MH - Indole Alkaloids/pharmacology MH - Meningitis, Pneumococcal/complications/drug therapy/*pathology MH - Neurons/drug effects MH - Primary Immunodeficiency Diseases MH - Rats MH - Rats, Sprague-Dawley MH - Receptor, trkB/metabolism MH - Signal Transduction/drug effects PMC - PMC5545027 OTO - NOTNLM OT - Brain-derived neurotrophic factor OT - Hippocampal apoptosis OT - Neuroinflammation OT - Streptococcus pneumoniae meningitis COIS- ETHICS APPROVAL AND CONSENT TO PARTICIPATE: The animal experiments were approved by the Animal Ethical and Welfare Committee of Xinhua Hospital (approval ID: 2014041). CONSENT FOR PUBLICATION: Not applicable. COMPETING INTERESTS: The authors declare that they have no competing interests. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2017/08/06 06:00 MHDA- 2018/05/04 06:00 PMCR- 2017/08/04 CRDT- 2017/08/06 06:00 PHST- 2017/03/05 00:00 [received] PHST- 2017/07/27 00:00 [accepted] PHST- 2017/08/06 06:00 [entrez] PHST- 2017/08/06 06:00 [pubmed] PHST- 2018/05/04 06:00 [medline] PHST- 2017/08/04 00:00 [pmc-release] AID - 10.1186/s12974-017-0930-6 [pii] AID - 930 [pii] AID - 10.1186/s12974-017-0930-6 [doi] PST - epublish SO - J Neuroinflammation. 2017 Aug 4;14(1):156. doi: 10.1186/s12974-017-0930-6.