title: The mood-stabilizer lithium prevents hippocampal apoptosis and improves spatial memory in experimental meningitis.
abstract: Pneumococcal meningitis is associated with high morbidity and mortality rates. Brain damage caused by this disease is characterized by apoptosis in the hippocampal dentate gyrus, a morphological correlate of learning deficits in experimental paradigms. The mood stabilizer lithium has previously been found to attenuate brain damage in ischemic and inflammatory diseases of the brain. An infant rat model of pneumococcal meningitis was used to investigate the neuroprotective and neuroregenerative potential of lithium. To assess an effect on the acute disease, LiCl was administered starting five days prior to intracisternal infection with live Streptococcus pneumoniae. Clinical parameters were recorded, cerebrospinal fluid (CSF) was sampled, and the animals were sacrificed 42 hours after infection to harvest the brain and serum. Cryosections of the brains were stained for Nissl substance to quantify brain injury. Hippocampal gene expression of Bcl-2, Bax, p53, and BDNF was analyzed. Lithium concentrations were measured in serum and CSF. The effect of chronic lithium treatment on spatial memory function and cell survival in the dentate gyrus was evaluated in a Morris water maze and by quantification of BrdU incorporation after LiCl treatment during 3 weeks following infection. In the hippocampus, LiCl significantly reduced apoptosis and gene expression of Bax and p53 while it increased expression of Bcl-2. IL-10, MCP-1, and TNF were significantly increased in animals treated with LiCl compared to NaCl. Chronic LiCl treatment improved spatial memory in infected animals. The mood stabilizer lithium may thus be a therapeutic alternative to attenuate neurofunctional deficits as a result of pneumococcal meningitis.
authors.affiliation: Neuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
authors.forename: Fabian D
authors.initials: FD
authors.lastname: Liechti
authors.affiliation: Neuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, Bern, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Stüdle
authors.affiliation: Clinical Pharmacology Laboratory, Institute for Infectious Diseases, University of Bern, Bern, Switzerland.
authors.forename: Regula
authors.initials: R
authors.lastname: Theurillat
authors.affiliation: Neuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, Bern, Switzerland.
authors.forename: Denis
authors.initials: D
authors.lastname: Grandgirard
authors.affiliation: Clinical Pharmacology Laboratory, Institute for Infectious Diseases, University of Bern, Bern, Switzerland.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Thormann
authors.affiliation: Neuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, Bern, Switzerland; Biology Division, Spiez Laboratory, Swiss Federal Office for Civil Protection, Spiez, Switzerland.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Leib
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001921:Brain / Q000473:pathology; D018932:Chemokine CCL2 / Q000134:cerebrospinal fluid; D018891:Dentate Gyrus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D016753:Interleukin-10 / Q000134:cerebrospinal fluid; D018021:Lithium Chloride / Q000097:blood / Q000134:cerebrospinal fluid / Q000494:pharmacology*; D008586:Meningitis, Pneumococcal / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008856:Microscopy, Fluorescence; D018696:Neuroprotective Agents / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D051381:Rats; D065852:Spatial Memory / Q000187:drug effects*; D013296:Streptococcus pneumoniae / Q000472:pathogenicity; D014409:Tumor Necrosis Factor-alpha / Q000134:cerebrospinal fluid; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D016753:Interleukin-10; D018021:Lithium Chloride