The antidepressant fluoxetine protects the hippocampus from brain damage in experimental pneumococcal meningitis

Neuroscience. 2015 Jun 25;297:89-94. doi: 10.1016/j.neuroscience.2015.03.056. Epub 2015 Apr 1.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: A significant neuroprotective effect of FLX on the hippocampus was observed in acute pneumococcal meningitis in infant rats.

Keywords: Streptococcus pneumoniae; hippocampus; neuroinfection; neuroinflammation; stem cell niche.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Anti-Bacterial Agents / therapeutic use
  • Antidepressive Agents, Second-Generation / therapeutic use*
  • Apoptosis / drug effects
  • Brain Injuries* / etiology
  • Brain Injuries* / pathology
  • Brain Injuries* / prevention & control
  • Ceftriaxone / therapeutic use
  • Cytokines / cerebrospinal fluid
  • Disease Models, Animal
  • Fluoxetine / therapeutic use*
  • Granulocyte Colony-Stimulating Factor / cerebrospinal fluid
  • Hippocampus / pathology*
  • Interleukin-3 / cerebrospinal fluid
  • Matrix Metalloproteinase 2 / cerebrospinal fluid
  • Matrix Metalloproteinase 9 / cerebrospinal fluid
  • Meningitis, Pneumococcal / cerebrospinal fluid
  • Meningitis, Pneumococcal / complications*
  • Meningitis, Pneumococcal / drug therapy
  • Rats
  • Recombinant Fusion Proteins / cerebrospinal fluid
  • Streptococcus pneumoniae / pathogenicity

Substances

  • Anti-Bacterial Agents
  • Antidepressive Agents, Second-Generation
  • Cytokines
  • Interleukin-3
  • Recombinant Fusion Proteins
  • myelopoietin
  • Fluoxetine
  • Granulocyte Colony-Stimulating Factor
  • Ceftriaxone
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9