Melatonin inhibits microglial activation, reduces pro-inflammatory cytokine levels, and rescues hippocampal neurons of adult rats with acute Klebsiella pneumoniae meningitis.
Acute bacterial meningitis caused by Klebsiella pneumoniae (K. pneumoniae) is a major health threat with a high mortality rate and severe neuro-cognitive sequelae. The intense pro-inflammatory cytokine released from calcium-mediated microglial activation plays an important role in eliciting neuronal damage in the hippocampal region. Considering melatonin possesses anti-inflammatory and immuno-modulatory properties, the present study determined whether melatonin can effectively decrease inflammatory responses and prevent hippocampal damage in animals subjected to K. pneumoniae. Adult rats inoculated with K. pneumoniae received a melatonin injection immediately thereafter at doses of 5, 25, 50, or 100 mg/kg. Following 24 h of survival, all experimental animals were processed for time-of-flight secondary ion mass spectrometry (for detecting glial calcium intensity), isolectin-B4 histochemistry (reliable marker for microglial activation), pro-inflammatory cytokine measurement as well as cytochrome oxidase and in situ dUTP end-labeling (representing neuronal bio-energetic status and apoptotic changes, respectively). Results indicate that in K. pneumoniae-infected rats, numerous calcium-enriched microglia, enhanced pro-inflammatory cytokine, and various apoptotic neurons with low bio-energetic activity were detected in hippocampus. Following melatonin administration, however, all parameters including glial calcium intensity, microglial activation, pro-inflammatory cytokine levels, and number of apoptotic neurons were successfully decreased with maximal change observed at a melatonin dose of 100 mg/kg. Enzymatic data corresponded well with above findings in which all surviving neurons displayed high bio-energetic activity. As effectively reducing glia-mediated inflammatory response is neuro-protective to hippocampal neurons, the present study supports the clinical use of melatonin as a potential therapeutic agent to counteract K. pneumoniae meningitis-induced neuro-cognitive damage.
Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
Un-In
UI
Wu
Fu-Der
FD
Mai
Ji-Nan
JN
Sheu
Li-You
LY
Chen
Yu-Ting
YT
Liu
Hai-Cheng
HC
Huang
Hung-Ming
HM
Chang
D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology*; D020287:In Situ Nick-End Labeling; D007711:Klebsiella pneumoniae / Q000472:pathogenicity*; D008297:Male; D013058:Mass Spectrometry; D008550:Melatonin / Q000494:pharmacology / Q000627:therapeutic use*; D008581:Meningitis / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology*; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D016207:Cytokines; D008550:Melatonin