Melatonin inhibits microglial activation, reduces pro-inflammatory cytokine levels, and rescues hippocampal neurons of adult rats with acute Klebsiella pneumoniae meningitis

• Published in: Journal of pineal research 2011-03, Vol.50 (2), p.159-170
• Main Authors: Wu, Un-In, Mai, Fu-Der, Sheu, Ji-Nan, Chen, Li-You, Liu, Yu-Ting, Huang, Hai-Cheng, Chang, Hung-Ming
• Format: Article
• Language: English
• Subjects: Animals; apoptosis; bacterial meningitis; Cytokines - metabolism; Hippocampus - cytology; In Situ Nick-End Labeling; interleukins; Klebsiella pneumoniae; Klebsiella pneumoniae - pathogenicity; Male; Mass Spectrometry; melatonin; Melatonin - pharmacology; Melatonin - therapeutic use; Meningitis - drug therapy; Meningitis - metabolism; Meningitis - microbiology; microglia; Microglia - drug effects; Microglia - metabolism; Neurons - drug effects; Neurons - metabolism; quantitative molecular imaging analysis; Rats; Rats, Wistar; tumor necrosis factor-α
• ISSN: 0742-3098; 1600-079X
• DOI: 10.1111/j.1600-079X.2010.00825.x

:  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.