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

Abstract

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.

Bacterial meningitis: an update of new treatment options

“…In an adult rabbit model of Str. pneumoniae and an adult rat model of K. pneumoniae meningitis, melatonin injected immediately after infection (20 mg/kg or up to 100 mg/kg) reduced microglial activation, proinflammatory cytokine levels and the number of apoptotic neurons [198,199]. Under clinical treatment conditions, that is, when adjunctive melatonin treatment was started at the beginning of antibiotic therapy 12 h after infection, it showed anti-inflammatory effects, but did not reduce neuronal injury in lapine Str.…”

Melatonin-Induced Oncostasis, Mechanisms and Clinical Relevance

“…The repression of the nocturnal circadian melatonin signal promotes tumor aerobic glycolysis and the expression and activation of the signaling pathways involved in tumor proliferation and survival that drive resistance in cancer cells to endocrine therapies and chemotherapies [40]. Therefore, the melatonin signal regulates metabolic and cell signaling activities to inhibit cancer initiation, promotion, and progression [162], and these effects can be mediated by melatonin MT 1 /MT 2 receptors [163].…”

Treatment strategies for central nervous system infections: an update

“…Melatonin, an antioxidant, had anti-inflammatory effects but did not reduce neuronal injury in experimental rabbit models of S. pneumoniae or E. coli meningitis [102]. However, melatonin has been shown to inhibit microglial activation, attenuate pro-inflammatory cytokine levels and rescue hippocampal neurons in adult rats with acute K. pneumoniae meningitis [103]. Hypothermia has also been suggested as a potential adjuvant treatment.…”