Abstract
Microglia activation results in release of proinflammatory molecules including cytokines, which contribute to neuronal damage in the central nervous system (CNS) if not controlled. Tetracycline antibiotics such as minocycline inhibit microglial activation and cytokine expression during CNS inflammation. In the present study we found that administration of chemically modified tetracycline-3 (COL-3), inhibits lipopolysaccharide (LPS)-induced microglial and p38 MAPK activation, as well as the increase in TNF-α, but not IL-1β expression, in the brains of BALB/c mice. COL-3 has been described to have no antibacterial activity. We observed that COL-3 had no activity against a Gram-negative bacteria, Escherichia coli; however surprisingly, COL-3 had antibacterial activity against a Gram-positive bacteria Staphylococcus aureus, with a minimum inhibitory concentration of 1 mg/ml. Our data show that COL-3 has some antibacterial activity against S. aureus, inhibits LPS-induced neuroinflammation, and displays potential as a therapeutic agent for treatment of conditions involving CNS inflammation.
Highlights
Neuroinflammation is an important factor in both the pathogenesis and progression of neurodegenerative diseases as well as in brain infections [1], [2], [3]
Brain sections were immunostained for CD11b and p38 MAPK; the latter because previous studies have indicated that minocycline blocks microglia activation via inhibition of p38 MAPK activation [33]
The results of this study show for the first time that the chemically modified tetracycline chemically modified tetracycline-3 (COL-3), which has been described to lack antibacterial activity, has antibacterial activity against S. aureus but not E. coli, inhibits both the LPS-induced microglia activation and LPS -induced elevation in the transcripts of the cytokine tumor necrosis factor-alpha (TNF-a)
Summary
Neuroinflammation is an important factor in both the pathogenesis and progression of neurodegenerative diseases as well as in brain infections [1], [2], [3]. A vital component of neuroinflammation is the chronic activation of microglia which are the major inflammatory cells resident in the central nervous system (CNS) and which constitute its innate immune system. Acute activation results in tissue repair and protective immune response induction. If it becomes chronic it can be deleterious to the brain, resulting in neurodegeneration. Such activation is observed during viral encephalitis, bacterial meningitis, multiple sclerosis, ischemia, trauma, Parkinson’s disease and similar conditions [1], [2], [3]
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