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COL-3, a chemically modified tetracycline, inhibits lipopolysaccharide-induced microglia activation and cytokine expression in the brain.

Edan RA, Luqmani YA, Masocha W - PLoS ONE (2013)

Bottom Line: Tetracycline antibiotics such as minocycline inhibit microglial activation and cytokine expression during CNS inflammation.COL-3 has been described to have no antibacterial activity.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University, Safat, Kuwait.

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.

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Effects of COL-3 on LPS-induced microglia activation in the brain.(A–C) Confocal laser microscopy images showing immunoreactivity of CD11b in the anterior commissure of fresh frozen sections of mice brains treated with vehicle (MC) (A), LPS (B) and LPS +40 mg/kg COL-3 (C). Immunoreactivity of CD11b was increased in LPS inoculated mice (B) compared to control mice (A) and was reduced by treatment with LPS+ COL-3 (C). Scale bar: 20 µm. (D) Relative expression of CD11b mRNA expression in brains of control mice, LPS-inoculated vehicle-treated and LPS-inoculated COL-3-treated mice at 24 h post inoculation. Each bar represents the mean ± S.E.M of the values obtained from four animals. *P<0.05 compared to control animals and #P<0.05 compared to LPS-inoculated mice pretreated with vehicle.
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pone-0057827-g001: Effects of COL-3 on LPS-induced microglia activation in the brain.(A–C) Confocal laser microscopy images showing immunoreactivity of CD11b in the anterior commissure of fresh frozen sections of mice brains treated with vehicle (MC) (A), LPS (B) and LPS +40 mg/kg COL-3 (C). Immunoreactivity of CD11b was increased in LPS inoculated mice (B) compared to control mice (A) and was reduced by treatment with LPS+ COL-3 (C). Scale bar: 20 µm. (D) Relative expression of CD11b mRNA expression in brains of control mice, LPS-inoculated vehicle-treated and LPS-inoculated COL-3-treated mice at 24 h post inoculation. Each bar represents the mean ± S.E.M of the values obtained from four animals. *P<0.05 compared to control animals and #P<0.05 compared to LPS-inoculated mice pretreated with vehicle.

Mentions: The effects of COL-3 on LPS-induced microglia activation was evaluated by both mRNA expression and immunohistochemical localization of target protein. Brain sections were immunostained for CD11b and also p38 MAPK; the latter because previous studies have indicated that minocycline blocks microglia activation via inhibition of p38 MAPK activation [33]. Confocal microscopy images were taken from the anterior commissure and the corpus callosum because strong immunoreactivity of p38 MAPK has been previously observed principally in these areas [34]. LPS-inoculated animals showed high reactivity of CD11b compared to vehicle-injected controls. Treatment with COL-3 reduced the LPS-induced increase in CD11b immunoreactivity (Fig. 1A–C). The levels of CD11b mRNA were also increased in the brains of LPS-inoculated mice compared to vehicle-injected controls. Treatment with COL-3 significantly inhibited the LPS-induced increase in CD11b mRNA (Fig. 1D).


COL-3, a chemically modified tetracycline, inhibits lipopolysaccharide-induced microglia activation and cytokine expression in the brain.

Edan RA, Luqmani YA, Masocha W - PLoS ONE (2013)

Effects of COL-3 on LPS-induced microglia activation in the brain.(A–C) Confocal laser microscopy images showing immunoreactivity of CD11b in the anterior commissure of fresh frozen sections of mice brains treated with vehicle (MC) (A), LPS (B) and LPS +40 mg/kg COL-3 (C). Immunoreactivity of CD11b was increased in LPS inoculated mice (B) compared to control mice (A) and was reduced by treatment with LPS+ COL-3 (C). Scale bar: 20 µm. (D) Relative expression of CD11b mRNA expression in brains of control mice, LPS-inoculated vehicle-treated and LPS-inoculated COL-3-treated mice at 24 h post inoculation. Each bar represents the mean ± S.E.M of the values obtained from four animals. *P<0.05 compared to control animals and #P<0.05 compared to LPS-inoculated mice pretreated with vehicle.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3585197&req=5

pone-0057827-g001: Effects of COL-3 on LPS-induced microglia activation in the brain.(A–C) Confocal laser microscopy images showing immunoreactivity of CD11b in the anterior commissure of fresh frozen sections of mice brains treated with vehicle (MC) (A), LPS (B) and LPS +40 mg/kg COL-3 (C). Immunoreactivity of CD11b was increased in LPS inoculated mice (B) compared to control mice (A) and was reduced by treatment with LPS+ COL-3 (C). Scale bar: 20 µm. (D) Relative expression of CD11b mRNA expression in brains of control mice, LPS-inoculated vehicle-treated and LPS-inoculated COL-3-treated mice at 24 h post inoculation. Each bar represents the mean ± S.E.M of the values obtained from four animals. *P<0.05 compared to control animals and #P<0.05 compared to LPS-inoculated mice pretreated with vehicle.
Mentions: The effects of COL-3 on LPS-induced microglia activation was evaluated by both mRNA expression and immunohistochemical localization of target protein. Brain sections were immunostained for CD11b and also p38 MAPK; the latter because previous studies have indicated that minocycline blocks microglia activation via inhibition of p38 MAPK activation [33]. Confocal microscopy images were taken from the anterior commissure and the corpus callosum because strong immunoreactivity of p38 MAPK has been previously observed principally in these areas [34]. LPS-inoculated animals showed high reactivity of CD11b compared to vehicle-injected controls. Treatment with COL-3 reduced the LPS-induced increase in CD11b immunoreactivity (Fig. 1A–C). The levels of CD11b mRNA were also increased in the brains of LPS-inoculated mice compared to vehicle-injected controls. Treatment with COL-3 significantly inhibited the LPS-induced increase in CD11b mRNA (Fig. 1D).

Bottom Line: Tetracycline antibiotics such as minocycline inhibit microglial activation and cytokine expression during CNS inflammation.COL-3 has been described to have no antibacterial activity.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University, Safat, Kuwait.

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.

Show MeSH
Related in: MedlinePlus