Minocycline reduces intracerebral hemorrhage-induced brain injury

Neurol Res. 2009 Mar;31(2):183-8. doi: 10.1179/174313209X385680. Epub 2008 Dec 5.


Objectives: Microglial activation and thrombin formation contribute to brain injury after intracerebral hemorrhage. Tumor necrosis factor-alpha and interleukin-1beta are two major pro-inflammatory cytokines. The present study investigated if thrombin stimulates tumor necrosis factor-alpha and interleukin-1beta secretion in vitro and if microglial inhibition reduces intracerebral hemorrhage-induced brain injury in vivo.

Methods: There were two parts in this study. In the first part, cultured rat microglial cells were treated with vehicle, thrombin (10 U/ml) or thrombin plus minocycline (1 or 10 microM), an inhibitor of microglia activation. Levels of tumor necrosis factor-alpha and interleukin-1beta in culture medium were measured by enzyme-linked immunosorbent assay 24 hours after thrombin treatment. In the second part, rats had an intracerebral injection of 100 microl autologous whole blood. Rats received minocycline or vehicle treatment. Brain edema was measured at day 3 and brain atrophy was determined at day 28 after intracerebral hemorrhage.

Results: Thrombin receptors were expressed in cultured microglia cells, and tumor necrosis factor-alpha and interleukin-1beta levels in the culture medium were increased after thrombin treatment. Minocycline reduced thrombin-induced up-regulation of tumor necrosis factor-alpha and interleukin-1beta. In vivo, minocycline reduced perihematomal brain edema, neurological deficits and brain atrophy.

Discussion: Thrombin stimulates microglia to release the pro-inflammatory cytokines, tumor necrosis factor-alpha and interleukin-1beta, and microglial inhibition with minocycline reduces brain injury after intracerebral hemorrhage, suggesting a critical role of microglia activation in intracerebral hemorrhage-related brain injury.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / cytology
  • Brain / drug effects
  • Brain / metabolism
  • Brain / pathology
  • Brain Edema / drug therapy
  • Brain Edema / etiology
  • Brain Injuries / drug therapy*
  • Brain Injuries / etiology*
  • Brain Injuries / pathology
  • Cells, Cultured
  • Cerebral Hemorrhage / chemically induced
  • Cerebral Hemorrhage / complications*
  • Collagenases
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Enzyme-Linked Immunosorbent Assay / methods
  • Functional Laterality
  • Hemostatics / pharmacology
  • Interleukin-1beta / metabolism
  • Male
  • Microglia / drug effects
  • Minocycline / therapeutic use*
  • Neurologic Examination / methods
  • Rats
  • Thrombin / adverse effects
  • Thrombin / pharmacology
  • Tumor Necrosis Factor-alpha / metabolism


  • Hemostatics
  • Interleukin-1beta
  • Tumor Necrosis Factor-alpha
  • Thrombin
  • Collagenases
  • Minocycline