Blockade of acute microglial activation by minocycline promotes neuroprotection and reduces locomotor hyperactivity after closed head injury in mice: a twelve-week follow-up study.
Traumatic brain injury (TBI) causes a wide spectrum of consequences, such as microglial activation, cerebral inflammation, and focal and diffuse brain injury, as well as functional impairment. In this study we aimed to investigate the effects of acute treatment with minocycline as an inhibitor of microglial activation on cerebral focal and diffuse lesions, and on the spontaneous locomotor activity following TBI. The weight-drop model was used to induce TBI in mice. Microglial activation and diffuse axonal injury (DAI) were detected by immunohistochemistry using CD11b and ss-amyloid precursor protein (ss-APP) immunolabeling, respectively. Focal injury was determined by the measurement of the brain lesion volume. Horizontal and vertical locomotor activities were measured for up to 12 weeks post-injury by an automated actimeter. Minocycline or vehicle were administered three times post-insult, at 5 min (90 mg/kg i.p.), 3 h, and 9 h post-TBI (45 mg/kg i.p.). Minocycline treatment attenuated microglial activation by 59% and reduced brain lesion volume by 58%, yet it did not affect DAI at 24 h post-TBI. More interestingly, minocycline significantly decreased TBI-induced locomotor hyperactivity at 48 h post-TBI, and its effect lasted for up to 8 weeks. Taken together, the results indicate that microglial activation appears to play an important role in the development of TBI-induced focal injury and the subsequent locomotor hyperactivity, and its short-term inhibition provides long-lasting functional recovery after TBI. These findings emphasize the fact that minocycline could be a promising new therapeutic strategy for head-injured patients.
Homsi
Shadi
S
Laboratoire de Pharmacologie de la Circulation Cérébrale (EA 2510), Université Paris Descartes, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France.
Piaggio
Tomaso
T
Croci
Nicole
N
Noble
Florence
F
Plotkine
Michel
M
Marchand-Leroux
Catherine
C
Jafarian-Tehrani
Mehrnaz
M
D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D005500:Follow-Up Studies; D005911:Gliosis / Q000188:drug therapy* / Q000473:pathology; D016489:Head Injuries, Closed / Q000188:drug therapy* / Q000473:pathology; D006948:Hyperkinesis / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D008911:Minocycline / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D013997:Time Factors; D016896:Treatment Outcome
D018696:Neuroprotective Agents; D008911:Minocycline