Minocycline synergizes with N-acetylcysteine and improves cognition and memory following traumatic brain injury in rats
There are no drugs presently available to treat traumatic brain injury (TBI). A variety of single drugs have failed clinical trials suggesting a role for drug combinations. Drug combinations acting synergistically often provide the greatest combination of potency and safety. The drugs examined (mino...
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Published in | PloS one Vol. 5; no. 8; p. e12490 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Public Library of Science
31.08.2010
Public Library of Science (PLoS) |
Subjects | |
Online Access | Get full text |
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Summary: | There are no drugs presently available to treat traumatic brain injury (TBI). A variety of single drugs have failed clinical trials suggesting a role for drug combinations. Drug combinations acting synergistically often provide the greatest combination of potency and safety. The drugs examined (minocycline (MINO), N-acetylcysteine (NAC), simvastatin, cyclosporine A, and progesterone) had FDA-approval for uses other than TBI and limited brain injury in experimental TBI models.
Drugs were dosed one hour after injury using the controlled cortical impact (CCI) TBI model in adult rats. One week later, drugs were tested for efficacy and drug combinations tested for synergy on a hierarchy of behavioral tests that included active place avoidance testing. As monotherapy, only MINO improved acquisition of the massed version of active place avoidance that required memory lasting less than two hours. MINO-treated animals, however, were impaired during the spaced version of the same avoidance task that required 24-hour memory retention. Co-administration of NAC with MINO synergistically improved spaced learning. Examination of brain histology 2 weeks after injury suggested that MINO plus NAC preserved white, but not grey matter, since lesion volume was unaffected, yet myelin loss was attenuated. When dosed 3 hours before injury, MINO plus NAC as single drugs had no effect on interleukin-1 formation; together they synergistically lowered interleukin-1 levels. This effect on interleukin-1 was not observed when the drugs were dosed one hour after injury.
These observations suggest a potentially valuable role for MINO plus NAC to treat TBI. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 Conceived and designed the experiments: PB. Performed the experiments: SGAB BS MH. Analyzed the data: SGAB AAF. Wrote the paper: AAF PB. |
ISSN: | 1932-6203 1932-6203 |
DOI: | 10.1371/journal.pone.0012490 |