Minocycline synergizes with N-acetylcysteine and improves cognition and memory following traumatic brain injury in rats.
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
These observations suggest a potentially valuable role for MINO plus NAC to treat TBI.
Abdel Baki
Samah G
SG
Departments of Physiology and Pharmacology, State University of New York-Downstate Medical Center, Brooklyn, New York, United States of America.
Schwab
Ben
B
Haber
Margalit
M
Fenton
André A
AA
Bergold
Peter J
PJ
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001930:Brain Injuries / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D003071:Cognition / Q000187:drug effects*; D003213:Conditioning, Psychological; D004357:Drug Synergism; D053583:Interleukin-1beta / Q000096:biosynthesis; D008568:Memory / Q000187:drug effects*; D008911:Minocycline / Q000494:pharmacology*; D009186:Myelin Sheath / Q000378:metabolism; D010465:Perception / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013647:Task Performance and Analysis; D013997:Time Factors
D053583:Interleukin-1beta; D008911:Minocycline; D000111:Acetylcysteine
Clin Neurophysiol. 2004 Jan;115(1):4-18
14706464
Neurobiol Learn Mem. 2007 Jul;88(1):87-93
17408988
J Neurotrauma. 2008 Mar;25(3):235-47
18352837
Expert Opin Biol Ther. 2008 Dec;8(12):1955-62
18990082
Neuroscience. 2000;101(2):289-95
11074152
Science. 2006 Aug 25;313(5790):1141-4
16931766
J Neurotrauma. 2007 Jul;24(7):1132-46
17610353
J Neurotrauma. 2009 Jun;26(6):925-39
19331514
Exp Neurol. 2007 Mar;204(1):220-33
17188268
Nat Rev Cardiol. 2010 Jun;7(6):303-4
20508606
Intensive Care Med. 2006 Jan;32(1):149-55
16249925
Biochem Soc Trans. 2007 Nov;35(Pt 5):1122-6
17956293
Neurotherapeutics. 2009 Jan;6(1):28-42
19110197
Brain Res. 2009 Sep 29;1291:122-32
19631631
Learn Mem. 2007 Nov 14;14(11):771-81
18007020
Eur J Neurosci. 2009 Aug;30(3):385-96
19614750
Brain Res Bull. 2001 Mar 15;54(5):559-63
11397548
Mediators Inflamm. 2008;2008:716458
18483565
J Neurosci Methods. 1980 Dec;3(2):129-49
6110810
J Neurosci. 2005 Mar 2;25(9):2413-9
15745968
Nat Biotechnol. 2009 Jul;27(7):659-66
19581876
J Neurotrauma. 2005 Feb;22(2):252-65
15716631
J Neurosci Res. 2004 Nov 1;78(3):347-61
15389835
Neurosurgery. 2001 Jun;48(6):1393-9; discussion 1399-401
11383749
Brain Res. 2009 Jul 14;1280:98-106
19464271
Science. 2010 May 14;328(5980):852-6
20466922
AJNR Am J Neuroradiol. 2009 Nov;30(10):1907-13
19749219
Nat Neurosci. 2009 Feb;12(2):182-9
19136971
Exp Neurol. 2008 May;211(1):283-91
18355811
Lancet Neurol. 2004 Dec;3(12):744-51
15556807
J Int Neuropsychol Soc. 2009 Jan;15(1):130-6
19128536
Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3531-6
11248112
Proc Natl Acad Sci U S A. 1998 Sep 15;95(19):11493-8
9736765
Behav Brain Res. 2009 Jan 23;196(2):168-79
18977395
J Neurosci. 2005 Oct 5;25(40):9205-12
16207880
Neurochem Res. 2006 Apr;31(4):473-81
16758355
PLoS Biol. 2008 Dec 23;6(12):2698-706
19108606
J Antimicrob Chemother. 2010 May;65(5):827-35
20228080
Neurobiol Learn Mem. 2009 Jan;91(1):41-9
18845265
J Neurotrauma. 2007 Oct;24(10):1596-608
17970623
Pharmacol Biochem Behav. 2003 Sep;76(2):231-42
14592674