Therapeutic targets and limits of minocycline neuroprotection in experimental ischemic stroke.
BACKGROUND
Minocycline, a second-generation tetracycline with anti-inflammatory and anti-apoptotic properties, has been shown to promote therapeutic benefits in experimental stroke. However, equally compelling evidence demonstrates that the drug exerts variable and even detrimental effects in many neurological disease models. Assessment of the mechanism underlying minocycline neuroprotection should clarify the drug's clinical value in acute stroke setting.


RESULTS
Here, we demonstrate that minocycline attenuates both in vitro (oxygen glucose deprivation) and in vivo (middle cerebral artery occlusion) experimentally induced ischemic deficits by direct inhibition of apoptotic-like neuronal cell death involving the anti-apoptotic Bcl-2/cytochrome c pathway. Such anti-apoptotic effect of minocycline is seen in neurons, but not apparent in astrocytes. Our data further indicate that the neuroprotection is dose-dependent, in that only low dose minocycline inhibits neuronal cell death cascades at the acute stroke phase, whereas the high dose exacerbates the ischemic injury.


CONCLUSIONS
The present study advises our community to proceed with caution to use the minimally invasive intravenous delivery of low dose minocycline in order to afford neuroprotection that is safe for stroke.
Matsukawa
Noriyuki
N
Department of Neurology, Medical College of Georgia, Augusta, GA 30912, USA. norim@med.nagoya-cu.ac.jp
Yasuhara
Takao
T
Hara
Koichi
K
Xu
Lin
L
Maki
Mina
M
Yu
Guolong
G
Kaneko
Yuji
Y
Ojika
Kosei
K
Hess
David C
DC
Borlongan
Cesar V
CV
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015153:Blotting, Western; D002452:Cell Count; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000172:deficiency; D000860:Hypoxia; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008911:Minocycline / Q000494:pharmacology* / Q000627:therapeutic use; D009048:Motor Skills / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D008911:Minocycline; D005947:Glucose