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Open Access Highly Accessed Research article

Therapeutic targets and limits of minocycline neuroprotection in experimental ischemic stroke

Noriyuki Matsukawa1, Takao Yasuhara1, Koichi Hara1, Lin Xu1, Mina Maki1, Guolong Yu1, Yuji Kaneko1, Kosei Ojika2, David C Hess1 and Cesar V Borlongan13*

Author affiliations

1 Department of Neurology, Medical College of Georgia, Augusta, GA 30912, USA

2 Department of Neurology and Neuroscience, Nagoya City University Graduate School of Medical Sciences, Nagoya, 467-8601, Japan

3 Research and Affiliations Service Line, Augusta VAMC, Augusta, GA 30912, USA

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Citation and License

BMC Neuroscience 2009, 10:126  doi:10.1186/1471-2202-10-126

Published: 6 October 2009

Abstract

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.

Conclusion

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.