Therapeutic targets and limits of minocycline neuroprotection in experimental ischemic stroke

Noriyuki Matsukawa, Takao Yasuhara, Koichi Hara, Lin Xu, Mina Maki, Guolong Yu, Yuji Kaneko, Kosei Ojika, David C Hess, Cesar V. Borlongan

Research output: Contribution to journalArticle

93 Citations (Scopus)

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.

Original languageEnglish (US)
Article number1471
Number of pages1
JournalBMC Neuroscience
Volume10
DOIs
StatePublished - Oct 6 2009

Fingerprint

Minocycline
Stroke
Cell Death
Neurological Models
Therapeutics
Middle Cerebral Artery Infarction
Cytochromes c
Tetracycline
Astrocytes
Pharmaceutical Preparations
Neuroprotection
Anti-Inflammatory Agents
Oxygen
Neurons
Glucose
Wounds and Injuries

ASJC Scopus subject areas

  • Neuroscience(all)
  • Cellular and Molecular Neuroscience

Cite this

Matsukawa, N., Yasuhara, T., Hara, K., Xu, L., Maki, M., Yu, G., ... Borlongan, C. V. (2009). Therapeutic targets and limits of minocycline neuroprotection in experimental ischemic stroke. BMC Neuroscience, 10, [1471]. https://doi.org/10.1186/1471-2202-10-126

Therapeutic targets and limits of minocycline neuroprotection in experimental ischemic stroke. / Matsukawa, Noriyuki; Yasuhara, Takao; Hara, Koichi; Xu, Lin; Maki, Mina; Yu, Guolong; Kaneko, Yuji; Ojika, Kosei; Hess, David C; Borlongan, Cesar V.

In: BMC Neuroscience, Vol. 10, 1471, 06.10.2009.

Research output: Contribution to journalArticle

Matsukawa, N, Yasuhara, T, Hara, K, Xu, L, Maki, M, Yu, G, Kaneko, Y, Ojika, K, Hess, DC & Borlongan, CV 2009, 'Therapeutic targets and limits of minocycline neuroprotection in experimental ischemic stroke', BMC Neuroscience, vol. 10, 1471. https://doi.org/10.1186/1471-2202-10-126
Matsukawa, Noriyuki ; Yasuhara, Takao ; Hara, Koichi ; Xu, Lin ; Maki, Mina ; Yu, Guolong ; Kaneko, Yuji ; Ojika, Kosei ; Hess, David C ; Borlongan, Cesar V. / Therapeutic targets and limits of minocycline neuroprotection in experimental ischemic stroke. In: BMC Neuroscience. 2009 ; Vol. 10.
@article{13cbc50cbbdb4a708cfd92fc26883b45,
title = "Therapeutic targets and limits of minocycline neuroprotection in experimental ischemic stroke",
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.",
author = "Noriyuki Matsukawa and Takao Yasuhara and Koichi Hara and Lin Xu and Mina Maki and Guolong Yu and Yuji Kaneko and Kosei Ojika and Hess, {David C} and Borlongan, {Cesar V.}",
year = "2009",
month = "10",
day = "6",
doi = "10.1186/1471-2202-10-126",
language = "English (US)",
volume = "10",
journal = "BMC Neuroscience",
issn = "1471-2202",
publisher = "BioMed Central",

}

TY - JOUR

T1 - Therapeutic targets and limits of minocycline neuroprotection in experimental ischemic stroke

AU - Matsukawa, Noriyuki

AU - Yasuhara, Takao

AU - Hara, Koichi

AU - Xu, Lin

AU - Maki, Mina

AU - Yu, Guolong

AU - Kaneko, Yuji

AU - Ojika, Kosei

AU - Hess, David C

AU - Borlongan, Cesar V.

PY - 2009/10/6

Y1 - 2009/10/6

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=70449507674&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70449507674&partnerID=8YFLogxK

U2 - 10.1186/1471-2202-10-126

DO - 10.1186/1471-2202-10-126

M3 - Article

C2 - 19807907

AN - SCOPUS:70449507674

VL - 10

JO - BMC Neuroscience

JF - BMC Neuroscience

SN - 1471-2202

M1 - 1471

ER -