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The Journal of Neuroscience, July 18, 2007, 27(29):7751-7761; doi:10.1523/JNEUROSCI.1661-07.2007

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Development/Plasticity/Repair
Minocycline Alleviates Death of Oligodendrocytes by Inhibiting Pro-Nerve Growth Factor Production in Microglia after Spinal Cord Injury

Tae Y. Yune,^1 * Jee Y. Lee,^1,2,4 * Gil Y. Jung,^1,2,4 Sun J. Kim,¹ Mei H. Jiang,¹ Young C. Kim,³ Young J. Oh,⁴ George J. Markelonis,⁵ and Tae H. Oh¹

¹Age-Related and Brain Diseases Research Center, Kyung Hee University, Seoul 130-701, Korea, ²Bioanalysis and Biotransformation Research Center, Korea Institute of Science and Technology, Seoul 136-791, Korea, ³College of Pharmacy, Seoul National University, Seoul 151-742, Korea, ⁴Department of Biology, College of Science, Yonsei University, Seoul 120-749, Korea, and ⁵Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland 21201

Correspondence should be addressed to Dr. Tae H. Oh, Age-Related and Brain Diseases Research Center, Medical Building 10th Floor, Kyung Hee University, Hoegi-Dong 1, Dongdaemun-Gu, Seoul 130-701, Republic of Korea. Email: toh{at}khu.ac.kr

Spinal cord injury (SCI) causes a permanent neurological disability, and no satisfactory treatment is currently available. After SCI, pro-nerve growth factor (proNGF) is known to play a pivotal role in apoptosis of oligodendrocytes, but the cell types producing proNGF and the signaling pathways involved in proNGF production are primarily unknown. Here, we show that minocycline improves functional recovery after SCI in part by reducing apoptosis of oligodendrocytes via inhibition of proNGF production in microglia. After SCI, the stress-responsive p38 mitogen-activated protein kinase (p38MAPK) was activated only in microglia, and proNGF was produced by microglia via the p38MAPK-mediated pathway. Minocycline treatment significantly reduced proNGF production in microglia in vitro and in vivo by inhibition of the phosphorylation of p38MAPK. Furthermore, minocycline treatment inhibited p75 neurotrophin receptor expression and RhoA activation after injury. Finally, minocycline treatment inhibited oligodendrocyte death and improved functional recovery after SCI. These results suggest that minocycline may represent a potential therapeutic agent for acute SCI in humans.

Key words: MAPKAPK-2; methylprednisolone; neuroprotection; p38MAPK; p75^NTR; RhoA

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Received Jan. 26, 2007; revised May 18, 2007; accepted June 9, 2007.

Correspondence should be addressed to Dr. Tae H. Oh, Age-Related and Brain Diseases Research Center, Medical Building 10th Floor, Kyung Hee University, Hoegi-Dong 1, Dongdaemun-Gu, Seoul 130-701, Republic of Korea. Email: toh{at}khu.ac.kr

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