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The Journal of Neuroscience, March 19, 2008, 28(12):3141-3149; doi:10.1523/JNEUROSCI.5547-07.2008

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Neurobiology of Disease
Methylprednisolone Protects Oligodendrocytes But Not Neurons after Spinal Cord Injury

Jin-Moo Lee,¹ Ping Yan,¹ Qingli Xiao,¹ Shawei Chen,² Kuang-Yung Lee,¹ Chung Y. Hsu,³ and Jan Xu¹

¹The Hope Center for Neurological Disorders and Department of Neurology, and ²Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110, and ³Taipei Medical University, Taipei City, Taiwan, 110

Correspondence should be addressed to Dr. Jan Xu, Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8111, St. Louis, MO 63110. Email: xuj{at}neuro.wustl.edu

Methylprednisolone (MP) is used to treat a variety of neurological disorders involving white matter injury, including multiple sclerosis, acute disseminated encephalomyelitis, and spinal cord injury (SCI). Although its mechanism of action has been attributed to anti-inflammatory or antioxidant properties, we examined the possibility that MP may have direct neuroprotective activities. Neurons and oligodendrocytes treated with AMPA or staurosporine died within 24 h after treatment. MP attenuated oligodendrocyte death in a dose-dependent manner; however, neurons were not rescued by the same doses of MP. This protective effect was reversed by the glucocorticoid receptor (GR) antagonist (11, 17)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one (RU486) and small interfering RNA directed against GR, suggesting a receptor-dependent mechanism. MP reversed AMPA-induced decreases in the expression of anti-apoptotic Bcl-x_L, caspase-3 activation, and DNA laddering, suggesting anti-apoptotic activity in oligodendrocytes. To examine whether MP demonstrated this selective protection in vivo, neuronal and oligodendrocyte survival was assessed in rats subjected to spinal cord injury (SCI); groups of rats were treated with or without MP in the presence or absence of RU486. Eight days after SCI, MP significantly increased oligodendrocytes (CC-1-immunoreactive cells) after SCI, but neuronal (neuronal-specific nuclear protein-immunoreactive cells) number remained unchanged; RU486 reversed this protective effect. MP also inhibited SCI-induced decreases in Bcl-x_L and caspase-3 activation. Consistent with these findings, the volume of demyelination, assessed by Luxol fast blue staining, was attenuated by MP and reversed by RU486. These results suggest that MP selectively inhibits oligodendrocyte but not neuronal cell death via a receptor-mediated action and may be a mechanism for its limited protective effect after SCI.

Key words: spinal cord injury; oligodendrocytes; neurons; glucocorticoids; methylprednisolone; apoptosis

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Received June 7, 2007; revised Jan. 25, 2008; accepted Jan. 30, 2008.

Correspondence should be addressed to Dr. Jan Xu, Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8111, St. Louis, MO 63110. Email: xuj{at}neuro.wustl.edu

This article has been cited by other articles:

				The Neuroscientist Comments Neuroscientist, June 1, 2008; 14(3): 230 - 231. [PDF]

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