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Published on: July 11, 2017
Methylprednisolone protects oligodendrocytes but not neurons after spinal cord injury
Jin-Moo Lee1, Ping Yan, Qingli Xiao
1The Hope Center for Neurological Disorders and Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Abstract:
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.
Insights
Methylprednisolone (MP) selectively protects oligodendrocytes, not neurons, from death after spinal cord injury (SCI). This neuroprotective effect is mediated by the glucocorticoid receptor (GR) and reduces demyelination.
Area of Science:
- Neuroscience
- Pharmacology
- Cell Biology
Background:
- Methylprednisolone (MP) is a corticosteroid used to treat neurological disorders characterized by white matter injury, such as multiple sclerosis and spinal cord injury (SCI).
- Its therapeutic effects are traditionally attributed to anti-inflammatory and antioxidant properties.
- The potential for direct neuroprotective mechanisms of MP remains incompletely understood.
Purpose of the Study:
- To investigate whether Methylprednisolone (MP) exerts direct neuroprotective effects on neurons and oligodendrocytes.
- To elucidate the mechanism underlying MP's potential neuroprotection, specifically examining the role of the glucocorticoid receptor (GR).
- To assess the in vivo efficacy of MP in protecting oligodendrocytes and reducing demyelination following spinal cord injury (SCI).
Main Methods:
- In vitro: Neurons and oligodendrocytes were treated with excitotoxins (AMPA) or apoptosis inducers (staurosporine) in the presence or absence of MP and a GR antagonist (RU486).
- In vivo: Rats subjected to SCI were treated with MP, RU486, or both. Cell survival (oligodendrocytes and neurons), apoptosis markers (Bcl-xL, caspase-3), and demyelination were assessed.
Main Results:
- MP dose-dependently protected oligodendrocytes from death in vitro, but not neurons. This effect was blocked by GR antagonism.
- MP reversed AMPA-induced decreases in anti-apoptotic Bcl-x(L) and inhibited caspase-3 activation in oligodendrocytes.
- In vivo, MP significantly increased oligodendrocyte survival post-SCI, reduced demyelination, and inhibited apoptosis markers. Neuronal survival remained unaffected. RU486 reversed these protective effects.
Conclusions:
- Methylprednisolone (MP) demonstrates selective, GR-dependent neuroprotection of oligodendrocytes, but not neurons, against cell death.
- MP's mechanism involves inhibiting apoptosis and reducing demyelination, particularly relevant in the context of spinal cord injury (SCI).
- These findings suggest a direct neuroprotective role for MP via GR signaling, contributing to its therapeutic benefits in white matter disorders.
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