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Caspase-3 activity is reduced after spinal cord injury in mice lacking dynorphin: differential effects on glia and neurons
Department of Anatomy and Neurobiology, University of Kentucky, Lexington, USA.
Department of Anatomy and Neurobiology, University of Kentucky, Lexington, USA and Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, USA.
Experimental Alcohol and Drug Addiction Research Section, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden. (Molecular neuropsychopharmacology)
Experimental Alcohol and Drug Addiction Research Section, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden. (Molecular neuropsychopharmacology)
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2007 (English)In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 148, no 3, 724-36 p.Article in journal (Refereed) Published
Abstract [en]

Dynorphins are endogenous opioid peptide products of the prodynorphin gene. An extensive literature suggests that dynorphins have deleterious effects on CNS injury outcome. We thus examined whether a deficiency of dynorphin would protect against tissue damage after spinal cord injury (SCI), and if individual cell types would be specifically affected. Wild-type and prodynorphin(-/-) mice received a moderate contusion injury at 10th thoracic vertebrae (T10). Caspase-3 activity at the injury site was significantly decreased in tissue homogenates from prodynorphin(-/-) mice after 4 h. We examined frozen sections at 4 h post-injury by immunostaining for active caspase-3. At 3-4 mm rostral or caudal to the injury, >90% of all neurons, astrocytes and oligodendrocytes expressed active caspase-3 in both wild-type and knockout mice. At 6-7 mm, there were fewer caspase-3(+) oligodendrocytes and astrocytes than at 3-4 mm. Importantly, caspase-3 activation was significantly lower in prodynorphin(-/-) oligodendrocytes and astrocytes, as compared with wild-type mice. In contrast, while caspase-3 expression in neurons also declined with further distance from the injury, there was no effect of genotype. Radioimmunoassay showed that dynorphin A(1-17) was regionally increased in wild-type injured versus sham-injured tissues, although levels of the prodynorphin processing product Arg(6)-Leu-enkephalin were unchanged. Our results indicate that dynorphin peptides affect the extent of post-injury caspase-3 activation, and that glia are especially sensitive to these effects. By promoting caspase-3 activation, dynorphin peptides likely increase the probability of glial apoptosis after SCI. While normally beneficial, our findings suggest that prodynorphin or its peptide products become maladaptive following SCI and contribute to secondary injury.

Place, publisher, year, edition, pages
2007. Vol. 148, no 3, 724-36 p.
Keyword [en]
apoptosis, astrocyte, excitotoxic cell death, oligodendrocyte, glutamate, traumatic injury
National Category
Pharmacology and Toxicology Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-120092DOI: 10.1016/j.neuroscience.2007.05.053PubMedID: 17698296OAI: oai:DiVA.org:uu-120092DiVA: diva2:302467
Available from: 2010-03-08 Created: 2010-03-07 Last updated: 2017-12-12

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Bakalkin, GeorgyYakovleva, T.

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