PloS one, 2014-03, Vol.9 (3), p.e92264-e92264
2014
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- Autor(en) / Beteiligte
- Titel
- Adenoviral-mediated glial cell line-derived neurotrophic factor gene transfer has a protective effect on sciatic nerve following constriction-induced spinal cord injury
- Ist Teil von
- PloS one, 2014-03, Vol.9 (3), p.e92264-e92264
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2014
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Neuropathic pain due to peripheral nerve injury may be associated with abnormal central nerve activity. Glial cell-line-derived neurotrophic factor (GDNF) can help attenuate neuropathic pain in different animal models of nerve injury. However, whether GDNF can ameliorate neuropathic pain in the spinal cord dorsal horn (SCDH) in constriction-induced peripheral nerve injury remains unknown. We investigated the therapeutic effects of adenoviral-mediated GDNF on neuropathic pain behaviors, microglial activation, pro-inflammatory cytokine expression and programmed cell death in a chronic constriction injury (CCI) nerve injury animal model. In this study, neuropathic pain was produced by CCI on the ipsilateral SCDH. Mechanical allodynia was examined with von Frey filaments and thermal sensitivity was tested using a plantar test apparatus post-operatively. Target proteins GDNF-1, GDNFRa-1, MMP2, MMP9, p38, phospho-p38, ED1, IL6, IL1β, AIF, caspase-9, cleaved caspase-9, caspase-3, cleaved caspase-3, PARP, cleaved PARP, SPECTRIN, cleaved SPECTRIN, Beclin-1, PKCσ, PKCγ, iNOS, eNOS and nNOS were detected. Microglial activity was measured by observing changes in immunoreactivity with OX-42. NeuN and TUNEL staining were used to reveal whether apoptosis was attenuated by GDNF. Results showed that administrating GDNF began to attenuate both allodynia and thermal hyperalgesia at day 7. CCI-rats were found to have lower GDNF and GDNFRa-1 expression compared to controls, and GDNF re-activated their expression. Also, GDNF significantly down-regulated CCI-induced protein expression except for MMP2, eNOS and nNOS, indicating that the protective action of GDNF might be associated with anti-inflammation and prohibition of microglia activation. Immunocytochemistry staining showed that GDNF reduced CCI-induced neuronal apoptosis. In sum, GDNF enhanced the neurotrophic effect by inhibiting microglia activation and cytokine production via p38 and PKC signaling. GDNF could be a good therapeutic tool to attenuate programmed cell death, including apoptosis and autophagy, consequent to CCI-induced peripheral nerve injury.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0092264Titel-ID: cdi_plos_journals_1508464055
- Format
- –
- Schlagworte
- Activation, Adenoviridae - genetics, Analysis, Animal models, Animals, Apoptosis, Apoptosis-inducing factor, Attenuation, Autophagy, Biochemistry, Biology and Life Sciences, Caspase, Caspase-3, Caspase-9, Cell death, Dorsal horn, Filaments, Gelatinase A, Gelatinase B, Gene Expression, Gene therapy, Gene transfer, Genetic Therapy, Genetic Vectors, Glial cell line-derived neurotrophic factor, Glial Cell Line-Derived Neurotrophic Factor - biosynthesis, Glial Cell Line-Derived Neurotrophic Factor - genetics, Health aspects, HEK293 Cells, Hospitals, Humans, Hyperalgesia - therapy, Immunocytochemistry, Immunoreactivity, Inflammation, Injuries, Interleukin 1, Interleukin 6, Kinases, Laboratories, Male, Matrix Metalloproteinase 2 - metabolism, Matrix Metalloproteinase 9 - metabolism, Medicine, Medicine and Health Sciences, Membrane proteins, Microglia, Neuronal-glial interactions, Neurons, Neuropathy, Pain, Pain perception, Peripheral neuropathy, Phagocytosis, Poly(ADP-ribose) polymerase, Prohibition, Protein Kinase C - metabolism, Protein Kinase C-delta - metabolism, Proteins, Rats, Rats, Sprague-Dawley, Research and Analysis Methods, Rodents, Sciatic Nerve - metabolism, Sciatic Nerve - physiopathology, Sciatica - therapy, Signaling, Spectrin, Spinal cord, Spinal Cord Injuries - therapy, Staining, Transduction, Genetic, Vectors (Biology)