AT2-receptor stimulation enhances axonal plasticity after spinal cord injury by upregulating BDNF expression

• Published in: Neurobiology of disease Vol. 51; no. SI; pp. 177 - 191
• Main Authors: Namsolleck, Pawel, Boato, Francesco, Schwengel, Katja, Paulis, Ludovit, Matho, Katherine S, Geurts, Nathalie, Thöne-Reineke, Christa, Lucht, Kristin, Seidel, Kerstin, Hallberg, Anders, Dahlöf, Björn, Unger, Thomas, Hendrix, Sven, Steckelings, U. Muscha
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2013; Elsevier
• Subjects: Angiotensin; Animals; AT2-receptor; Axons - metabolism; Brain-Derived Neurotrophic Factor - biosynthesis; Disease Models, Animal; Immunohistochemistry; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Nerve Regeneration - drug effects; Neurology; Neuronal Plasticity - drug effects; Neuronal Plasticity - physiology; Neuroprotective Agents - pharmacology; New therapies; Real-Time Polymerase Chain Reaction; Receptor, Angiotensin, Type 2 - agonists; Recovery of Function - drug effects; Reverse Transcriptase Polymerase Chain Reaction; Spinal Cord Injuries - metabolism; Spinal cord injury; Up-Regulation; New therapies; Spinal cord injury; AT2-receptor; Angiotensin
• DOI: 10.1016/j.nbd.2012.11.008
• ISSN: 0969-9961; 1095-953X

Abstract It is widely accepted that the angiotensin AT2-receptor (AT2R) has neuroprotective features. In the present study we tested pharmacological AT2R-stimulation as a therapeutic approach in a model of spinal cord compression injury (SCI) in mice using the novel non-peptide AT2R-agonist, Compound 21 (C21). Complementary experiments in primary neurons and organotypic cultures served to identify underlying mechanisms. Functional recovery and plasticity of corticospinal tract (CST) fibers following SCI were monitored after application of C21 (0.3 mg/kg/day i.p.) or vehicle for 4 weeks. Organotypic co-culture of GFP-positive entorhinal cortices with hippocampal target tissue served to evaluate the impact of C21 on reinnervation. Neuronal differentiation, apoptosis and expression of neurotrophins were investigated in primary murine astrocytes and neuronal cells. C21 significantly improved functional recovery after SCI compared to controls, and this significantly correlated with the increased number of CST fibers caudal to the lesion site. In vitro, C21 significantly promoted reinnervation in organotypic brain slice co-cultures (+ 50%) and neurite outgrowth of primary neurons (+ 25%). C21-induced neurite outgrowth was absent in neurons derived from AT2R-KO mice. In primary neurons, treatment with C21 further induced RNA expression of anti-apoptotic Bcl-2 (+ 75.7%), brain-derived neurotrophic factor (BDNF) (+ 53.7%), the neurotrophin receptors TrkA (+ 57.4%) and TrkB (+ 67.9%) and a marker for neurite growth, GAP43 (+ 103%), but not TrkC. Our data suggest that selective AT2R-stimulation improves functional recovery in experimental spinal cord injury through promotion of axonal plasticity and through neuroprotective and anti-apoptotic mechanisms. Thus, AT2R-stimulation may be considered for the development of a novel therapeutic approach for the treatment of spinal cord injury.