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|Title: ||SELECTIVE AT2-RECEPTOR STIMULATION PROMOTES NEUROREGENERATION AND IMPROVES FUNCTIONAL OUTCOME IN AN ANIMAL MODEL OF SPINAL CORD INJURY|
|Authors: ||Namsolleck, P.|
Steckelings, U. M.
|Issue Date: ||2010|
|Publisher: ||LIPPINCOTT WILLIAMS & WILKINS|
|Citation: ||JOURNAL OF HYPERTENSION, 28. p. E540-E540|
|Abstract: ||We have previously shown that the angiotensin AT2-receptor (AT2R) is upregulated in neuronal injury and when stimulated with angiotensin II promotes reinnervation and remyelination. The present study aimed to test AT2R- stimulation by the novel selective, non-peptide AT2R-agonist Compound 21 (C21) as a potential therapeutic approach for the treatment of experimental spinal cord injury in mice. Complementary experiments in primary neurons and organotypic cultures served to identify underlying neuroprotective mechanisms. Spinal cord injury was induced by controlled extradural contusion (10 mN for 10 sec) at T9 in anaesthetised female Balb/C mice. 0.5 μl fluorescent dextrane was injected into the left motor cortex for ex vivo tracking of motor neurons. Animals were treated with C21 (0.3 mg/kg/day i.p.) or vehicle for 4 weeks. Locomotor deficits were evaluated daily by Basso Mouse Scale and foot print analysis. The impact of C21 (1 μM) on reinnervation was evaluated in a co-culture system consisting of green-fluorescent-protein-(GFP)-positive entorhinal cortices and hippocampal target tissue. Neuronal differentiation and apoptosis were investigated in primary murine, neuronal cells. After spinal cord injury, C21 significantly attenuated locomotor deficits when compared to vehicle treatment (1.6 points on Basso Scale). Functional recovery was accompanied by a significantly increased number of motor neurons crossing the lesional area. In vitro, C21 significantly induced axonal ingrowth from entorhinal cortices into the hippocampal target tissue (+50%) as well as neurite outgrowth (+25%)from primary neurons. C21-induced neurite outgrowth was absent in neurons derived from AT2R-deficient mice. Treatment with C21 further significantly induced expression of anti-apoptotic Bcl-2 (+75.7%), of the neurotrophin BDNF (+53.7%), the neurotrophin receptor TrkB (+57.4%) and the marker for neurite sprouting, GAP43 (+103%). Specific stimulation of the AT2 receptor with the non-peptide AT2R-agonist C21 ameliorated locomotor function after experimental spinal cord injury in mice through the promotion of axonal outgrowth resulting in reinnervation and through anti-inflammatory, anti-apoptotic and neuroprotective mechanisms. Thus AT2R-stimulation may be considered a novel therapeutic approach for disease states requiring neuroprotection and neurogeneration.|
|Notes: ||[Namsolleck, P.; Schwengel, K.; Thoene-Reineke, C.; Seidel, K.; Lucht, K.; Unger, T.; Steckelings, U. M.] Charite, Cardiovasc Res Ctr, CCR, D-13353 Berlin, Germany. [Boato, F.] Charite, Ctr Anat, D-13353 Berlin, Germany. [Hendrix, S.] Hasselt Univ, Biomed Res Inst BIOMED, Hasselt, Belgium. [Hendrix, S.] Hasselt Univ, Dept Morphol, Hasselt, Belgium.|
|ISI #: ||000283023405074|
|Type: ||Journal Contribution|
|Appears in Collections: ||Research publications|
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