title: Combined ampakine and BDNF treatments enhance poststroke functional recovery in aged mice via AKT-CREB signaling.
abstract: Cerebral ischemia results in damage to neuronal circuits and lasting impairment in function. We have previously reported that stimulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors with the ampakine, CX1837, increases brain-derived neurotrophic factor (BDNF) levels and affords significant motor recovery after stroke in young mice. Here, we investigated whether administration of CX1837 in aged (24 months old) mice was equally effective. In a model of focal ischemia, administration of CX1837 from 5 days after stroke resulted in a small gain of motor function by week 6 after stroke. Mice that received a local delivery of BDNF via hydrogel implanted into the stroke cavity also showed a small gain of function from 4 to 6 weeks after stroke. Combining both treatments, however, resulted in a marked improvement in motor function from 2 weeks after insult. Assessment of peri-infarct tissue 2 weeks after stroke revealed a significant increase in p-AKT and p-CREB after the combined drug treatment. Using the pan-AKT inhibitor, GSK-690693, or deletion of CREB from forebrain neurons using the CREB-flox/CAMKii-cre mice, we were able to block the recovery of motor function. These data suggest that combined CX1837 and local delivery of BDNF are required to achieve maximal functional recovery after stroke in aged mice, and is occurring via the AKT-GSK3-CREB signaling pathway.
authors.affiliation: 1] Department of Anatomy, Brain Health Research Centre, University of Otago, Dunedin, New Zealand [2] Department of Psychology, University of Otago, Dunedin, New Zealand [3] Florey Institute of Neuroscience and Mental Health, Parkville, Melbourne, Australia.
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Clarkson
authors.affiliation: Department of Anatomy, Brain Health Research Centre, University of Otago, Dunedin, New Zealand.
authors.forename: Kim
authors.initials: K
authors.lastname: Parker
authors.affiliation: School of Biomedical Sciences and Pharmacy, The University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Nilsson
authors.affiliation: School of Biomedical Sciences and Pharmacy, The University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: F Rohan
authors.initials: FR
authors.lastname: Walker
authors.affiliation: Department of Anatomy, Brain Health Research Centre, University of Otago, Dunedin, New Zealand.
authors.forename: Emma K
authors.initials: EK
authors.lastname: Gowing
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011422:Propionates / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D020521:Stroke / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D011422:Propionates; D051057:Proto-Oncogene Proteins c-akt