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 brainderived 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.

Nafamostat Mesilate Improves Neurological Outcome and Axonal Regeneration after Stroke in Rats

“…Neurological outcome and axonal regeneration are tightly regulated by many extracellular factors [1]. Neurotrophins including brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and neurotrophin-3 (NT3) promote neuronal survival and synaptic plasticity, whereas the nogo receptor and its ligands restrict the process [2,3].…”

Nano-particle delivery of brain derived neurotrophic factor after focal cerebral ischemia reduces tissue injury and enhances behavioral recovery

“…Although previous studies have shown the efficacy of BDNF in improving post-stroke recovery in animal models (Clarkson et al., 2015; Yu et al, 2013), BDNF was given quite quickly after stroke onset, a therapeutic time-window that is often not practical in clinical situations. In this study, extended therapeutic windows were evaluated, with treatment delayed for over 12 hours after stroke onset.…”

Harnessing the Potential of Biomaterials for Brain Repair after Stroke

“…Although BDNF expression is upregulated after stroke injury this effect is transient and is reduced with age, making plasticity-based recovery paradigms difficult in chronic stroke and aged populations. While systemically delivered AMPAkine stimulated recovery in young animals, by inducing BDNF release (Clarkson et al, 2011), recovery was dampened in aged animals (Clarkson et al, 2015) due to reduced BDNF expression in this population. Interestingly, combining the systemically administered AMPAkine with local BDNF delivery through a HA-based hydrogel modified with collagen-binding domains improved recovery in aged animals to levels comparable to young animals (Clarkson et al, 2015).…”

“…While systemically delivered AMPAkine stimulated recovery in young animals, by inducing BDNF release (Clarkson et al, 2011), recovery was dampened in aged animals (Clarkson et al, 2015) due to reduced BDNF expression in this population. Interestingly, combining the systemically administered AMPAkine with local BDNF delivery through a HA-based hydrogel modified with collagen-binding domains improved recovery in aged animals to levels comparable to young animals (Clarkson et al, 2015). This is one of the few studies involving biomaterials that investigated mechanistic pathways mediating this process, demonstrating that BDNF delivered from the hydrogel upregulates canonical BDNF signaling pathways.…”

“…As one set of studies demonstrated, aged animals have a lessrobust capacity for plasticity and require modifications to their treatment to achieve the same outcome found in young animals (Clarkson et al, 2015). Future studies should also incorporate the guidelines set forward by Stroke Therapy Academic Industry Round Table (STAiRS) for preclinical studies in order to build a knowledge base for the field that has practical translation aspects [Stroke Therapy Academic Industry Roundtable (STAIR), 1999; Saver et al, 2009].…”