A Critical Threshold of Rehabilitation Involving Brain-Derived Neurotrophic Factor Is Required for Poststroke Recovery

MacLellan, Crystal L.; Keough, Michael B.; Granter‐Button, Shirley; Chernenko, Garry; Butt, Stephanie; Corbett, Dale

doi:10.1177/1545968311407517

Cited by 124 publications

(128 citation statements)

References 49 publications

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“…31 Recent studies in rodents have shown that this recovery is most likely because of acivitydriven changes in BDNF. 19 In the present study, we failed to see any significant elevation in BDNF levels after stroke, indicating that the endogenous neuroplastic mechanisms involved in improving motor functions in young, are lacking or impaired in aged mice. Further, treatment with CX1837 resulted in a smaller increase in BDNF levels compared with previous published data in young mice (75% increase in young versus 54% increase in aged mice).…”

Section: Discussioncontrasting

confidence: 66%

“…This dynamic relationship between BDNF and recovery has been previously identified by other authors to be critical, 8 with BDNF levels not only need to be increased, but also need to reach a critical threshold in order for recovery to be evident. 19 As the more modest levels of recovery observed in aged animals could have been attributed to age-related deficits in BDNF production, we next investigated whether localized delivery of BDNF could enhance the effects of CX1837. Our results here indicated that local hydrogel delivery of BDNF alone was able to enhance functional recovery in aged mice (36% gain of function at 6 weeks).…”

Section: Discussionmentioning

confidence: 99%

“…19 Based on the findings in Figure 1, it is likely that BDNF levels did not reach this threshold or that this threshold is shifted in the aged mice. Further, data presented in Figure 2 indicate that in addition to BDNF being released into and elevated in peri-infarct tissues, an activity component may also be required to enhance recovery.…”

Section: Combined Hydrogel Delivery Of Brain-derived Neurotrophic Facmentioning

confidence: 95%

“…6 Further, others have reported that BDNF can enhance motor recovery after stroke, although this is dependent on BDNF reaching a threshold level. 8,19 Based on our observation that CX1837 may not be stimulating BDNF levels to reach a certain threshold, we aim to test whether local delivery of BDNF via hydrogel infusion into the stroke cavity could enhance functional recovery.…”

Section: Cx1837 Improves Motor Recovery After Stroke In Agedmentioning

confidence: 99%

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Combined Ampakine and BDNF Treatments Enhance Poststroke Functional Recovery in Aged Mice via AKT-CREB Signaling

Clarkson

Parker

Nilsson

et al. 2015

J Cereb Blood Flow Metab

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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.

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Section: Discussioncontrasting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Section: Combined Hydrogel Delivery Of Brain-derived Neurotrophic Facmentioning

confidence: 95%

Section: Cx1837 Improves Motor Recovery After Stroke In Agedmentioning

confidence: 99%

See 2 more Smart Citations

Combined Ampakine and BDNF Treatments Enhance Poststroke Functional Recovery in Aged Mice via AKT-CREB Signaling

Clarkson

Parker

Nilsson

et al. 2015

J Cereb Blood Flow Metab

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“…12 For example, blocking brain-derived neurotrophic growth factor inhibits recovery after ischemia, 13,14 whereas effective rehabilitation induces an enhancement of brain-derived neurotrophic growth factor. 15 Rehabilitation likely induces usedependent activation of intact tissue bordering the stroke that mediates neuroplastic changes and subsequent functional improvement. This possibility, although suggested previously, 8,16,17 has not been directly tested in the earliest stages of poststroke rehabilitation.…”

Section: Introductionmentioning

confidence: 99%

Early Poststroke Experience Differentially Alters Periinfarct Layer II and III Cortex

Clarke

Langdon

Corbett

2014

J Cereb Blood Flow Metab

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Early poststroke rehabilitation effectively improves recovery of function, likely by engaging multiple plasticity processes through use-dependent activation of neural circuits. The loci of such neuroplastic reorganization have not been examined during the initial phase of behavioral recovery. In the current study, we sought to evaluate sub-components of rehabilitation and to identify brain sites first engaged by early rehabilitation. Rats were subjected to endothelin-1 ischemia and placed in either enriched environment (EE), daily reach training (RT), combination of enriched environment and reach training (ER), or standard housing (ST) starting 7 days post ischemia. Functional and histopathological assessments were made after 2, 5, and 10 days of treatment. Animals exposed to 10 days of ER treatment exhibited significantly more use-dependent neuronal activity (FosB/DFosB expression) in perilesional cortex than those exposed to EE, RT, or ST treatments. Similar trends were observed in both perilesional striatum and contralesional forelimb motor cortex. This use-dependent plasticity was not explained by differences in neuronal death, inflammation, or lesion volume. The increased activity likely contributes to the neuroplastic changes and functional recovery observed after extended periods of rehabilitation. Importantly, EE or RT alone did not lead to enhanced activity suggesting that combination therapy is necessary to promote maximum recovery.

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Computational Neurorehabilitation

Schweighofer

2022

Neurorehabilitation Technology

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A Critical Threshold of Rehabilitation Involving Brain-Derived Neurotrophic Factor Is Required for Poststroke Recovery

Abstract: Data suggest that there is a critical threshold of rehabilitation, below which recovery will not occur, and that BDNF mediates functional recovery. The use of intensive rehabilitation therapies for stroke patients is strongly supported.

Cited by 124 publications

References 49 publications

Combined Ampakine and BDNF Treatments Enhance Poststroke Functional Recovery in Aged Mice via AKT-CREB Signaling

Combined Ampakine and BDNF Treatments Enhance Poststroke Functional Recovery in Aged Mice via AKT-CREB Signaling

Early Poststroke Experience Differentially Alters Periinfarct Layer II and III Cortex

Computational Neurorehabilitation

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