Post-stroke recovery: the role of activity-dependent release of brain-derived neurotrophic factor

Abstract

Stroke remains the leading cause of long-term disability with no pharmacological approaches available to limit the degree of damage or aid in recovery. Considerable effort has been made to minimize neuronal damage using neuroprotective compounds. However, attempts have so far failed to translate into the clinic. Brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase type B are actively produced throughout the brain and are involved in regulating neuronal activity and normal day-to-day function. Further, BDNF has been shown to play a role in both protection and recovery of functions after stroke. This review focuses on the endogenous release of BDNF as well as activity-induced (pharmacological and physical) elevation in BDNF, and the role this plays during both acute (hours to days) and subacute (days to weeks) periods after stroke. Exogenous administration has previously been shown not to cross the blood–brain barrier; therefore, we have focused this review on approaches that allow us to directly stimulate, using pharmacological therapies and mimetics, physical activity and potential drug delivery systems that can be used to administer BDNF. Finally, we also discuss the role of BDNF polymorphisms and the influence of epigenetic regulation of BDNF on post-stroke recovery.

Keywords::

• ampakine
• BDNF polymorphisms
• exercise
• post-stroke recovery
• tropomyosin-related kinase type B

Acknowledgements

The authors are grateful to R McPhee (Department of Anatomy, University of Otago) for the schematic diagram.

Financial & competing interests disclosure

This review was completed during tenure of The Sir Charles Hercus Fellowship from the Health Research Council of New Zealand (A.N.C). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Brain-derived neurotrophic factor (BDNF) does not cross the blood–brain barrier and therefore drug and remedial therapies are required to stimulate an increase in BDNF signaling.

• BDNF is expressed in multiple forms and most likely within different cellular compartments. Further work is required to fully understand the role of each form of BDNF as well as from which cellular compartment BDNF is being released from and the impact that this has on post-stroke recovery.

• BDNF needs to reach a threshold level to have any effect on recovery. Further work is required to ascertain what this level is.

• What is the exact role of epigenetics and polymorphisms in post-stroke recovery, and could this account in part for the heterogeneity in recovery among stroke patients?

• BDNF is able to promote neurogenesis, axonal sprouting and synaptogenesis. However, it is not clear what the crucial mechanism responsible of BDNF-mediated recovery.

• What role does the p75 receptor play in BDNF-mediated recovery?

• What are the main cellular and molecular mechanisms involved in the aerobic exercise-mediated increase of BDNF?

Notes