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Brain-derived neurotrophic factor-mediated effects on mitochondrial respiratory coupling and neuroprotection share the same molecular signalling pathways

Markham, Anthony, Cameron, Ian, Bains, Rasneer, Franklin, Paul, Kiss, JP, Schwendimann, L, Gressens, P and Spedding, M Brain-derived neurotrophic factor-mediated effects on mitochondrial respiratory coupling and neuroprotection share the same molecular signalling pathways. European Journal Neuroscience, 35 (3). pp. 366-374. ISSN 1460-9568

Item Type: Article

Abstract

Intracerebral injection of ibotenate into mouse pups induced grey matter lesions and white matter cysts; co-administration of brain-derived neurotrophic factor (BDNF) produced a dose-dependent reduction in these lesions. In contrast, glial cell line-derived neurotrophic factor (GDNF) had no significant effect, whereas nerve growth factor (NGF) or interleukin-1β (IL-1β) resulted in dose-dependent exacerbation. The neuroprotective effects of BDNF were abolished by co-administration of anti-BDNF antibody or MEK inhibitors, or ABT-737, a BH3 mimetic and Bcl-2 antagonist. The actions of BDNF, GDNF and NGF were measured in a parallel in vitro study on the oxidative metabolism of mouse brain mitochondria. BDNF produced a concentration-dependent increase in the respiratory control index (RCI, a measure of respiratory coupling efficiency, ATP synthesis, and organelle integrity) when co-incubated with synaptosomes containing signal transduction pathways; but GDNF failed to modify RCI, and NGF had only weak effects. BDNF had no effect on pure mitochondria, and enhanced oxidation only when complex I substrates were used. The effect of BDNF was inhibited by anti-BDNF antibody, MEK inhibitors or ABT-737, and also by IL-1β, indicating that the mitochondrial effects are mediated via the same MEK-Bcl-2 pathway as the neuroprotection. The complex I inhibitor rotenone, a compound implicated in the aetiology of Parkinson's disease, inhibited both the in vitro mitochondrial and in vivo neuroprotective effects of BDNF. The ability of BDNF to modify brain metabolism and the efficiency of oxygen utilization via a MEK-Bcl-2 pathway may be an important component of the neuroprotective action observed with this neurotrophin.

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More Information

Depositing User: Glenda Young

Identifiers

Item ID: 3376
Identification Number: https://doi.org/10.1111/j.1460-9568.2011.07965.x
ISSN: 1460-9568
URI: http://sure.sunderland.ac.uk/id/eprint/3376
Official URL: http://onlinelibrary.wiley.com/resolve/openurl?gen...

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Catalogue record

Date Deposited: 25 Jan 2013 15:17
Last Modified: 18 Dec 2019 15:34

Contributors

Author: Anthony Markham
Author: Ian Cameron
Author: Rasneer Bains
Author: Paul Franklin
Author: JP Kiss
Author: L Schwendimann
Author: P Gressens
Author: M Spedding

University Divisions

Faculty of Health Sciences and Wellbeing
Faculty of Health Sciences and Wellbeing > School of Pharmacy and Pharmaceutical Sciences

Subjects

Sciences > Pharmacy and Pharmacology

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