title: Brain-derived neurotrophic factor-mediated effects on mitochondrial respiratory coupling and neuroprotection share the same molecular signalling pathways.
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.
authors.affiliation: Institute of Pharmacy, Chemistry and Biomedical Sciences, School of Health, Natural and Social Science, University of Sunderland, Sunderland, UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: Markham
authors.forename: Ian
authors.initials: I
authors.lastname: Cameron
authors.forename: Rasneer
authors.initials: R
authors.lastname: Bains
authors.forename: Paul
authors.initials: P
authors.lastname: Franklin
authors.forename: Janos P
authors.initials: JP
authors.lastname: Kiss
authors.forename: Leslie
authors.initials: L
authors.lastname: Schwendimann
authors.forename: Pierre
authors.initials: P
authors.lastname: Gressens
authors.forename: Michael
authors.initials: M
authors.lastname: Spedding
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D019069:Cell Respiration / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000494:pharmacology; D006801:Humans; D007051:Ibotenic Acid / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018690:Excitatory Amino Acid Agonists; D051100:Glial Cell Line-Derived Neurotrophic Factor; D053583:Interleukin-1beta; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D007051:Ibotenic Acid