BDNF prevents NMDA-induced toxicity in models of Huntington's disease: the effects are genotype specific and adenosine A2A receptor is involved.
NMDA receptor-mediated excitotoxicity is thought to play a pivotal role in the pathogenesis of Huntington's disease (HD). The neurotrophin brain-derived neurotrophic factor (BDNF), which is also highly involved in HD and whose effects are modulated by adenosine A2 ARs, influences the activity and expression of striatal NMDA receptors. In electrophysiology experiments, we investigated the role of BDNF toward NMDA-induced effects in HD models, and the possible involvement of A2ARs. In corticostriatal slices from wild-type mice and age-matched symptomatic R6/2 mice (a model of HD), NMDA application (75 μM) induced a transient or a permanent (i.e., toxic) reduction of field potential amplitude, respectively. BDNF (10 ng/mL) potentiated NMDA effects in wild-type, while it protected from NMDA toxicity in R6/2 mice. Both effects of BDNF were prevented by A2 AR blockade. The protective effect of BDNF against NMDA-induced toxicity was reproduced in a cellular model of HD. These findings may have very important implications for the neuroprotective potential of BDNF and A2 AR ligands in HD.
Section of Central Nervous System Pharmacology, Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy.
Alberto
A
Martire
Section of Central Nervous System Pharmacology, Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy.
Rita
R
Pepponi
Section of Central Nervous System Pharmacology, Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy.
Maria Rosaria
MR
Domenici
Section of Central Nervous System Pharmacology, Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy.
Antonella
A
Ferrante
Section of Central Nervous System Pharmacology, Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy.
Valentina
V
Chiodi
Section of Central Nervous System Pharmacology, Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy.
Patrizia
P
Popoli
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005838:Genotype; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016202:N-Methylaspartate / Q000633:toxicity*; D018408:Patch-Clamp Techniques; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*
D019208:Brain-Derived Neurotrophic Factor; D043705:Receptor, Adenosine A2A; D016202:N-Methylaspartate
Adenosine A2A receptors; Huntington's disease; NMDA; R6/2 mice; brain‐derived neurotrophic factor; striatum