Neuropeptide FF decreases cortical and amygdala excitability via NPFF1 and/or NPFF2 receptors.
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1
University Ghent, Internal Diseases - Neurology, Belgium
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2
Vrije Universiteit Brussel, Department of Pharmaceutical Chemistry, Drug Analysis & Drug Information, Belgium
In approximately 30% of epilepsy patients, seizures cannot be controlled with currently available antiepileptic drugs. For these patients, new treatments with novel mechanisms of action are needed. Neuropeptide systems are promising targets for the treatment of epilepsy. Several neuropeptides such as neuropeptide Y, galanin and somatostatin have already been implicated in the control of seizure activity. Many others, however, have not been investigated in this regard. Neuropeptide FF (NPFF) is a member of the RF-amide family. NPFF and its receptors (NPFF1R and NPFF2R) are differentially distributed throughout the central nervous system. We have studied the effects of NPFF receptor ligands in two rat models that can be used to predict the anticonvulsant activity of potential antiepileptic drugs: the motor cortex stimulation model (MCSM) and the amygdala kindling model.
In the MCSM, a 50Hz stimulus train of pulses with increasing intensity is delivered to the motor cortex and the threshold intensity for eliciting a motor response is determined through behavioural observation. The threshold is a measure for cortical excitability and correlates with anticonvulsant activity in seizure models and humans. We found that intracerebroventricular (i.c.v.; flow rate 3µl/h) administration of NPFF (2nmol/2h; n=7) significantly increased the threshold with 143±27µA [p<0.05 compared to control]). Threshold increase could be prevented by pretreatment with the dual NPFF receptor antagonist RF9 (i.c.v. 6.25nmol/2.5h; n=6). Administration of RF9 alone had no effect on the threshold.
In the amygdala kindling model, electrical stimulation of the amygdala is performed to determine the threshold for eliciting an afterdischarge (AD). Subsequent daily stimulations at or above this threshold result in limbic seizures of gradually increasing severity. The kindling model is used to screen anticonvulsant drugs. Continuous administration of NPFF (i.c.v. 2nmol/2h) for 2h prior to stimulation significantly increased the threshold for eliciting an AD compared to control (435±72µA [n=10] vs. 131±23µA [n=8] [p<0.05]). However, when rats subsequently underwent daily stimulations above this threshold, repeated administration of NPFF did not significantly delay or prevent kindling acquisition. The ADT of the threshold to evoke a generalized seizure in fully kindled animals was also not altered by administration of NPFF (20nmol/2h).
We conclude that NPFF reduces cortical excitability through NPFF receptor activation, indicating it may have anticonvulsant properties in neocortical focal epilepsy. NPFF reduces amygdala excitability in naïve animals, but does not increase AD or seizure threshold in fully kindled animals and NPFF does not delay kindling acquisition, suggesting that it has no effect on limbic epileptogenesis.
Acknowledgements
Ine Buffel is supported by a junior researcher (‘Aspirant’) grant from the Fund for Scientific Research-Flanders (FWO).
Keywords:
RF-amides,
Neuropeptide FF,
RF9,
cortical excitability,
kindling model
Conference:
Belgian Brain Council 2014
MODULATING THE BRAIN: FACTS, FICTION, FUTURE, Ghent, Belgium, 4 Oct - 4 Oct, 2014.
Presentation Type:
Poster Presentation
Topic:
Basic Neuroscience
Citation:
Buffel
I,
Portelli
J,
Raedt
R,
Vonck
K,
Smolders
IJ,
Boon
P and
Meurs
A
(2014). Neuropeptide FF decreases cortical and amygdala excitability via NPFF1 and/or NPFF2 receptors..
Conference Abstract:
Belgian Brain Council 2014
MODULATING THE BRAIN: FACTS, FICTION, FUTURE.
doi: 10.3389/conf.fnhum.2014.214.00027
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Received:
27 Jun 2014;
Published Online:
30 Jun 2014.
*
Correspondence:
Mrs. Ine Buffel, University Ghent, Internal Diseases - Neurology, Ghent, 9000, Belgium, Ine.Buffel@UGent.be