neuropeptide-y and Magnesium-Deficiency

Neuropeptide Y (NPY) has been implicated in antiepileptic action in different in vivo and in vitro epilepsy models in rats and mice. Both Y2 and Y5 receptors could mediate the seizure-suppressant effect of NPY. However, lack of selective ligands precluded previous studies from conclusively evaluating the role of Y5 receptors in anti-epileptiform action of NPY. In the present study, using the new highly selective Y5 receptor antagonist, CGP71683A, and agonist, [cPP]hPP, we show that the Y5 receptor subtype is centrally involved in NPY-induced suppression of spontaneous epileptiform (interictaform) bursting in the CA3 area of rat hippocampal slices. This novel finding underscores the importance of Y5 receptors as a potential target for future antiepileptic therapy, particularly, for interictal components of temporal lobe epilepsy.

Topics: Action Potentials; Animals; Anticonvulsants; Epilepsy, Temporal Lobe; Female; Hippocampus; In Vitro Techniques; Magnesium Deficiency; Male; Naphthalenes; Neurons; Neuropeptide Y; Pyrimidines; Rats; Rats, Wistar; Receptors, Neuropeptide Y

Previous studies show that neuropeptide Y (NPY) inhibits in vitro seizures in rodent hippocampus. Here, we explored the effect of NPY application on epileptiform discharges induced by perfusion with magnesium-free solution in slices of entorhinal cortex from two different mouse strains. NPY significantly reduced the duration of epileptiform discharges with a peak effect of 36-50%. This is the first study showing anti-epileptiform effect of NPY in the entorhinal cortex and also the first evidence that NPY inhibits seizures in a cortical region in mice. The entorhinal cortex has a central role in transferring information between the hippocampus and the rest of the brain. Therefore our data further strengthen the concept of NPY and its receptors as widespread regulators of epileptiform activity and as a potential future target for antiepileptic therapy.

Topics: Action Potentials; Animals; Anticonvulsants; Culture Media; Entorhinal Cortex; Epilepsy; Magnesium Deficiency; Male; Mice; Neuropeptide Y; Organ Culture Techniques; Patch-Clamp Techniques

Neuropeptide Y (NPY) potently inhibits glutamate-mediated synaptic transmission in areas CA1 and CA3 of the rat hippocampus without affecting other synaptic inputs onto principal cells of the hippocampal formation, suggesting that its biological role may include the regulation of excitability within the hippocampus. Here we examine NPY's actions in three in vitro models of epilepsy [0 Mg2+-, picrotoxin-, and stimulus-train-induced bursting (STIB)] with the use of extracellular and whole cell patch-clamp recordings from rat hippocampal-entorhinal cortex slices. Perfusion of the slice with saline that had Mg2+ omitted (0 Mg2+) or that had picrotoxin (100 microM) added resulted in brief spontaneous bursts (SBs) resembling interictal discharges. SB frequency is significantly reduced in both models by 1 microM NPY and by the Y2-preferring agonists peptide (P)YY(3-36) (1 microM) and 1-4-(6-aminohexanoic acid)-25-36 ([ahx(5-24)] NPY; 3 microM). The Y1-preferring agonist Leu31-Pro34NPY (1 microM) is considerably less potent, but also reduces burst frequency, even in the presence of the selective Y1 receptor antagonist GR231118, suggesting the involvement of a different receptor. In STIB, high-frequency stimulus trains to stratum radiatum of area CA2/CA3 result in clonic or tonic-clonic ictaform primary afterdischarges (primary ADs) as well as longer, spontaneous secondary ictaform discharges and SBs similar to those in the other models. Primary AD duration is greatly reduced or abolished by Y2- but not Y1-preferring agonists. SBs, although variable, were inhibited by both Y1 and Y2 agonists. In single and dual whole cell recordings from CA3 pyramidal cells, we frequently observed spontaneous, rhythmic synchronous events (SRSEs) arising after several STIB stimuli. Once established, SRSEs persist in the absence of further stimuli and are insensitive to the application of NPY. SRSEs in pyramidal cells typically occur at 2-4 Hz, are outward currents when cells are clamped near rest (>100 pA at a holding potential of -55 mV), reverse between -60 and -70 mV, and are inhibited by 100 microM picrotoxin, indicating involvement of gamma-aminobutyric acid-A receptors. They are inhibited by blockers of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) but not N-methyl-D-aspartate receptors. Whole cell patch-clamp recordings from interneurons in CA3 after STIB reveal NPY-insensitive, rhythmic, inward AMPA-receptor-mediated currents that are similar in frequency

Topics: Animals; Anticonvulsants; Electric Stimulation; Epilepsy; Hippocampus; Magnesium Deficiency; Male; Membrane Potentials; Neuropeptide Y; Patch-Clamp Techniques; Picrotoxin; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y