Neuropeptide Y suppresses absence seizures in a genetic rat model primarily through effects on Y₂ receptors

Abstract

Neuropeptide Y (NPY) potently suppresses absence seizures in a model of genetic generalized epilepsy, genetic absence epilepsy rats of Strasbourg (GAERS). Here we investigated the Y-receptor subtype(s) on which NPY exerts this anti-absence effect. A dual in vivo approach was used: the cumulative duration of seizures was quantified in adult male GAERS in 90-min electroencephalogram recordings following intracerebroventricular (i.c.v.) injection of: (i) subtype-selective agonists of Y1 ([Leu31Pro34]NPY, 2.5 nmol), Y2 (Ac[Leu(28,31)]NPY24-36, 3 nmol), Y5 receptors [hPP1(-17),Ala31,Aib32]NPY, 4 nmol), NPY (3 nmol) or vehicle; and following (ii) i.c.v. injection of antagonists of Y1 (BIBP3226, 20 nmol), Y2 (BIIE0246, 20 nmol) and Y5 (NPY5RA972, 20 nmol) receptors or vehicle, followed by NPY (3 nmol). Injection of the Y1- and Y5-selective agonists resulted in significantly less mean seizure suppression (37.4% and 53.9%, respectively) than NPY (83.2%; P < 0.05), while the Y2 agonist had similar effects to NPY (62.3% suppression, P = 0.57). Food intake was not increased following injection of the Y2 agonist, while significant increases in food intake were seen following NPY and the other Y-subtype agonists. Compared with vehicle, NPY injection suppressed seizures following the Y1 and Y5 antagonists (45.3% and 80.1%, respectively, P < 0.05), but not following the Y2 antagonist (5.1% suppression, P = 0.46). We conclude that NPY Y2 receptors are more important than Y1 and Y5 receptors in mediating the effect of NPY to suppress absence seizures in a genetic rat model. Y2 receptor agonists may represent targets for novel drugs against genetic generalized epilepsies without resulting in appetite stimulation.

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

“…Although less extensively studied, NPY may also be beneficial in models of generalized seizures, the pentylenetetrazole [62] and the electroconvulsive seizures [63], and models of absence epilepsy [28]. Studies using transgenic animals also suggest a role of NPY in the control of seizures.…”

“…In principle, all neuropeptides present in the thalamo-cortical absence seizure genesis loop are potential participants of absence epilepsy mechanism. For example, neuropeptide Y was suggested as a putative antiepileptic peptide in the thalamo-cortical loop and suppressed absence seizures [27,28]. Several other neuropeptides are also involved in the generation and maintenance of seizures, and therefore, their receptors represent potential drug targets.…”

“…Some neuropeptides, e.g. NPY [28], dynorphin [139], TRH [305,306] are known to be involved in absence epilepsy, too. However, many other neuropeptides have not been thoroughly investigated in animal models of absence epilepsies.…”

Long-Term Valproate Treatment Increases Brain Neuropeptide Y Expression and Decreases Seizure Expression in a Genetic Rat Model of Absence Epilepsy

“…NPY signals through identified Y1, Y2, Y4, and Y5 receptors that couple to G-proteins, inhibiting adenylate cyclase and thus decreasing intracellular calcium levels [14], [15]. Multiple receptors have been implicated in mediating NPY’s seizure suppression action, including Y1, Y2 and Y5 subtypes [16], [17], [18].…”

Neuropeptide Y Has a Protective Role during Murine Retrovirus-Induced Neurological Disease

“…induced seizures (21,23,24,36,37). The Y1, Y2, and Y5 receptor are also expressed by macrophages, with different functions for these receptors in the macrophage response to NPY (11).…”