neuropeptide-y and Epilepsy--Absence

This study aimed to evaluate the effects of leptin, ghrelin and neuropeptide-Y on the development of nonconvulsive seizure activity and their role on combating oxidative stress and cytokines produced by the systemic immune response in the WAG/Rij rat model for genetic absence epilepsy. Current study showed that all three peptides aggravated spike wave discharges activity and affected the oxidative stress in WAG/Rij rats without any significant changes in the levels of IL-1β, IL-6 and TNF-α except leptin that only induced an increment in the concentration of IL-1β. Our results support the modulatory role of these endogenous peptides on absence epilepsy.

Topics: Animals; Disease Models, Animal; Epilepsy, Absence; Ghrelin; Leptin; Male; Neuropeptide Y; Oxidative Stress; Rats

Neuropeptide Y (NPY) potently suppresses spike-wave discharges (SWDs) in a genetic rat model of absence epilepsy (GAERS), but the underlying neurophysiologic mechanisms are not clear. We therefore sought to determine the in vivo effects of NPY on neuronal firing in the cortico-thalamo-cortical network activity, known to play a critical role in the generation of SWDs in these rats.. NPY was administered intracerebroventricularly (ICV) or in separate experiments locally on the neurons of caudal thalamic reticular nucleus (NRT) by use of juxtacellular iontophoresis in triple-barrel electrodes in male GAERS aged 12-15 weeks, in vivo under neuroleptic anesthesia. Drug infusions and electroencephalography (EEG) monitoring were performed simultaneously with juxtacellular single neuronal recordings. Effect of NPY on electrically induced SWD induction threshold were also measured.. NPY administration ICV led to a decrease in the total length of SWDs in EEG recordings. Both ICV administration and iontophoresis of NPY on NRT neurons led to an increase in interictal neuronal firing of NRT neurons. During ictal periods, ICV NPY administration reduced the number of thalamic action potentials per SWDs, as well as reduced waveform correlations between field potentials within the NRT and the cortical EEG. NPY administration ICV did not significantly alter the firing patterns of relay thalamic neurons interictally and cortical neurons during ictal and interictal periods. In addition, SWD induction threshold in the S2 region of the cortex was significantly increased after NPY administration.. Our results show alterations in cortico-thalamo-cortical local and network properties following ICV administration of NPY, suggesting mechanisms of SWD suppression in GAERS. Cellular and network alteration of NRT activity, resulting from a direct action of NPY, may be a contributor to this effect.

Topics: Animals; Cerebral Cortex; Disease Models, Animal; Electrodes, Implanted; Electroencephalography; Epilepsy, Absence; Evoked Potentials; Intralaminar Thalamic Nuclei; Male; Nerve Net; Neurons; Neuropeptide Y; Rats; Thalamic Nuclei

The intergeniculate leaflet (IGL) of the thalamus is a retinorecipient structure implicated in orchestrating circadian rhythmicity. The IGL network is highly GABAergic and consists mainly of neuropeptide Y-synthesising and enkephalinergic neurons. A high density of GFAP-immunoreactive astrocytes has been observed in the IGL, with a probable function in guarding neuronal inhibition. Interestingly, putatively enkephalinergic IGL neurons generate action potentials with an infra-slow oscillatory (ISO) pattern in vivo in urethane anesthetised Wistar rats, under light-on conditions only. Absence epilepsy (AE) is a disease characterised by spike-wave discharges present in the encephalogram, directly caused by hypersynchronous thalamo-cortical oscillations. Many pathologies connected with the arousal system, such as abnormalities in sleep architecture and an insufficient brain sleep-promoting system accompany the epileptic phenotype. We hypothesise that disturbances in the function of biological clock structures, controlling this rhythmic physiological process, may be responsible for the observed pathomechanism. To test this hypothesis, we performed an in vitro patch-clamp study on WAG/Rij rats, a well-validated genetic model of AE, in order to assess dampened GABAergic synaptic transmission in the IGL expressed as a lower IPSC amplitude and reduced sIPSC frequency. Moreover, our in vivo extracellular recordings showed higher firing rate of ISO IGL neurons with an abnormal reaction to a change in constant illumination (maintenance of rhythmic neuronal activity in darkness) in the AE model. Additional immunohistochemical experiments indicated astrogliosis in the area of the IGL, which may partially underlie the observed changes in inhibition. Altogether, the data presented here show for the first time the disinhibition of IGL neurons in a model of AE, thereby proposing the possible involvement of circadian-related brain structures in the epileptic phenotype.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Age Factors; Animals; Animals, Newborn; Disease Models, Animal; Epilepsy, Absence; Excitatory Amino Acid Antagonists; GABA Agents; Geniculate Bodies; Inhibitory Postsynaptic Potentials; Male; Nerve Net; Neural Inhibition; Neuropeptide Y; Rats; Rats, Mutant Strains; Rats, Wistar; Sodium Channel Blockers; Tetrodotoxin; Valine

The intergeniculate leaflet (IGL) is a flat retinorecipient thalamic structure implicated in orchestrating circadian rhythm, historically considered to be a subdivision of the neighboring ventrolateral geniculate nucleus (VLG). IGL consists of two main neuronal subpopulations: enkephalinergic and neuropeptide Y (NPY)-synthesizing cells. These cell types have different functions, connectivity and firing pattern in vivo, which suggest that they have different membrane currents to support their functional differences. We therefore performed patch-clamp experiments combined with immunohistochemical staining to clarify possible differences in the subthreshold currents of IGL neurons. Our results suggest that IGL neurons can be divided into two subpopulations based on two ionic currents. A T-type calcium current (IT) was identified in neurons that do not synthesise NPY, whereas all NPY-positive neurons were found to express a marked A-type potassium current (IA). Due to the fact that the clear electrophysiological discriminants between IGL and VLG are lacking, we decided to compare the amplitudes of the identified currents between those two structures. Our data suggest that VLG neurons can be characterized by a high amplitude IT and a low IA. Finally, we compared both currents with WAG/Rij rats, a well-established model of absence epilepsy, with co-occurring retinal pathologies, sleep-onset disturbances, and seizures exhibiting circadian rhythmicity. Data presented in this study uncovered pathologies in the IT exhibiting neurons of the IGL and VLG. In conclusion, the data presented here suggest that different subthreshold current expression supports the functional differences of thalamic nuclei. Those differences are promising for possible pharmacological manipulations of specified cell types in pathophysiologies including absence epilepsy.

Topics: Animals; Calcium; Disease Models, Animal; Epilepsy, Absence; Immunohistochemistry; Male; Membrane Potentials; Neurons; Neuropeptide Y; Patch-Clamp Techniques; Potassium; Rats, Wistar; Thalamic Nuclei

The mechanisms by which valproate, one of the most widely prescribed anti-epileptic drugs, suppresses seizures have not been fully elucidated but may involve up-regulation of neuropeptide Y (NPY). We investigated the effects of valproate treatment in Genetic Absence Epilepsy Rats from Strasbourg (GAERS) on brain NPY mRNA expression and seizure control. GAERS were administered either valproate (42 mg.kg(-1) hr(-1)) or saline continuously for 5 days. Electroencephalograms were recorded for 24 hrs on treatment days 1, 3 and 5 and the percentage of time spent in seizure activity was analysed. NPY mRNA expression was measured in different brain regions using qPCR. Valproate treatment suppressed seizures by 80% in GAERS (p<0.05) and increased NPY mRNA expression in the thalamus (p<0.05) compared to saline treatment. These results demonstrate that long-term valproate treatment results in an upregulation of thalamic expression of NPY implicating this as a potential contributor to the mechanism by which valproate suppresses absence seizures.

Topics: Animals; Anticonvulsants; Brain; Epilepsy, Absence; Male; Neuropeptide Y; Rats; Rats, Wistar; Seizures; Up-Regulation; Valproic Acid

Neuropeptide Y (NPY) is an inhibitory neurotransmitter that suppresses focal and generalized seizures in animal models. In this study, we investigated the sites within the thalamocortical circuit that NPY acts to suppress seizures in genetic absence epilepsy rats from Strasbourg (GAERS).. In conscious freely moving GAERS, NPY was administered via intracerebral microcannulae implanted bilaterally into one of the following regions: primary somatosensory cortex (S1), secondary somatosensory cortex (S2), the primary motor cortex (M1), caudal nucleus reticular thalamus (nRT), or ventrobasal thalamus (VB). Animals received vehicle and up to three doses of NPY, in a randomized order. Electroencephalography (EEG) recordings were carried out for 30 min prior to injection and 90 min after the injection of NPY or vehicle.. Focal microinjections of NPY into the S2 cortex suppressed seizures in a dose-dependent manner, with the response being significantly different at the highest dose (1.5 mm) compared to vehicle for total time in seizures postinjection (7.2 ± 3.0% of saline, p < 0.01) and average number of seizures (9.4 ± 4.9% of saline, p < 0.05). In contrast NPY microinjections into the VB resulted in an aggravation of seizures.. NPY produces contrasting effects on absence-like seizures in GAERS depending on the site of injection within the thalamocortical circuit. The S2 is the site at which NPY most potently acts to suppress absence-like seizures in GAERS, whereas seizure-aggravating effects are seen in the VB. These results provide further evidence to support the proposition that these electroclinically "generalized" seizures are being driven by a topographically restricted region within the somatosensory cortex.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Epilepsy, Absence; Male; Microinjections; Neural Inhibition; Neuropeptide Y; Random Allocation; Rats; Rats, Mutant Strains; Somatosensory Cortex

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.

Topics: Analysis of Variance; Animals; Disease Models, Animal; Drug Interactions; Electroencephalography; Epilepsy, Absence; Male; Neuropeptide Y; Rats; Rats, Mutant Strains; Receptors, Neuropeptide Y

Evidence from studies in rodents and humans support an anti-seizure action of neuropeptide Y (NPY) in focal, acquired epilepsy. However, the effects of NPY in generalized genetic epilepsy remain unexplored. In this study, adult male Genetic Absence Epilepsy Rats of Strasbourg (GAERS) were implanted with extradural electrodes and an intracerebroventricular (icv) cannula. Six and 12 nmol NPY or vehicle was administered icv in a random order (n=6), and the effect of NPY on seizure activity quantitated from a 90-min EEG recording. A rapid onset and sustained seizure suppression was observed following NPY treatment compared to vehicle, with both 6 and 12 nmol NPY having a significantly decreased mean percentage time in seizure (5.7 +/- 1.4% and 5.0 +/- 1.7% vs. 15.8 +/- 3.4%) and mean number of seizures per minute (0.5 +/- 0.1 and 0.4 +/- 0.1 vs. 1.1 +/- 0.1). There was no significant difference between the degree of seizure suppression after 6 and 12 nmol NPY. The results of this study demonstrate that NPY suppresses absence seizures in GAERS. This suggests that NPY modulates pathological oscillatory thalamocortical activity and may represent a new therapeutic approach for the treatment of generalized epilepsies.

Topics: Action Potentials; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Electroencephalography; Epilepsy, Absence; Male; Neuropeptide Y; Rats

Immunoreactive- (IR-) somatostatin (SRIF), neuropeptide Y (NPY) and corticotropin-releasing factor (CRF) contents were investigated in the brain of tremor rats with absence-like seizure and spontaneously epileptic rats (SER), which is a genetically defined double-mutant (zi/zi, tm/tm) obtained by mating zitter homozygote (zi/zi) with tremor heterozygote (tm/+) and shows both absence-like seizure and tonic convulsions. Increased levels of IR-NPY and IR-CRF were observed in several regions including the amygdala and hippocampus in homozygous SER compared to heterozygous SER (zi/zi, tm/+ or +/+). Homozygous tremor rats (tm/tm) showed lower levels of IR-NPY and IR-CRF contents mainly in the hippocampus and mesolimbic system (entorhinal and pyriform cortex and nucleus accumbens) than heterozygous tremor rats. IR-SRIF contents of homozygous SER were higher in frontal cortex than heterozygous SER and in amygdala than homozygous tremor rats. No change of IR-SRIF between groups was noted in the hippocampus among brain structures underlying epileptogenicity. The results suggest that the change of neuropeptide levels, most conspicuous in NPY among three peptides tested, may be involved in the phenotypical manifestation of seizures in SER and tremor rats, and that the development of tonic convulsion and absence seizures may be differently associated with the change of brain neuropeptide levels.

Topics: Animals; Brain; Corticotropin-Releasing Hormone; Epilepsy; Epilepsy, Absence; Male; Neuropeptide Y; Rats; Rats, Mutant Strains; Somatostatin; Tremor