Steroid hormones in the regulation of absence seizures. A putative role of the limbic system. Manipulations with the hypothalamo-pituitary-gonadal and hypothalamo-pituitary-adrenal systems

Contains fulltext : 30936_sterhoint.pdf (publisher's version ) (Open Access)RU Radboud Universiteit Nijmegen, 24 oktober 2007Promotor : Coenen, A.M.L. Co-promotor : Luijtelaar, E.L.J.M. van150 p

Hormones and absence epilepsy in genetic models

Steroid hormones are known to have a tremendous impact on seizures and might play a prominent role in epileptogenesis. However, little is known about the role of steroid hormones in absence epilepsy. Here we review recently combined electrophysiological, pharmacological and behavioural studies in a genetic absence epilepsy model, rats of the WAG/Rij strain, towards the role of the hypothalamic-pituitary-adrenal (HPA) and the hypothalamic-pituitary-gonadal (HPG) hormonal systems on the susceptibility to absence seizures and the pathogenesis of absence epilepsy. Steroid hormones affect seizures, however, progesterone, administered in the neocortex has opposite effects compared to systemic administration. This outcome is in agreement with the cortical focus theory that assumes a local cortical origin for the typical spike-wave discharges (SWDs). Next, the role of corticosterone, stressors such as footshocks, and the anticipation of stressful events on SWDs is discussed: it seems that all three facilitate the occurrence of absence seizures. Estrogens are not playing a role in the occurrence of SWDs; however progesterone administered systemically, also in physiological concentrations and in contrast to what is often seen in other forms of epilepsy, has proepileptic effects. This is most likely due to the non-genomic effects through an action on classical GABAA receptors. Interestingly, progesterone reduces absence seizures during pregnancy. Finally, it is suggested that the limbic system may exert an extra-cortical remote control of the absence seizures generated in the cortico-thalamo-cortical loop. It is proposed that the effects on seizures are due to chronic changes in ovarian steroid hormonal milieu in the limbic system. This hypothesis provides additional insight on the hormonal regulation of absence epilepsy and helps to understand controversial effects on the relation between steroid hormones and absence seizures

Absence seizures are reduced by the enhancement of GABA-ergic inhibition in the hippocampus in WAG-Rij rats

Contains fulltext : 55257.pdf (publisher's version ) (Closed access)5 p

The role of ovarian steroid hormones in the regulation of basal and stress induced absence seizures

Item does not contain fulltext8 p

Stress, glucocorticoids and absences in a genetic epilepsy model

Contains fulltext : 102917.pdf (publisher's version ) (Closed access)Although stress can alter the susceptibility of patients and animal models to convulsive epilepsy, little is known about the role of stress and glucocorticoid hormones in absence epilepsy. We measured the basal and acute stress-induced (foot-shocks: FS) concentrations of corticosterone in WAG/Rij rats, non-epileptic inbred ACI rats and outbred Wistar rats. The WAG/Rij strain is a genetic model for absence epilepsy and comorbidity for depression, which originates from the population of Wistar rats and, therefore, shares their genetic background. In a separate experiment, WAG/Rij rats were exposed to FS on three consecutive days. Electroencephalograms (EEGs) were recorded before and after FS, and the number of absence seizures (spike-wave-discharges, SWDs) was quantified. Both WAG/Rij rats and ACI rats exhibited elevated basal levels of corticosterone and a rapid corticosterone increase in response to acute stress. The WAG/Rij rats also displayed the most rapid normalization of corticosterone during the recovery phase compared to that of ACI and Wistar rats. FS had a biphasic effect on SWDs; an initial suppression was followed by an aggravation of the SWDs. By the third day, this aggravation of seizures was present in the hour preceding FS. This increase in SWDs may arise from anticipatory stress about the upcoming FS. Together, these results suggest that the distinct secretion profile of corticosterone found in WAG/Rij rats may contribute to the severity of the epileptic phenotype. Although the acute stressor results in an initial suppression of SWDs followed by an increase in SWDs, stress prior to a predictable negative event aggravates absences.5 p

Hormones and absence epilepsy

Hormones have an extremely large impact on seizures and epilepsy. Stress and stress hormones are known to reinforce seizure expression, and gonadal hormones affect the number of seizures and even the seizure type. Moreover, hormonal concentrations change drastically over an individual's lifetime, especially in women. The prevailing view on steroid hormones is that estrogen and corticosteroid hormones are proconvulsant, whereas progesterone is anticonvulsant, but recent studies in various absence models show that this is not the case in absence epilepsy. Progesterone facilitates the occurrence of absences, most likely through its conversion to the neurosteroid allopregnanolone and the non-genomic action of this neurosteroid on classical GABAA receptors. On the other hand, during pregnancy, when progesterone is enhanced, spike-wave discharges, typical for absence seizures, are diminished, suggesting an opposite relation between absence seizures and progesterone. How progesterone affects absence seizures differently during pregnancy, and during the various phases of the ovarian cycle is a challenging question. Most likely local neuroplastic changes of delta subunit containing GABAA receptors are interesting candidates to be involved in how and in which way progesterone exerts its effects on absence seizures and how this may be different across puberty, various phases of the ovulation cycle, pregnancy, and menopause. Estradiol fails to have an effect on absence seizures, while testosterone probably exerts its effects via its metabolites 5alpha-dihydrotestosterone and later to the GABAA receptor agonist 3alpha-androstanediol. Stressors also modulate absence seizures, it is tentatively proposed that this may occur also via modulation of GABAA receptors

Hormones and absence epilepsy

Hormones have an extremely large impact on seizures and epilepsy. Stress and stress hormones are known to reinforce seizure expression, and gonadal hormones affect the number of seizures and even the seizure type. Moreover, hormonal concentrations change drastically over an individual's lifetime, especially in women. The prevailing view on steroid hormones is that estrogen and corticosteroid hormones are proconvulsant, whereas progesterone is anticonvulsant. The neuroactive steroids may exert some of their effects nongenomically through their action on classical GABA receptors. However, understanding the interaction between the GABA system and hormones in absence epilepsy is complicated by the peculiar pharmacological profile exhibited by absence epilepsy (which is opposite to the profile seen in other types of seizures). Moreover, absences are associated with hyperfunction of the GABAergic inhibitory system. Thus, the relations between hormones that modulate the GABA receptors and absence epilepsy must be given special attention. Outcomes of recent pharmacological studies with progesterone show that acute systemic administration exacerbates absence seizures, that absence seizures are virtually reduced during pregnancy when plasma levels are chronically elevated, and that intrahippocampal administration of progesterone reduces spike-wave discharges. This suggests a complicated relationship between progesterone and absence seizures. How progesterone affects absence seizures is an important, fascinating, and challenging question

Genetic absence rats have a lower threshold for limbic type of afterdischarges: a cortical stimulation study

Item does not contain fulltextClassical theories on absence epilepsy suggest that a hyperexcitable cortex is a precondition for the occurrence of absence seizures. In the present experiment seizure thresholds and cortical epileptic afterdischarges (AD) were determined in a comparative study of genetically epileptic WAG/Rij, congenic ACI and Wistar rats. Fifteen-second series of low-frequency (8 Hz) stimulation of the sensorimotor cortex were applied in 80- and 180-day-old rats (n= 10-12) with implanted electrodes. Intervals between the stimulation series were at least 10 min, intensity was stepwise increased. Threshold intensities were estimated for movements directly induced by stimulation, AD of spike-and-wave type, clonic seizures accompanying this type of AD and transition into limbic type of AD. Strain differences were found for the threshold for elicitation of stimulus-bound movements reflecting direct activation of the motor cortex, for the threshold of spike-and-wave AD, for maximal clonic intensity of seizures accompanying direct stimulation and AD and for duration of the spike-and-wave AD. ACI's had the lowest thresholds and maximal severity of seizures, whereas WAG/Rij rats had largest duration of AD. Both age and strain differences were found for the transition to the limbic type of AD threshold: WAG/Rij rats had lowest threshold, whereas in Wistar and ACI rats this threshold decreased with age. The decrease of this threshold correlated with the increase of the incidence and total duration of spontaneous SWDs in WAG/Rij rats (R=-0.56, -0,53, p<0.03). It can be concluded that it is not the excitability of the sensorimotor cortex per se that distinguishes genetic epileptic rats from its controls, rather the long duration of spike-wave AD and the lower threshold for spread of epileptic activity into the limbic system

Absence seizures and progesterone in wag/rij rats: effects of pregnancy

Item does not contain fulltextSpontaneously occurring spike-wave discharges (SWDs) and serum concentrations of ovarian steroid hormones were investigated before, during and after pregnancy in WAG/Rij rats, a rat strain with genetically determined absence seizures. Eight groups of rats were included in the assays of progesterone and estradiol: rats at diestrus, at various days of pregnancy and at lactating days while EEG's were recorded at the same days in rats equipped with cortical EEG electrodes. Serum concentration of progesterone was 3-fold increased at the 3rd day of pregnancy and remained elevated till the 18th day of pregnancy, thereafter it returned to control values before delivery. Estradiol was elevated only at the 18th day of pregnancy. The number of SWDs were decreased from 3rd up to 18th days of pregnancy and progressively increased to control level 2 days before parturition. Thereafter a new decrease was found 2-3 after giving birth. These results demonstrate that the changes in plasma progesterone concentration corresponds to the changes in number of SWDs and have a similar time-course. It can be concluded that an increased level of progesterone that occur during pregnancy is associated with a decreased number of SWDs. However, the relationship between SWDs and concentration of progesterone found here is opposite to non-pregnancy data and an antiepileptogenic reaction might have taken place