Circulating levels of allopregnanolone, an anticonvulsant metabolite of progesterone, in women with partial epilepsy in the postcritical phase

PURPOSE: Several lines of evidence indicate that there exists a relation between ovarian hormones and epilepsy. Estrogens decrease seizure threshold and increase brain excitability, whereas progesterone has an inhibitory effect and reduces epileptiform activity. Recently considerable interest has turned to neuroactive steroids, a group of progesterone metabolites, as endogenous modulators of excitability of the central nervous system (CNS). Their ability to alter neuronal firing rapidly occurs through interaction with gamma-aminobutyric acid (GABA) A receptor complex. In a previous experience, serum allopregnanolone (3alpha-OH-5alpha-pregnan-20-one) levels were measured in 15 women with partial epilepsy in the intercritical phase, and no significant differences were found between patients and control subjects. METHODS: To find out if there are changes in serum allopregnanolone levels after epileptic seizure, blood samples were drawn immediately, 15 min, and 6 h after a seizure in seven fertile females with partial epilepsy. RESULTS: The most interesting finding is that allopregnanolone increases in serum during the first 15 min after partial seizures (p < 0.05) and decreases after 6 h. CONCLUSIONS: These data are consistent with a role for allopregnanolone in the control of neuronal excitability and seizures.     

Reduced serum level of THDOC, an anticonvulsant steroid, in women with perimenstrual catamenial epilepsy

Purpose: Seizure exacerbation in catamenial epilepsy (CE) is associated with the decrease in progesterone secretion and increase in estradiol secretion during the premenstrual period. Moreover, experimental evidence suggests that tetrahydrodeoxycorticosterone (THDOC), a positive modulator of the type A receptor for γ-aminobutyric acid (GABA), and dehydroepiandrosterone sulfate (DHEAS), a negative modulator of this receptor, might play a crucial role in modulating seizure frequency during the menstrual cycle. Following these studies it seems of interest to investigate possible variations, among other hormonal parameters, of THDOC and DHEAS in CE patients.
Methods: The serum concentrations of progesterone (P4), pregnenolone, allopregnanolone (AP), THDOC, DHEAS, cortisol, and DHEAS/cortisol ratio were measured throughout the menstrual cycle at the 7th, 11th, 15th, 19th, 23rd, and 27th day from the onset of spontaneous menstrual blood loss in young premenopausal women with CE (n = 17) and age-matched controls (n = 13).
Results: At each time of the study, the serum concentration of THDOC and the DHEAS/cortisol ratio were lower (p < 0.05) in women with CE than in control women. The concentrations of P4, pregnenolone, and AP did not differ between the two groups of subjects.
Conclusions: The reduced serum concentration of THDOC and the reduced DHEAS/cortisol ratio detected throughout the menstrual cycle in women with CE might play a role in CE. Moreover, the peculiar pattern of CE seizure exacerbation might suggest that these neuroendocrine variations are worth investigating in other epileptic syndromes, particularly in those characterized by relevant and uncontrolled variations in seizure frequency.     

The anticonvulsant effects of progesterone and 5alpha-dihydroprogesterone on amygdala-kindled seizures in rats

PURPOSE: Progesterone has been shown to be anticonvulsant in several animal seizure models. The purpose of the present study was to investigate the anticonvulsant actions of progesterone and its primary metabolite 5alpha-dihydroprogesterone in the amygdala kindling model. METHODS: Female Wistar rats were implanted in the right basolateral amygdala with a long-term, bipolar electrode. The subjects were kindled to 30 stage 5 seizures and stability tested. Multiple doses of progesterone and 5alpha-dihydroprogesterone were then tested for anticonvulsant activity against focal electrographic and generalized convulsive kindled seizures. The time course of progesterone's anticonvulsant action also was examined. RESULTS: Progesterone had a median effective dose (ED50) of 103 mg/kg against generalized convulsions at 15 min after injection. Subjects were not sedated at the time of seizure testing, although sedation developed later (40-60 min after injection). In time-course experiments, it was found that 120 mg/kg of progesterone caused complete suppression of the generalized convulsion from 20 to 160 min after injection. Suppression of the focal discharge also was seen in some animals between 20 and 160 min. 5alpha-dihydroprogesterone had an ED50 of 2.9 mg/kg against generalized kindled convulsions and an ED50 of 4.3 mg/kg against focal afterdischarge 15 min after injection. 5alpha-dihydroprogesterone did not produce sedation 15 min after injection, or at any later time interval. CONCLUSIONS: Progesterone is anticonvulsant only at high doses when tested against amygdala kindled seizures. 5alpha-dihydroprogesterone is considerably more potent than progesterone. At low, nonsedative doses, it was effective against both the kindled amygdala focal afterdischarge and the generalized convulsion.     

Locally applied progesterone metabolites alter neuronal responsiveness in the cerebellum

Ongoing studies in this laboratory have demonstrated that both systemically and locally administered sex steroids 17β estradiol (E₂) and progesterone (P) alter cerebellar Purkinje cell responses to microiontophoretically applied amino acid neurotransmitters GABA and glutamate (GLUT) in the urethane-anesthetized, ovariectomized adult rat. In the present study, we have examined the effects of several locally pressure ejected P metabolites on Purkinje cell responsiveness to GABA and GLUT: 5α-pregnane-20-one (5α DHP), 5α-pregnane-3α-ol-20-one (3α OH-DHP) and 5α-pregnane-3β-ol-20-one (3β OH-DHP). GABA-induced inhibition was markedly enhanced immediately after onset of local application of 3α OH-DHP or 5α DHP, unaccompanied by alterations in background discharge. Both metabolites also attenuated excitatory responses to GLUT by 0–3 min after initiation of steroid application. In both cases, recovery to control levels of response was observed 6–9 min after termination of pressure application. These results are similar to those seen after local or systemic injection of P. In contrast, 3β OH-DHP did not produce any alteration in Purkinje cell responses to either amino acid. As 5α DHP and 3α OH-DHP can be localized in cerebellar tissue after P administration, the results presented here suggest that the neuronal effects of systemic P may be mediated by local membrane actions of P or its metabolites.     

Associations of histories of depression and PMDD diagnosis with allopregnanolone concentrations following the oral administration of micronized progesterone

Twenty-three women with premenstrual dysphoric disorder (PMDD) and 29 non-PMDD controls were compared for plasma progesterone (P) and its neuroactive steroid metabolite allopregnanolone (ALLO), as well as the ALLO/P ratio following the double-blind, placebo controlled administration of 300 mg oral micronized progesterone. Approximately half of each group had prior depression (DEP) (13 PMDD, 12 non-PMDD), though all were free of current depression. Progesterone and ALLO were sampled 160, 190, 225, and 255 min after progesterone administration. Changes over time in plasma concentrations and the ALLO/P ratio were assessed using area under the curve analyses. Women with prior DEP had lower ALLO levels (p=0.05) and marginally lower P levels (p<0.07) following progesterone administration compared to never depressed women, and this was especially evident in the non-PMDD women (p<0.01). PMDD women with no prior DEP had higher pre-progesterone ALLO/P ratios than all other groups (Ps<0.05) and higher ratios than the never depressed, non-PMDD women following oral progesterone (p<0.05). Results could not be accounted for by group differences in steroid hormone binding protein concentrations. For all women, progesterone administration was associated with increased confusion, fatigue, and with reduced confidence (Ps<0.01), even after controlling for placebo-associated mood change. These results suggest a persistent effect of prior DEP on P and ALLO concentrations following oral progesterone and that PMDD women, especially those with no prior DEP, may have alterations in the metabolic pathways underlying the conversion of P to ALLO.     

Alteration of NMDA receptor–mediated synaptic interactions in the lateral amygdala associated with seizure activity in a mouse model of chronic temporal lobe epilepsy

Purpose: Because results from both animal models and human temporal lobe epilepsy (TLE) have pointed to synaptic network alterations in the amygdala, we have tested the hypothesis that glutamatergic transmission in the lateral amygdala (LA) is critically involved. Methods: Using the pilocarpine mouse model, LA slices were prepared ex vivo in the recurrent phase of TLE (Pilo group), and LA projection neurons (PNs) were recorded using patch‐clamp techniques. Intrinsic and synaptic properties of LA PNs were analyzed and compared with those in age‐matched saline‐injected controls. Results: Only mild changes were observed in intrinsic properties of LA PNs, whereas both spontaneous excitatory postsynaptic currents (sEPSCs) and miniature EPSCs (mEPSCs) were significantly increased in Pilo as compared to saline controls. This difference was sensitive to AP5, but persisted during action of NBQX, indicating mediation by N‐methyl‐d ‐aspartate (NMDA) receptors. Moreover, these changes were associated with an increase in frequency but not amplitude of mEPSCs, indicative of a contribution of presynaptic mechanisms. Discussion: In conclusion, dynamic changes seem to occur in glutamatergic transmission within the amygdala during TLE, to which a functional upregulation of presynaptic NMDA receptors in LA PNs makes a significant contribution.     

Changes in sex steroid levels in women with epilepsy on treatment: Relationship with antiepileptic therapies and seizure frequency

Purpose:   Reproductive dysfunction in epilepsy is attributed to the seizures themselves and also to antiepileptic drugs (AEDs), which affect steroid production, binding, and metabolism. In turn, neuroactive steroids may influence neuronal excitability. A previous study in this cohort of consecutive women with epilepsy showed that patients with more frequent seizures had higher cortisol and lower dehydroepiandrosterone sulfate levels than those with rare or absent seizures. The present study was aimed at evaluating, in these same women, the possible relationship between some clinical parameters, seizure frequency, AED therapies, and sex hormone levels.
Methods:   Estradiol (E2), progesterone (Pg), sex hormone-binding globulin (SHBG), and free estrogen index (FEI) were measured during the luteal phase in 113 consecutive females, 16–47 years old, with different epilepsy syndromes on enzyme-inducing AED (EIAED) and/or non–enzyme-inducing AED (NEIAED) treatments, and in 30 age-matched healthy women. Hormonal data were correlated with clinical parameters (age, epilepsy syndrome, disease onset, and duration), seizure frequency assessed on the basis of a seizure frequency score (SFS), and AED therapies.
Results:   E2, Pg, and FEI were lower, whereas SHBG levels were higher in the epilepsy patients than in the controls. However, sex steroid and SHBG levels were not different between groups of patients categorized according to SFS. Therapies with EIAEDs accounted for changes in E2 levels and FEI.
Conclusions:   Despite globally decreased sex steroid levels in serum, actual hormone titers were not significantly correlated with SFS in consecutive epilepsy women; rather, these hormonal changes were explained by AED treatments, mainly when EIAED polytherapies were given.     

Anticonvulsant efficacy of the low-affinity partial benzodiazepine receptor agonist ELB 138 in a dog seizure model and in epileptic dogs with spontaneously recurrent seizures

PURPOSE: Ataxia, sedation, amnesia, ethanol and barbiturate potentiation, loss of efficacy (tolerance), development of dependence, and the potential for drug abuse limit the clinical use of benzodiazepines (BZDs) for long-term treatment of epilepsy or anxiety. BZD ligands that are in current use act as full allosteric modulators of gamma-aminobutyric acid (GABA)-gated chloride channels and, on long-term administration, trigger a functional uncoupling between the GABAA and BZD recognition sites. Partial allosteric modulators, which have a low intrinsic activity at the BZD recognition site of the GABAA receptor, might eventually overcome the limitations of full agonists such as diazepam (DZP). METHODS: In the present study, the new low-affinity partial BZD-receptor agonist ELB 138 [former name AWD 131-138; 1-(4-chlorophenyl)-4-morpholino-imidazolin-2-one] was evaluated in a dog seizure model and in epileptic dogs with spontaneously recurrent seizures. RESULTS: ELB 138 was shown to increase potently the pentylenetetrazole (PTZ) seizure threshold in dogs. Prolonged oral administration with twice-daily dosing of ELB 138 with either 5 or 40 mg/kg over a 5-week period was not associated with loss of anticonvulsant efficacy in the PTZ dog model. To study whether physical dependence developed during long-term treatment, the BZD antagonist flumazenil was injected after 5 weeks of treatment with ELB 138. Compared with prolonged treatment with DZP, only relatively mild abstinence symptoms were precipitated in dogs treated with ELB 138, particularly at the lower dosage (5 mg/kg, b.i.d.). In a prospective trial in dogs with newly diagnosed epilepsy, ELB 138 markedly reduced seizure frequency and severity without significant difference to standard treatments (phenobarbital or primidone) but was much better tolerated than the standard drugs. In dogs with chronic epilepsy, most dogs exhibited a reduction in seizure frequency and severity during add-on treatment with ELB 138. CONCLUSIONS: The data demonstrate that the partial BZD receptor agonist ELB 138 exerts significant anticonvulsant efficacy without tolerance in a dog seizure model as well as in epileptic dogs with spontaneously recurrent seizures. These data thus substantiate that partial agonism at the BZD site of GABAA receptors offers advantages versus full agonism and constitutes a valuable approach for treatment of seizures.     

Evaluation of GABA system and cell damage in parahippocampus of patients with temporal lobe epilepsy showing antiepileptic effects after subacute electrical stimulation

PURPOSE: The gamma-aminobutyric acid (GABA) system and neuronal loss were evaluated in the parahippocampal cortex (PHC) of patients with intractable mesial temporal lobe epilepsy (MTLE) who received subacute electrical stimulation and showed antiepileptic effects. METHODS: GABA tissue content, GABA(A) and benzodiazepine (BZD) receptor levels, as well as neuronal density were determined in PHC of five patients (ESAE group) with an MTLE history of 14.8 +/- 2.5 years and seizure frequency of 11 +/- 2.9 per month, two (40%) of them with mesial sclerosis. This group demonstrated antiepileptic effects after subacute electrical stimulation (130 Hz, 450 micros, 200-400 microA), applied continuously during 16 to 20 days in PHC. Values were compared with those obtained from patients with severe MTLE (history of 21.7 +/- 2.8 years and seizure frequency of 28.2 +/- 14 per month) in whom electrical stimulation did not induce antiepileptic effects (ESWAE group, n = 4), patients with MTLE in whom no electrical stimulation was applied (MTLE group, n = 4), and autopsy material acquired from subjects without epilepsy (n = 4 obtained from three subjects). RESULTS: The ESAE group demonstrated high GABA tissue levels (219%), as well as a significantly higher cell count (58.5%) when compared with the MTLE group. The ESWAE group showed enhanced BZD-receptor levels (38%), whereas their values for GABA tissue levels and GABA(A) receptor were similar to those obtained from the MTLE group. CONCLUSIONS: It is suggested that subacute electrical stimulation of PHC is more effective in patients with less severe epilepsy, an effect associated with a high GABA tissue content and a low rate of cell loss.     

AWD 140-190: a potent anticonvulsant in the amygdala-kindling model of partial epilepsy

PURPOSE: Evaluation of the effect of the new anticonvulsant drug, AWD 140-190 [4-(p-bromophenyl)-3-morpholino-1H-pyrrole-2-carboxylic acid methyl ester] on focally induced seizures and on epileptogenesis in the kindling model. METHODS: Effects of AWD 140-190 were studied in amygdala kindled rats after oral and intraperitoneal administration. In addition, the effect on kindling development was evaluated. In all experiments, behavioral changes in the rats in response to AWD 140-190 were monitored closely. RESULTS: AWD 140-190 exerted potent anticonvulsant activity against focal seizures. After intraperitoneal and oral administration in fully kindled rats, the substance dose-dependently increased the threshold for induction of afterdischarges starting at 15 mg/kg. AWD 140-190 only weakly influenced the seizure severity of the animals after stimulation at the elevated afterdischarge threshold current. No adverse effects were observed up to 30 mg/kg after intraperitoneal and oral administration in the open field and in the rotarod test. No differences were found between kindled and nonkindled rats when comparing neurotoxicity of AWD 140-190. Prolonged treatment with AWD 140-190 during kindling acquisition did not prevent kindling, but significantly retarded the development of fully kindled seizures during the treatment. CONCLUSIONS: This study demonstrates that AWD 140-190 has anticonvulsant effects in the amygdala kindling model in rats, suggesting that the substance is particularly effective against partial seizures. AWD 140-190 is orally active and devoid of neurotoxic effects in anticonvulsant doses, thus indicating that this compound has potential for antiepileptic therapy. AWD 140-190 retards the kindling development during the treatment. This effect could be explained by the acute anticonvulsant effect of the substance.     

Increased apparent oral clearance of valproic acid during intake of combined contraceptive steroids in women with epilepsy

PURPOSE: To determine potential changes in total and unbound serum valproic acid (VPA) concentrations at steady-state during a cycle of intake of combined hormonal contraceptive (HC) steroids. METHODS: Blood samples were collected from nine women stabilized on VPA monotherapy on two separate randomized occasions: (i) at the end of the 4- to 7-day HC-free interval, and (ii) on the last day of the HC intake period. Trough concentrations of VPA in serum and serum ultrafiltrates were determined by fluorescence polarization immunoassay. RESULTS: In all women, total and unbound VPA concentrations were higher during the HC-free interval than during HC intake (means +/- SD: 425 +/- 184 vs. 350 +/- 145 micromol/L, respectively, for total VPA, p = 0.002, and 55 +/- 37 vs. 39 +/- 25 micromol/L, respectively, for unbound VPA, p = 0.005). Compared with the HC-free interval, HC intake was associated with a mean 21.5% increase in VPA total apparent oral clearance (from 8.0 +/- 5.2 to 9.7 +/- 6.4 ml/h/kg, p = 0.01) and a 45.2 % increase in VPA unbound apparent oral clearance (from 79 +/- 81 to 115 +/- 121 ml/h/kg, p = 0.029). CONCLUSIONS: The apparent oral clearance of total and unbound VPA increases during the HC intake period compared with the HC-free interval, probably due to induction of glucuronosyltransferase by ethinylestradiol. The magnitude of the change varies across individuals, being potentially clinically relevant in some cases. Serum VPA concentrations should be monitored when adding or discontinuing HC steroids, and possibly during the on-off intervals of a HC cycle.     

A prospective randomised trial on the effect of monitoring plasma anticonvulsant levels in epilepsy

Summary To evaluate whether knowledge of plasma levels of anti-epileptic drugs has an effect on therapeutic outcome, 127 epileptic outpatients were randomly assigned to two groups (A and B). Plasma levels of group A were reported to the treating physician who attempted to keep the plasma levels within the therapeutic range. The treating physician was not informed of the results of plasma lavel determinations of group B. Data from 105 patients were available for assessment at the end of the study year. Therapeutic results of groups A and B were not significantly different. The reduction in seizure frequency was associated with an increase in plasma concentrations of the anti-epileptic drugs. Thus, under the conditions of the study, knowledge of plasma levels of anti-epileptic drugs did not further improve therapeutic results.

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Zusammenfassung Um festzustellen, ob die Kenntnis des Plasmaspiegels der Antiepileptika das Therapieergebnis verbessern kann, wurden 127 ambulant behandelte Patienten mit Epilepsie in randomisierter Reihenfolge in zwei Gruppen eingeteilt (A und B). Die Plasmaspiegel der Antiepileptika in Gruppe A wurden dem behandelnden Arzt mitgeteilt, der versuchen sollte, die Plasmaspiegel in den Therapeutischen Bereich zu bringen. Die Ergebnisse der Plasmaspiegelbestimmung in Gruppe B (Kontrollgruppe) wurden dem behandelnden Arzt nicht mitgeteilt. Am Ende des Untersuchungsjahres konnten die Daten von 105 Patienten ausgewertet werden. Das Behandlungsergebnis von Gruppe A und von Gruppe B war am Ende des Beobachtungsjahres nicht signifikant verschieden. Die Abnahme der Anfallshäufigkeit ging mit einem Anstieg der Plasmakonzentration der Antiepileptika einher. Somit konnte unter den Bedingungen dieser Studie das Therapieergebnis durch die Kenntnis der Plasmaspiegel der Antiepileptika nicht weiter verbessert werden.

     

Blood levels of cytokines in children with idiopathic partial and generalized epilepsy

PurposeAntiepileptic drugs have been reported to reduce the levels of serum immunoglobulins and affect the production and levels of certain cytokines. We investigated the effects of valproic acid (VPA) and topiramate (TPM) on the blood levels of interleukin (IL)-1α, IL-1β, IL-6, IL-10, and TNF-α in children with idiopathic generalized and partial epilepsy.MethodsForty prepubertal children aged 6–12 (mean 8.3 ± 1.7) years, 19/40 (47.5%) female and 21/40 (52.5%) male, with idiopathic generalized or partial epilepsy diagnosed in the child neurology outpatient clinic were included. The patients were divided into two treatment groups: 20 were treated with VPA and 20 with TPM. The plasma levels of IL-1α, IL-1β, IL-6, IL-10, TNF-α were measured using ELISA method before the initiation of treatment and at the 6th and 12th months of the treatment. The Chi-square test was used to compare qualitative data. To compare the periods, recurrence measurements were done using variance analysis and Freidman 2-sided variance analysis. p < 0.05 was considered as statistically significant.ResultsIn the VPA group, the levels of IL-1α significantly increased at 12 months while the levels of IL-10 decreased at 6 months of treatment compared to values before treatment (p < 0.05). There was no significant difference in levels of IL-1β, IL-6, TNF-α (p > 0.05). In the TPM group, lower levels of IL-10 were observed at 6th and 12th months compared to the onset of treatment (p < 0.05).ConclusionThe results of this study demonstrated that VPA and TPM might lead to changes in the levels of cytokines in epileptic patients. The next step would be to investigate the relation of these findings to the outcome of epilepsy and response to treatment.     

Amino acid neurotransmitter levels in gliomas and their relationship to the incidence of epilepsy

The cause of epilepsy due to gliomas is not known. Explanations that it is due to mass effect, infiltration and site of the tumour appear insufficient. We have investigated the possibility that epilepsy due to gliomas is caused by interference with normal GABA and glutamate uptake and metabolism in the surrounding cortex. Analysis of human glioma biopsy specimens for the amino acid neurotransmitters and glutamine has shown that gliomas associated with epilepsy have a higher concentration of glutamine. This may be of importance since an elevated concentration of glutamine has been shown to be associated with the onset and severity of cobalt-induced epilepsy.     

Seizure frequency and sex steroids in women with partial epilepsy on antiepileptic therapy

Purpose:   Neuroactive sex steroids influence neuron excitability, which is enhanced by estradiol (E2) and decreased by progesterone (Pg). In epilepsy, the production, metabolism, biologic availability, and activity of sex hormones may be affected by seizures themselves or by antiepileptic drugs (AEDs). This cross-sectional observational study was aimed at evaluating the relationships between sex steroids, seizure frequency, and other clinical parameters in women with partial epilepsy (PE) on AED treatments.
Methods:   Serum E2, Pg, sex hormone binding globulin (SHBG) levels, free E2 (fE2), and E2/Pg ratios were determined during the follicular and luteal phases in 72 adult women with PE, and in 30 healthy controls. Hormonal data were correlated with seizure frequency, age, body weight, body mass index (BMI), disease onset and duration, and AED therapies.
Results:   In patients, E2, fE2, and Pg levels were lower in both ovarian phases, whereas those of SHBG were higher than in controls. No significant changes in hormone levels and in prevalence of anovulatory cycles were observed between patients grouped according to their seizure frequency. However, when compared with those in healthy controls, luteal fE2 and Pg levels were chiefly impaired in women with more frequent seizures, mostly undergoing AED polytherapies, but not in those with absent or rarer seizures.
Conclusions:   The actual changes in sex steroid levels and E2/Pg ratios did not explain an increased seizure frequency in adult women with AED-treated PE, but patients with more severe disease showed more relevant changes in their sex hormone profile and impaired Pg levels during the luteal phase.     

Effects of intravenous progesterone infusions on the epileptic discharge frequency in women with partial epilepsy

Earlier work showed that in a group of women suffering from partial epilepsy, there is a decrease in seizure frequency during the luteal phase of the menstrual cycle. Moreover, iv progesterone infusions decrease the discharge frequency from penicillin epileptic foci in cats, when given in doses that reach plasma concentrations as observed during pregnancy. In the present study, iv progesterone infusions, reaching plasma concentrations as during the luteal phase, were given to 7 women with partial epilepsy. The inclusion criterion was that they should have more than one epileptic discharge per 5 min on an ordinary EEG . A 6 h EEG-registration was made. Blank and progesterone solutions were infused for 2 h respectively and the progesterone infusion was followed by a 2 h EEG recording period. 4 of the 7 patients showed a significant decrease in spike frequency during the infusion. In the patients not showing this effect, the plasma progesterone binding capacity was high. The 2 patients with the most marked progesterone effect had low progesterone binding capacity and no antiepileptic treatment. Somnolence during the test might also have influenced the results in 2 of the patients.     

Evaluation of the anticonvulsant profile of progesterone in male amygdala-kindled rats

While there is clinical evidence that progesterone has anticonvulsant activity in women with complex partial seizures, previous studies on the anticonvulsant effect of progesterone in experimental animal models are inconclusive. Moreover, the effect of progesterone on seizure parameters in fully amygdala-kindled rats which best resemble complex partial seizures has not been evaluated. Therefore, in the present work the anticonvulsant effect of progesterone at doses of 10, 30, 60 and 75 mg/kg in fully amygdala-kindled male rats was studied. Only at the high and sedative dose of 75 mg/kg, progesterone suppressed behavioral seizures and afterdischarges elicited 10 min after intraperitoneal (i.p.) administration. Pretreatment with the progesterone antagonist, 17β-hydroxy-11β-(4-dimethylaminophenyl)-17-(prop-1-ynyl)-estra-4,9-dien-3-one (RU 38486) at the dose of 3 mg/kg did not inhibit the anticonvulsant activity of progesterone, while pretreatment with the GABA_A receptor antagonist, bicuculline (2 mg/kg) blocked the anticonvulsant effect of progesterone. Neither RU 38486 nor bicuculline had any effect on the seizure parameters. These findings suggest that only at large and sedative doses, progesterone has some anticonvulsant activity in male amygdala-kindled rats which may be partly mediated via the GABA_A receptor complex interaction.     

Long-term study of gamma-vinyl GABA in the treatment of epilepsy

ABSTRACT – The purpose of this study was to investigate the long-term efficacy and tolerability of gamma-vinyl GABA (GVG) in the treatment of epilepsy. 36 patients with severe therapy resistant epilepsies participated, the majority exhibiting complex partial seizures. The mean follow-up period was 9.3 months. GVG was administered as add-on therapy, to keep serum levels of concomitant treatment constant. The mean dose of GVG was 2.6 g's per day.
Fifty-six per cent of the patients, including three patients with juvenile myoclonic epilepsy, experienced more than a 50% reduction in seizure frequency. No signs of tolerance development to the antiepileptic effect of GVG was demonstrated.
Two patients were withdrawn from GVG treatment due to increased seizure frequency, and two due to side effects in the form of vomiting and nausea. Incidentally, the side effects observed were harmless and transient. Fifty per cent of the patients experienced no side effects at all.
GVG seems to be a valuable antiepileptic compound. The results of this long-term study confirm observations from several short controlled trials.     

The contribution of in vitro studies to the understanding of epilepsy

The slice technique has turned out to be a valuable tool in the study of fundamental epileptic processes. Intracellular recording from brain tissue in vitro may be maintained for hours. The effect of changes in the perfusion medium may be studied easily without interference from the blood-brain barrier and tissue from different brain regions may be studied in isolation. Generally, brain cells in slices behave as brain cells in vivo in spite of the obvious possibilities for distorted metabolism. The cellular basis of the epileptic process is believed to be large depolarizing potentials. Although similar potentials recorded from cells in slices have been shown to be synaptic potentials, abnormal membrane properties are also induced by epileptogenic substances. The spread of the epileptic process may occur by direct electrical coupling via gap junctions, by local increases in extracellular potassium concentration or by synaptic transmission. Reduced GABA'ergic inhibition, account, at least in part, for epileptic discharges induced by epileptogenic drugs. The role for this mechanism in naturally occurring epilepsy is unknown, but it is probably involved somehow. GABA increases the conductance of the neuronal membrane to Cl. In hippocampal dendrites, it probably in addition increases the conductance to Na because here the induced inhibitory response is depolarizing. The somatic and dendritic membranes are also different in their excitatory responses. In the hippocampus, calcium spikes predominate in the dendrites whereas steady discharges consisting of sodium spikes are characteristic of the soma. The same receptor complex seems to be involved in dendrites and soma in the enhancing effect of benzodiazepines on GABA responses. However, GABA-benzodiazepine receptor complexes in other parts of the brain are probably constituted in different ways. We know of many disturbances in the brain which may be involved in epilepsy. A single critical deviation from normal physiology in naturally occurring epilepsy has not been identified. Possibly, the process may be initiated by any one of several factors, which all take part when the disease is established.