sodium-oxybate and Epilepsy

Topics: Animals; Anticonvulsants; Barbiturates; Benzodiazepines; Disease Models, Animal; Epilepsy; Etomidate; gamma-Aminobutyric Acid; Hydroxybutyrates; Isonicotinic Acids; Mice; Muscimol; Rats; Receptors, Cell Surface; Receptors, GABA-A; Sodium Oxybate

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare inherited metabolic disorder caused by a defect of γ-aminobutyrate (GABA) catabolism. Despite the resultant hyper-GABAergic environment facilitated by the metabolic defect, individuals with this disorder have a paradoxically high prevalence of epilepsy. We aimed to study the characteristics of epilepsy in SSADHD and its concordance with GABA-related metabolites and neurophysiologic markers of cortical excitation.. Subjects in an international natural history study of SSADHD underwent clinical assessments, electroencephalography, transcranial magnetic stimulation (TMS), magnetic resonance spectroscopy for GABA/N-acetyl aspartate quantification, and plasma GABA-related metabolite measurements.. Epilepsy is highly prevalent in SSADHD, and its onset and severity correlate with an age-related decline in GABA and GABA-related metabolite levels as well as TMS markers of reduced cortical inhibition. The reduction of GABAergic activity in this otherwise hyper-GABAergic disorder demonstrates a concordance between epileptogenesis and compensatory responses. These findings may furthermore inform the timing of molecular interventions for SSADHD.

Topics: Amino Acid Metabolism, Inborn Errors; Aminobutyrates; Child; Developmental Disabilities; Epilepsy; gamma-Aminobutyric Acid; Humans; Seizures; Sodium Oxybate

Topics: Adjuvants, Anesthesia; Adult; Cataplexy; Diagnosis, Differential; Epilepsy; Humans; Male; Narcolepsy; Polysomnography; REM Sleep Parasomnias; Sodium Oxybate

The role of GABA(B) receptors in sleep is still poorly understood. GHB (γ-hydroxybutyric acid) targets these receptors and is the only drug approved to treat the sleep disorder narcolepsy. GABA(B) receptors are obligate dimers comprised of the GABA(B2) subunit and either one of the two GABA(B1) subunit isoforms, GABA(B1a) and GABA(B1b). To better understand the role of GABA(B) receptors in sleep regulation, we performed electroencephalogram (EEG) recordings in mice devoid of functional GABA(B) receptors (1(-/-) and 2(-/-)) or lacking one of the subunit 1 isoforms (1a(-/-) and 1b(-/-)). The distribution of sleep over the day was profoundly altered in 1(-/-) and 2(-/-) mice, suggesting a role for GABA(B) receptors in the circadian organization of sleep. Several other sleep and EEG phenotypes pointed to a more prominent role for GABA(B1a) compared with the GABA(B1b) isoform. Moreover, we found that GABA(B1a) protects against the spontaneous seizure activity observed in 1(-/-) and 2(-/-) mice. We also evaluated the effects of the GHB-prodrug GBL (γ-butyrolactone) and of baclofen (BAC), a high-affinity GABA(B) receptor agonist. Both drugs induced a state distinct from physiological sleep that was not observed in 1(-/-) and 2(-/-) mice. Subsequent sleep was not affected by GBL whereas BAC was followed by a delayed hypersomnia even in 1(-/-) and 2(-/-) mice. The differential effects of GBL and BAC might be attributed to differences in GABA(B)-receptor affinity. These results also indicate that all GBL effects are mediated through GABA(B) receptors, although these receptors do not seem to be involved in mediating the BAC-induced hypersomnia.

Topics: Anesthetics, Intravenous; Animals; Baclofen; Behavior, Animal; Delta Rhythm; Electrodes, Implanted; Electroencephalography; Electromyography; Epilepsy; GABA Agonists; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Receptors, GABA-B; Sleep; Sleep Deprivation; Sleep, REM; Sodium Oxybate; Theta Rhythm

Benzodiazepine treatment of life-threatening gamma-hydroxybutyrate (GHB) withdrawal is frequently unsatisfactory. Animal studies suggest strongly that treatment with GABA(B) agonists, such as baclofen, will be a more effective strategy.. A case report from the medical intensive care unit (ICU) of the university tertiary care hospital.. A 61-year-old woman was admitted to the medical ICU for severe withdrawal symptoms from chronic GHB use. This manifested as delirium, tremor, and seizures despite only small decreases in GHB dose and treatment with benzodiazepines. The addition of baclofen allowed the rapid sequential decreases in the GHB dose without seizure or delirium and resulted in long-term improvement of her tremor.. Baclofen, a GABA(B) agonist, may be a useful agent in the treatment of severe GHB withdrawal.

Topics: Adjuvants, Anesthesia; Baclofen; Benzodiazepines; Delirium; Epilepsy; Female; GABA Agonists; Humans; Middle Aged; Sodium Oxybate; Substance Withdrawal Syndrome; Tremor

Combining the methods of microdialysis and EEG recording, we have examined the effect of unilaterally, intracortically applied gamma-hydroxybutyrate (GHB) on frontal cortical EEG activity in freely moving rats. GHB, a natural endogenous GABA metabolite, is known to induce rhythmic spike and wave activity, resembling generalized petit mal epilepsy. Without GHB, spontaneous high voltage spindles (HVS, 6-9 Hz) were observed during awake and immobile behavior in most of the animals (HVS rats), while others never had any HVS. In those both groups of animals intracortical application of GHB induced epileptogenic spikes (< 0.5 Hz) behaviorally accompanied by occasional myoclonic jerks and epileptic discharges (< 2 Hz) with behavioral convulsions and contraversive movements towards the left hindlimb (seizures) but did not induce HVS or spike and waves, as reported after systemic application. In the group of rats with spontaneous occurring HVS the amplitude of the HVS on the side of the microdialysis probe was suppressed by GHB and GHB-induced spikes invading the contralateral cortex frequently triggered and terminated local HVS. The results point to different neural mechanisms for the generation of HVS and spikes and epileptic discharges (seizures) induced after local intracortical application of GHB.

Topics: Animals; Electroencephalography; Epilepsy; Frontal Lobe; Functional Laterality; Male; Rats; Rats, Wistar; Sodium Oxybate

The effects of intrathalamic injections of gamma-hydroxybutyric acid (GHB) and of NCS 382 85, a specific antagonist of GHB receptors, were evaluated in rats with spontaneous generalized absence epilepsy. Bilateral injections of GHB (25 and 50 micrograms/side) into the mediolateral thalamus increased spontaneous spike and wave discharges (SWD) in a dose-dependent fashion. This effect was suppressed by administration of NCS 382 85 (50 micrograms/side). Bilateral injection of NCS 382 85 alone (50 and 100 micrograms/side) into the same sites had no effect on SWD duration. Injection of GHB or NCS 382 85 into the midline thalamus and the area of reticular nuclei did not modify the SWD. These data suggest that GHB receptors in the mediolateral thalamus may be involved in the control of spontaneous SWD in this rat model of petit mal epilepsy.

Topics: Animals; Benzocycloheptenes; Epilepsy; Male; Microinjections; Organ Specificity; Rats; Rats, Inbred Strains; Rats, Mutant Strains; Sodium Oxybate; Stereotaxic Techniques; Thalamus; Time Factors

gamma-Hydroxybutyric acid (GHB) produces a constellation of EEG and behavioral changes when given to animals, which represent an experimental model of generalized absence seizures. gamma-Butyrolactone (GBL), the prodrug of GHB, produces these changes more rapidly and consistently than GHB, such that the rat treated with GBL is a more reproducible and predictable model of absence seizures. The hypothesis that the epileptogenic effects of GBL are due solely to its conversion to GHB was tested. The regional concentration of both compounds in brain was determined in time-course and dose-response studies, as well as at the onset of EEG changes, induced by both GHB and GBL. Also, the EEG and behavioral effects of both drugs were ascertained after intrathalamic injection in the rat. gamma-Butyrolactone produced a rapid onset of bilaterally synchronous spike and wave discharges in the rat, which correlated with a rapid appearance of GHB in brain in the GBL-treated animals. In the GHB-treated animals, EEG changes occurred 20 min after administration of GHB when levels of GHB in the brain were peaking. The threshold concentration of GHB in brain for EEG changes, in both GHB-and GBL-treated animals was 240 x 10(-6) M. The concentration of GBL in brain peaked 1 min after administration of GBL and fell rapidly to undetectable levels within 5 min. Bilateral injection of GHB into thalamus resulted in a brief burst of spike and wave discharges, while GBL, administered into the thalamus, had no effect. The use of GBL as a prodrug for GHB in this model of generalized absence seizures is valid, since GBL itself was inactive.

Topics: 4-Butyrolactone; Animals; Brain; Brain Chemistry; Dose-Response Relationship, Drug; Electrodes; Electroencephalography; Epilepsy; Gas Chromatography-Mass Spectrometry; Injections, Intraperitoneal; Male; Rats; Rats, Inbred Strains; Seizures; Sodium Oxybate

The effects of derivatives of gamma-hydroxybutyrate (GHB) and gamma-butyrolactone were examined in Wistar rats from a strain in which spontaneous spike-and-wave discharges can be recorded electroencephalographically. For each compound, the effects were compared to those obtained in rats from a strain without spontaneous seizures. Administration of GHB (62.5-375 mg/kg, i.p.) increased, in a dose-dependent manner, the duration of spontaneous spike-and-wave discharges. In non-epileptic rats, this compound (250 and 375 mg/kg) induced bursts of spikes of a lower frequency and smaller amplitude than spontaneous spike-and-wave discharges. Similar results were obtained in both strains, respectively, after injection of gamma-butyrolactone (85-170 mg/kg, i.p.). This latter compound, however, showed greater potency in its epileptogenic effects than GHB. Administration of trans gamma-hydroxycrotonic acid (up to 1000 mg/kg, i.p.), a semi-rigid analogue of GHB was without any effect in both strains of rats. Injection of gamma-crotonolactone (42.5-170 mg/kg, i.p.), suppressed the spike-and-wave discharges in epileptic rats and had no effect in non-epileptic animals. These results confirm the similarities between seizures induced by GHB and spontaneous spike-and-wave discharges in the rat. The neural mechanism of the epileptogenic effect of GHB is discussed.

Topics: 4-Butyrolactone; Animals; Electroencephalography; Epilepsy; Furans; Hydroxybutyrates; Male; Rats; Rats, Inbred Strains; Sodium Oxybate

Magnetic field (MF) intensifies the activity of penicillin-induced epileptogenic foci (EF) in the rabbit hippocamp. The same effect was obtained with gutimin. Injections of sodium hydroxybutyrate produced but little changes in hypersynchronous activity as compared to the data of control experiments. Combined influence of MF and gutimin on the rabbits somewhat reduced the quantity of the electrographic correlates of the seizures as compared with the results obtained with MF or gutimin alone. Meanwhile the use of MF coupled with sodium hydroxybutyrate reduced the number of the correlates and the amount of interictal epileptiform discharges as compared with these parameters in experiments where MF alone was applied or in control. It is assumed that MF induces slight hypoxia in the tissues thereby provoking an increase in the epileptogenic foci, whereas sodium hydroxybutyrate but not gutimin compensates for pathological action of MF.

Topics: Animals; Epilepsy; Hippocampus; Hydroxybutyrates; Magnetics; Penicillins; Rabbits; Sodium Oxybate