GABA in Epilepsy: The Pharmacologic Basis

Summary: GABA transmission plays a key role in controlling seizure activity. The precise nature of its effect depends on the particular location in the brain and the pathway involved. Animal studies have helped to define specific brain regions such as the substantia nigra and area tempestas that are critical in controlling seizure activity. Antiepileptic drugs such as vigabatrin [gamma vinyl GABA (GVG)], a drug rationally developed to treat resistant epilepsy, can enhance GABA transmission in these regions and may thereby afford seizure protection.     

Progression and Generalization of Seizure Discharge: Anatomical and Neurochemical Substrates

Summary: Seizure activity is generated and propagated by specific subcortical circuits. The substantia nigra (SN) and the area tempestas (AT) have been identified as two exemplary substrates for the control of experimental seizures. In animal models, GABAergic transmission has been shown to protect against seizures of different origins and methods of induction. Neuroactive peptides and excitatory amino acids may work with GABA in the SN to control the propagation of a wide variety of seizure types. In contrast, inhibition of AT pons selectively protects against seizures associated with limbic circuits. The AT is also a site from which bilaterally synchronous convulsions can be triggered in response to manipulations of cholinergic, GABAergic, and excitatory amino acid receptors. Definition of other pathways of seizure development and the effects of pharmacologic treatments on discrete brain regions await further research efforts.     

Regulation of Limbic Motor Seizures by GABA and Glutamate Transmission in Nucleus Tractus Solitarius

PURPOSE: The nucleus of the solitary tract (NTS) is a primary site at which vagal afferents terminate. Because afferent vagal nerve stimulation has been demonstrated to have anticonvulsant effects, it is likely that changes in synaptic transmission in the NTS can regulate seizure susceptibility. We tested this hypothesis by examining the influence of gamma-aminobutyric acid (GABA) ergic and glutamatergic transmission in the NTS on seizures evoked by systemic and focal bicuculline and systemic pentylenetetrazol (PTZ) in rats. METHODS: Muscimol (256 pmol), a GABA(A)-receptor agonist, bicuculline methiodide (177 pmol), a GABA(A)-receptor antagonist, kynurenate (634 pmol), a glutamate-receptor antagonist, or lidocaine (100 nl; 5%), a local anesthetic, was microinjected into the mediocaudal (m)NTS. Ten minutes later, seizure activity was induced by either a focal microinfusion of bicuculline methiodide (177 pmol) into the rostral piriform cortex, systemic PTZ (50 mg/kg, i.p.), or systemic bicuculline (0.35 mg/kg, i.v.). RESULTS: Muscimol in mNTS (but not in adjacent regions of NTS) attenuated seizures in all seizure models tested, whereas bicuculline methiodide into mNTS did not alter seizure responses. Kynurenate infusions into mNTS significantly reduced the severity of seizures evoked both systemically and focally. Anticonvulsant effects also were obtained with lidocaine application into the same region of mNTS. Unilateral injections were sufficient to afford seizure protection. CONCLUSIONS: Our results demonstrate that an increase in GABA transmission or a decrease in glutamate transmission in the rat mNTS reduces susceptibility to limbic motor seizures. This suggests that inhibition of mNTS outputs enhances seizure resistance in the forebrain and provides a potential mechanism for the seizure protection obtained with vagal stimulation.     

Multiple roles of midline dorsal thalamic nuclei in induction and spread of limbic seizures

PURPOSE: Studies have suggested that the medial dorsal nucleus of the thalamus plays a role in the behavioral expression of limbic seizures, but it is unclear whether this region is a key component for the primary seizure circuitry or a path for seizure spread from one region to another. This study was undertaken to determine the potential role of this region in limbic seizure activity. METHODS: Adult male rats received kindling stimulation either under urethane anesthesia or while awake. Glutamate or its agonists or the GABA antagonist bicuculline or agonist muscimol were infused into the medial dorsal nucleus. In another series, kindling acquisition was compared among three thalamic sites as well as with the amygdala and hippocampus RESULTS: Drugs that enhanced excitatory drive or blocked GABA resulted in significant prolongation of electrographic seizure activity compared to saline infused controls. Enhanced GABA activity resulted in a significant reduction of seizure duration. Infusion of the compounds lateral to the medial dorsal nucleus did not affect seizure duration. In the kindling studies the medial dorsal region is the only thalamic nucleus from which hippocampal seizures can be induced, but with an elevated afterdischarge threshold compared to the two limbic sites. However, the seizures generalized more rapidly from the medial dorsal region. CONCLUSIONS: This study demonstrates that the medial dorsal nucleus and other dorsal midline nuclei have a significant role in the primary seizure circuits of limbic seizures as well as in spread of seizure activity to other regions.     

Vigabatrin: effect on brain GABA levels measured by nuclear magnetic resonance spectroscopy

Vigabatrin is undoubtedly one of the most exciting anti-epilepsy drugs in use today. Many open and controlled clinical trials have confirmed that it is particularly effective in controlling partial epileptic seizures with or without secondary generalization. Vigabatrin acts to increase GABA levels in the presynaptic nerve terminal by inhibiting the activity of GABA-transaminase. There is no direct correlation between the blood or brain concentration of vigabatrin and its clinical effect, so monitoring vigabatrin levels is not predictive of patient response. However, it is possible to relate the activity of vigabatrin to levels of GABA in the brain, measured by nuclear magnetic resonance spectroscopy (NMRS). NMRS studies show that following administration of vigabatrin, brain concentrations of GABA rise to about 2-3 times their baseline values. This'extra' GABA is held within the nerve terminal, and is only released during synaptic transmission. Although there appears to be a clear dose-response relationship up to 3 g/day, it is not well documented if higher doses result in proportionately higher brain GABA levels. This finding seems to support the results of clinical studies suggesting that the optimal dose of vigabatrin may be 3 g/day. There is also some evidence for a correlation between the concentration of GABA in the brain and the clinical outcome. Continuing investigations using NMRS aim to confirm these preliminary findings, and to determine the time course and extent of changes in brain GABA levels after vigabatrin administration.     

Cerebral Transplants for Seizures: Preliminary Results

Several critical brain regions have been identified in which application of gamma-aminobutyric acid (GABA) potentiating agents in small quantities can suppress or prevent generalized and kindled amygdala seizures, i.e., substantia nigra and deep prepiriform cortex. Severity of audiogenic seizures in the genetically epilepsy prone rat (GEPR) is reduced by injection of norepinephrine (NE) into the lateral ventricles and by GABA in inferior colliculus. The present investigation examines the potential for raising epileptic thresholds by increasing local GABAergic or NE inhibitory activity by means of brain transplants of tissue rich in GABA or NE neurons. Two models of epilepsy were used: amygdala-kindled seizures and sound-induced seizures in GEPRs. Transplantation of embryonic cerebellar or cortical tissue to the deep prepiriform area of amygdala kindled rats transiently raised seizure thresholds in three of the nine animals. Transplantation of embryonic cerebellar or cortical tissue to the inferior colliculus or adrenal medulla tissue to lateral ventricles of GEPRs did not appreciably reduce the intensity of audiogenic seizures in these animals.     

电刺激丘脑底核对大鼠杏仁核电点燃的抑制作用

目的 在大鼠杏仁核电点燃癫痫模型中研究丘脑底核高频深部电刺激对点燃的抑制作用及其对Glu、GABA浓度的影响.方法 建立大鼠杏仁核电刺激点燃模型,观察丘脑底核高频深部电刺激对点燃发作的抑制作用,应用高效液相色谱（HPLC）测定大鼠脑组织中Glu、GABA的浓度.结果 对丘脑底核高频深部电刺激（130 Hz,0.2 ms,5 V）能够有效抑制大鼠杏仁核电点燃（P＜0.05）;并可以降低纹状体内Glu浓度,升高纹状体内GABA浓度（P＜0.05）.结论 丘脑底核高频深部脑电刺激能有效抑制大鼠杏仁核电点燃,其作用机制可能与改变Glu、GABA浓度平衡有关.     

Effects of vigabatrin on brain GABA+/Cr signals in focus-distant and focus-near brain regions monitored by 1H-NMR spectroscopy

The new antiepileptic drug vigabatrin (VGB) increases gamma-aminobutyric acid (GABA) in the brain. We compared GABA+/Cr signals measured focus-near and focus-distant and correlated it with the degree of response to VGB. Brain GABA+/Cr signals were measured in 17 epileptic patients in structurally normal appearing tissue by nuclear proton magnetic resonance (1H-NMR) spectroscopy using a special editing sequence for GABA. In 11 patients the measurements were done in brain areas distant to focus and in six near to focus. Full-responders (seizure reduction of >or=50% at the end of the treatment phase) and partial-responders (seizure reduction of >or=50% at the end of the first month of treatment but 相似文献   

GABA changes with vigabatrin in the developing human brain

PURPOSE: Changes in gamma-aminobutyric acid (GABA) physiology are important in determining seizure susceptibility in the developing nervous system. Noninvasive measurements of brain GABA in adults with epilepsy have demonstrated important relations among seizure control, brain GABA levels, and changes in brain GABA with drugs designed to alter GABA metabolism. The purpose of this study was to demonstrate the changes in GABA in the occipital lobes of children with epilepsy after treatment with vigabatrin (VGB). METHODS: Ten proton nuclear magnetic resonance spectroscopic (NMRS) studies were obtained on four subjects with epilepsy. The subjects were between ages 1 and 5 years. Occipital lobe GABA levels were measured before and after treatment with VGB. RESULTS: Brain GABA levels increased significantly in these subjects after VGB treatment (p < 0.05, paired Student's t test). In one subject, brain GABA was decreased in the region of the epileptic focus compared with the homologous region of the opposite hemisphere. A nearly fivefold increase in GABA occurred in the epileptic region after VGB treatment in this subject. CONCLUSIONS: VGB increases brain GABA levels in children with epilepsy. NMRS can be used to monitor the response of brain GABA levels to drugs known to alter GABA physiology and serve as an important tool to understand the role of GABA-mediated inhibition in pediatric epilepsies.