cyclic-gmp and Epilepsy

Topics: Animals; Biogenic Amines; Catecholamines; Cyclic AMP; Cyclic GMP; Epilepsy; gamma-Aminobutyric Acid; Humans; Mice; Neurotransmitter Agents; Seizures

Topics: Acidosis; Animals; Biological Transport, Active; Brain Ischemia; Calcium; Cell Membrane; Cerebrovascular Disorders; Cyclic GMP; Electrophysiology; Energy Metabolism; Epilepsy; Fatty Acids, Nonesterified; Free Radicals; Glutathione; Hypoglycemia; Hypoxia, Brain; Ions; Lactates; Lactic Acid; Microscopy, Electron; Mitochondria; Neuroglia; Neurons; Phospholipids; Time Factors

The imbalance between excitation and inhibition is a defining feature of epilepsy. GluA1 is an AMPA receptor subunit that can strengthen excitatory synaptic transmission when upregulated in the postsynaptic membrane, which has been implicated in the pathogenesis of epilepsy. cGKII, a cGMP-dependent protein kinase, regulates the GluA1 levels at the plasma membrane.. To explore the role of cGKII in epilepsy, we investigated the expression of cGKII in patients with temporal lobe epilepsy (TLE) and in a pilocarpine-induced rat model and then performed behavioral, histological, and electrophysiological analyses by applying either a cGKII agonist or inhibitor in the hippocampus of the animal model.. cGKII expression was upregulated in the epileptogenic brain tissues of both humans and rats. Pharmacological activation or inhibition of cGKII induced changes in epileptic behaviors in vivo and epileptic discharges in vitro. Further studies indicated that cGKII activation disrupted the balance of excitation and inhibition due to strengthened AMPAR-mediated excitatory synaptic transmission. Moreover, cGKII regulated epileptic seizures by phosphorylating GluA1 at Ser845 to modulate the expression and function of GluA1 in the postsynaptic membrane.. These results suggest that cGKII plays a key role in seizure activity and could be a potential therapeutic target for epilepsy.

Topics: 4-Aminopyridine; Adolescent; Adult; Animals; Brain; Carbazoles; Child; Cyclic GMP; Cyclic GMP-Dependent Protein Kinase Type II; Disease Models, Animal; Epilepsy; Evoked Potentials; Female; Hippocampus; Humans; Male; Pilocarpine; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Synaptic Transmission; Thionucleotides; Up-Regulation; Young Adult

Mutation of serine 1179 to aspartate on the endothelial NO synthase (eNOS) increases NO production in the absence of stimulation by agonists. The present study was designed to determine the effect of recombinant S1179DeNOS gene expression on the vasomotor function of human pial arteries.. Pial arteries were isolated from 28 patients undergoing temporal lobectomy for intractable seizures. Adenoviral vectors (10(10) pfu/mL) encoding beta-galactosidase (AdCMVLacZ) or S1179DeNOS (AdCMVS1179DeNOS) were used for ex vivo gene transfer, and vasomotor function was evaluated in control and transduced arteries.. Contractions to cumulative additions of U46619 were not affected by expression of LacZ or S1179DeNOS. Endothelium-dependent relaxations to bradykinin or endothelium-independent relaxations to Diethylaminodiazen-1-ium-1,2-dioate were significantly reduced in arteries expressing S1179DeNOS. A superoxide dismutase mimetic, manganese (III) tetrakis (4-benzoic acid) porphyrin chloride, failed to improve the reduced relaxations to bradykinin. The levels of cGMP were significantly elevated in arteries expressing S1179DeNOS.. Our results support the concept that high local production of NO in pial arterial wall causes adaptive reduction of vasodilator reactivity to NO.

Topics: Adult; Aspartic Acid; Cerebral Arteries; Cyclic GMP; Endothelium, Vascular; Epilepsy; Female; Gene Expression; Humans; Male; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Point Mutation; Recombinant Proteins; Serine; Vasodilation

In the hippocampus of freely-moving rats, basal extracellular levels of cGMP are inhibited by L-NARG or ODQ whereas they are increased by NO donors or phosphodiesterase inhibitors. Activation of NMDA receptors also augments cGMP dialysate levels in a MK-801 and L-NARG sensitive manner, an effect dramatically diminished during ageing. Experiments with AMPA, AMPA receptor antagonists and cyclothiazide revealed complex relationships with GABAergic circuits that potently control the NO/cGMP pathway. Furthermore, the activity of this neurochemical cascade is also modulated by hippocampal nicotinic receptors via enhancement of endogenous glutamate release and stimulation of NMDA receptors. From a behavioural point of view, increased hippocampal excitation leads to the appearance of epileptic-like manifestations that, however, seem unrelated to the increase of NO/cGMP formation.

Topics: Aging; Animals; Cyclic GMP; Epilepsy; gamma-Aminobutyric Acid; Glutamic Acid; Hippocampus; Nitric Oxide; Receptors, N-Methyl-D-Aspartate; Receptors, Nicotinic; Signal Transduction

Intrahippocampal perfusion of bicuculline (50 microM) in Mg2+-free medium caused elevation of extracellular cGMP and epileptic-like behaviour. Both effects were partially prevented by blocking NMDA receptors with MK-801 or Mg2+ ions. Similarly, the GABA(B) receptor antagonists CGP52432 (0.1-30 microM) and CGP35348 (0.3-1 mM) evoked increases of extracellular cGMP. CGP52432 also elicited behavioural responses ranging from wet dog shakes to convulsions. MK-801 or Mg2+ ions reduced the effects of CGP52432. Local application of muscimol (100-300 microM) or (-)baclofen (300 microM) caused inhibition of extracellular cGMP. Administration of the AMPA/kainate receptor antagonist NBQX (100 microM) caused cGMP elevation which was almost abolished by co-perfusion of muscimol and (-)baclofen. In the presence of physiological Mg2+, perfusion of AMPA (30 microM) failed to affect cGMP levels, although rats displayed wet dog shakes episodes. When AMPA was co-perfused with low concentrations of bicuculline or CGP52432, cGMP elevations were observed in 60% of the rats. Addition of both antagonists to AMPA resulted in 85% of rats displaying a cGMP response. To conclude: (a) extracellular hippocampal cGMP is controlled by inhibitory GABA(A) and GABA(B) receptors tonically activated through GABAergic interneurons receiving AMPA/kainate-mediated glutamatergic inputs; (b) the GABAergic receptors are not endogenously saturated and can be further stimulated by exogenous agonists; (c) blockade of the GABA-mediated inhibition causes increase of cGMP and epileptic-like behaviour, due largely to endogenous activation of NMDA receptors; (d) reproducible cGMP responses to AMPA can be observed when the inhibitory GABAergic inputs to the NO/guanylyl cyclase system are blocked, confirming the previously proposed existence of AMPA/kainate receptors able to increase the nucleotide synthesis.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Behavior, Animal; Cyclic GMP; Epilepsy; Excitatory Amino Acid Agonists; gamma-Aminobutyric Acid; Hippocampus; Microdialysis; Nitric Oxide; Quinoxalines; Rats; Receptors, AMPA; Receptors, GABA-A; Receptors, GABA-B; Receptors, Glutamate; Receptors, Kainic Acid; Receptors, N-Methyl-D-Aspartate

Topics: Amino Acid Oxidoreductases; Animals; Arginine; Calcium; Cells, Cultured; Cerebellar Cortex; Cyclic GMP; Electron Spin Resonance Spectroscopy; Enzyme Activation; Epilepsy; Feedback; Free Radicals; Glutamic Acid; Guanylate Cyclase; Kindling, Neurologic; Mice; Molsidomine; N-Methylaspartate; Nerve Tissue Proteins; Neurons; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Rats; Receptors, N-Methyl-D-Aspartate

In response to NMDA receptor activation, hippocampal, striatal and cerebellar neurons synthesize nitric oxide (NO), which in turn elevates cGMP levels via guanylate cyclase. NO is increasingly being considered as a transsynaptic retrograde messenger, involved in neuronal plasticity. The effect of an inhibitor of NO synthase, L-NG-nitroarginine (NOArg), was studied on amygdala kindling and on kindled seizures in rats. NOArg increased kindling rate, particularly in its initial period, but did not modify seizure severity in previously kindled rats, although we have no definitive explanation for this effect. However, an enhanced post-synaptic excitability could be attributed to the blockade of the negative feed-back exerted by NO on the NMDA receptor.

Topics: Amino Acid Oxidoreductases; Amygdala; Animals; Arginine; Cyclic GMP; Epilepsy; Kindling, Neurologic; Male; Neuronal Plasticity; Nitric Oxide Synthase; Nitroarginine; Rats; Rats, Sprague-Dawley

The high seizure susceptibility in epileptic fowl is due to an autosomal recessive mutation. Cyclic AMP and cyclic GMP concentrations were determined in brains from two day old epileptic chicks (homozygotes) during an inter-ictal period as well as during and following a seizure evoked by stroboscopic stimulation. The data were compared to values obtained from non-epileptic carrier chicks (heterozygotes) sacrificed in an unstimulated state or subjected to the seizure evoking stimulus. During the inter-ictal state in epileptics no abnormalities were found in cyclic nucleotide concentrations indicating that the high seizure susceptibility is not related to abnormalities of these nucleotides. Although seizure activity in epileptics was associated with reduced cyclic AMP in the optic lobes this also occurred in carrier chicks subjected to the seizure evoking stimulus. The only significant changes in cyclic GMP levels, occurring as a result of seizures in epileptics, were an increase in cyclic GMP in the cerebral hemispheres during the seizure and a decrease in the optic lobes during the postictal period.

Topics: Animals; Brain; Chickens; Cyclic AMP; Cyclic GMP; Disease Models, Animal; Epilepsy; Heterozygote; Homozygote; Seizures; Tissue Distribution

Topics: Animals; Brain; Cyclic AMP; Cyclic GMP; Epilepsy; Guinea Pigs; In Vitro Techniques; Nucleotides, Cyclic; Seizures

Topics: Animals; Anticonvulsants; Brain Chemistry; Cyclic AMP; Cyclic GMP; Epilepsy; Humans; Seizures

Topics: Animals; Brain; Cyclic AMP; Cyclic GMP; Epilepsy; Humans; Kinetics; Seizures

Topics: Adolescent; Adult; Aged; Cyclic AMP; Cyclic GMP; Epilepsy; Female; Glycols; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Male; Methoxyhydroxyphenylglycol; Middle Aged; Phenylacetates

Evidence exists that cyclic nucleotides play an important role in the stabilisation of developing synapses during the early postnatal period, and later on participate in the generation of the slow excitatory and inhibitory postsynaptic potentials. It is postulated that enterotoxins of Escherichia coli, due to their long-lasting and specific action on cyclic nucleotide-dependent processes, provide a unique mechanism for selective impairment of synaptogenesis in the abscence of cell loss. Therefore it seems possible that early enteritis, when caused by certain pathogenic strains of Escherichia coli, might be an aetiological factor in the genesis of idiopathic epilepsy.

Topics: Cyclic AMP; Cyclic GMP; Enterotoxins; Epilepsy; Escherichia coli; Escherichia coli Infections; Membrane Potentials; Synapses

Transplants of rat hippocampus into the anterior chamber of the eye of a host animal were used to assess the effects of cholinergic and adrenergic neuronal inputs on the generation and duration of seizure activity. Cholinomimetics initiated both seizures and hypersynchronous neuronal activity in the transplants. Cyclic guanosine monophosphate (GMP) derivatives and isobutyl methylxanthine elicited similar changes. Reflex activation of the cholinergic parasympathetic input to the iris and transplant by illumination of the ipsilateral retina also induced seizures or increased the rate of penicillin-induced interictal spike discharge. Application of beta-adrenergic agonists inhibited interictal spikes and paroxysmal depolarizing shifts induced by penicillin. Fluorescence histochemical studies showed that host sympathetic adrenergic fibers derived from the ground plexus of the iris invaded the transplant to form fine varicose nerve terminals. Activation of these adrenergic afferents to the transplant diminished both the amplitude and frequency of penicillin-induced epileptiform activity. Epileptiform activity in hippocampal occular transplants is strongly modulated by cholinergic and adrenergic neuronal inputs, with the former exerting a facilatory influence and the latter, an inhibitory effect.

Topics: Adrenergic Fibers; Animals; Anterior Chamber; Cholinergic Fibers; Cyclic GMP; Epilepsy; Female; Hippocampus; Neural Pathways; Photic Stimulation; Rats; Retina; Transplantation, Homologous

Cyclic guanosine monophosphate (cGMP) levels have been measured in the cerebrospinal fluid of patients with various neurological diseases. The subjects with epilepsy or cerebrovascular diseases do not show any difference from the controls. Moreover, in the CSF of patients having cerebral tumors the levels of cGMP are markedly increased. This change is in line with previous in vitro studies on the increase of cGMP during cell growth and cell proliferation showing that the role of the nucleotide is important for the control of the life cycle of the cell.

Topics: Adolescent; Adult; Aged; Alzheimer Disease; Brain Neoplasms; Cerebrovascular Disorders; Cyclic GMP; Epilepsy; Female; Humans; Hydrocephalus, Normal Pressure; Male; Middle Aged; Multiple Sclerosis

Lumbar cerebrospinal fluid (CSF) gamma-aminobutyric acid (GABA) levels determined by fluorometric assay in four seizure patients were found to be significantly lower during bilateral, continuous cerebellar stimulation than those determined after a 7-day period without stimulation. The CSF GABA concentrations during chronic unilateral, alternating cerebellar stimulation were reduced in three seizure patients but unchanged in a fourth patient. The percentage decrease in CSF GABA appeared to be independent of cerebellar stimulation frequency. These findings suggest that GABA-mediated neuronal transmission is depressed during cerebellar surface stimulation and this evoked reduction in GABA activity may compromise the efficacy of cerebellar stimulation in the treatment of epilepsy. Lumbar CSF cyclic guanosine monophosphate levels determined by radioimmunoassay were not significantly altered by either mode or frequency of cerebellar stimulation.

Topics: Aminobutyrates; Cerebellar Cortex; Cyclic GMP; Electric Stimulation Therapy; Epilepsy; Epilepsy, Tonic-Clonic; gamma-Aminobutyric Acid; Humans