Pathogenic role of glutamate in hyperthermia-induced seizures

Hyperthermia induces seizures in both humans and rodents, but the underlying mechanism remains unknown. The present study showed that hyperthermia, causing rapid increase in body temperature, increases the concentration of glutamate (Glu) released into a cortical perfusate before onset of seizures in rats and that this increase in Glu concentration correlated with a decrease in seizure threshold temperature. These results indicate that increased cortical extracellular Glu induced by hyperthermia contributes to onset of seizures. The same mechanism may be involved in clinical seizures induced by fever in patients with febrile convulsions or epilepsy.     

Effects of oviducal cells on the survival and fertilizing ability of fowl spermatozoa

The activity of the dissociative anaesthetics ketamine and gamma-hydroxybutyrate against seizures induced by mercaptopropionate and pentylenetetrazol have been determined. Ketamine (90 mg/kg) prevented the seizures induced by both convulsants, but gamma-hydroxybutyrate had negligible anticonvulsant activity. Mercaptopropionate (150 mg/kg) produced a rapid fall in whole brain glutamate decarboxylase activity which correlated with the onset of convulsions. Ketamine given prior to the mercaptopropionate prevented the convulsions, but had no effect on the reduction of enzyme activity. It was concluded that although ketamine was an anticonvulsant it did not act by preventing the inhibition of glutamate decarboxylase responsible for mercaptopropionate-induced convulsions.     

Structure and expression of bombyxin E1 gene: a novel family gene that encodes bombyxin-IV, an insect insulin-related neurosecretory peptide

Comparison was made of the ability of two dihydropyridine calcium channel antagonists, nitrendipine and felodipine, to prevent a range of signs of ethanol withdrawal. The increases in handling-induced behavior seen in mice during withdrawal from chronic ethanol treatment were prevented by administration of nitrendipine, 50 mg/kg, but not by, felodipine, 10 mg/kg, a dose that caused a similar displacement of dihydropyridine binding in central nervous system tissue, in vivo and in vitro. A higher dose of felodipine, 20 mg/kg, also had no effects. Nitrendipine, but not felodipine, prevented audiogenic seizures during the withdrawal phase. Similarly, nitrendipine prevented both the decrease in thresholds for N-methyl-DL-aspartate seizures and the increase in thresholds for convulsions due to 4-aminopyridine, which were seen during the withdrawal period, while felodipine did not alter either of these changes. Withdrawal from the ethanol chronic treatment increased the thresholds to seizures produced by intravenous aminophylline; this change was also prevented by nitrendipine. The significance of this increase in thresholds was lost after felodipine administration. In naive mice (not treated with ethanol) the doses of nitrendipine and felodipine used in the withdrawal studies were tested against the effects of convulsant drugs. Both dihydropyridines increased, to similar extents, the thresholds for seizures produced by bicuculline, pentylenetetrazol, and by N-methyl-DL-aspartate. The thresholds for aminophylline were unaltered by either dihydropyridine. In contrast, the thresholds for seizures due to 4-aminopyridine in the naive animals were not changed by felodipine, but were increased by nitrendipine. The results suggest that changes in potassium, as well as calcium, may possibly be involved in some of the stages of the ethanol withdrawal syndrome.     

Risk factors for preeclampsia, abruptio placentae, and adverse neonatal outcomes among women with chronic hypertension. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units

The study comprised 80 children aged 6 to 9 years with a history of febrile convulsions. A neurological examination, an interview to assess psychiatric anomalies, and a series of neuropsychological tests were performed on patients with previous febrile convulsions and on matched healthy controls. Children with non-febrile seizures or CNS infections were excluded. Recurrence of febrile seizures in the study group was 41% (N=33), 18 children (22%) had prolonged febrile convulsions, six (7.5%) patients and two controls showed discrete neurological abnormalities. Behavioral anomalies were exhibited by 22% of the patients and 6% of the healthy children. The neuropsychological test results did not demonstrate significant differences between the children with febrile convulsions and the healthy controls. However, in children with prolonged febrile convulsions, non-verbal intelligence was found to be significantly lower as compared with children with simple febrile seizures and with controls. None of the other parameters tested yielded any differences between patients and controls. Children with multiple recurrences of febrile convulsions performed poorer in all tests when compared with children with only one febrile seizure or with controls. Other factors such as a positive family history of epilepsy, age at onset of febrile convulsions, or duration of the seizure were not found to be of prognostic significance.     

Carbamoylation of brain glutamate receptors by a disulfiram metabolite

S-Methyl-N,N-diethylthiolcarbamate sulfoxide (DETC-MeSO), a metabolite of the drug disulfiram, is a selective carbamoylating agent for sulfhydryl groups. Treatment of glutamate receptors isolated from mouse brain with DETC-MeSO blocks glutamate binding. In vivo, carbamoylated glutathione, administered directly to mice or formed by reaction of DETC-MeSO with glutathione in the blood, also blocks brain glutamate receptors. Carbamoyl groups appear to be delivered to brain glutamate receptors or to liver aldehyde dehydrogenase in vivo by a novel glutathione-mediated mechanism. Seizures caused by the glutamate analogs N-methyl-D-aspartate and methionine sulfoximine, or by hyperbaric oxygen, are prevented by DETC-MeSO, indicating that carbamoylation of glutamate receptors gives an antagonist effect. These observations offer an explanation for some of the previously reported neurological effects of disulfiram, such as its ability to prevent O2-induced seizures. Furthermore, some of the physiology of the disulfiram-ethanol reaction, that could not be accounted for based on the known inhibition of aldehyde dehydrogenase alone, may be explained by disulfiram's effect on glutamate receptors.     

Effects of misoprostol on pentylenetetrazol-induced seizures in mice

The effects of prostaglandin E-analogue misoprostol on the susceptibility to pentilenetetrazol (PTZ)-induced seizures were examined in mice. Misoprostol (200-800 micrograms/kg), given subcutaneously 45 min before the subconvulsive dose of PTZ (30 mg/kg, i.p) provoked dose-dependent clonic-tonic seizures (30 to 100%) and mortality in mice. At 300 g/kg, s.c., misoprostol pretreatment significantly (p < 0.05) lowered the onset latency to first convulsion as well as the latency to mortality induced by a convulsive dose of PTZ (60 mg/kg, i.p.). At this dose misoprostol was found to lower the CD50 and Ld50 values for PTZ by 21% and 36% respectively. The results suggest that prostaglandins are likely to lower the threshold for convulsions.     

Nerve gas-induced seizures: role of acetylcholine in the rapid induction of Fos and glial fibrillary acidic protein in piriform cortex

Soman (pinacolymethylphosphonofluoridate), a highly potent irreversible inhibitor of acetylcholinesterase (AChE), causes seizures and rapidly increases Fos and glial fibrillary acidic protein (GFAP) staining in piriform cortex (PC). This suggests that the inhibition of AChE by soman leads to increased acetylcholine (ACh) and neuronal excitability in PC. The sole source of cholinergic input to PC is from the nucleus of the diagonal band (NDB). To investigate the role of ACh in soman-induced seizures, we lesioned cholinergic neurons in NDB unilaterally with 192-IgG-saporin. By 10 d, saporin eliminated staining for choline acetyltransferase (ChAT), the synthetic enzyme for ACh, in NDB ipsilateral to the lesion. Staining for AChE, the degradative enzyme for ACh, was eliminated in PC ipsilateral to the lesioned NDB. By 45-60 min after soman, increased Fos and GFAP staining in PC was evident only ipsilateral to the unlesioned NDB. By 90-120 min after soman, Fos and GFAP staining increased bilaterally in PC. In a second experiment, electrical stimulation electrodes were implanted unilaterally in the NDB to activate focally the projections to PC in unanesthetized rats. Within 5 min of NDB stimulation, there were clear behavioral and EEG signs of convulsions. After 45-60 min of NDB stimulation, there was increased Fos and GFAP staining in layer II of PC ipsilateral to the stimulation site. Pretreatment with the selective muscarinic receptor antagonist scopolamine blocked the convulsions and prevented increased Fos and GFAP staining in PC. These results suggest that ACh release in PC triggers the initiation of seizures and gliosis after soman administration, predominantly by the activation of muscarinic receptors.     

Effects of neonatal status epilepticus on rat brain development

A single, 2-hour episode of status epilepticus induced by flurothyl (1,500 mul) in 4-day-old rats irreversibly curtailed brain weight and brain DNA. Status epilepticus inhibited DNA synthesis but did not increase DNA breakdown and produced no histologic lesions. Rats with status epilepticus showed delayed behavioral milestones and reduced seizure thresholds several weeks after status. After milder convulsions (flurothyl 750 mul, bicuculline), brain DNA was curtailed at 7 days but returned to normal at 30 days. These results suggest that, in the immature brain, epileptic seizures too mild to cause cell necrosis can inhibit DNA synthesis and permanently curtail brain DNA content. This may account for the great vulnerability of the immature brain to epileptic seizures.     

Differential expression of apoptosis receptors on diffuse and intestinal type stomach carcinoma

1. A transient two fold increase in the cyclic GMP content was observed in rat freshly isolated glomeruli 6 to 9 h after a single subcutaneous injection of 20 mg kg-1 cyclosporine A (CsA) in conscious animals. 2.In vitro stimulation with endothelin 3 (ET-3) of isolated glomeruli obtained from CsA-untreated rats resulted in a dose-dependent increase in cyclic GMP content. The increase observed with 10 nM ET-3 was similar to that observed in glomeruli isolated 9 h after in vivo CsA administration. 3. The rise in glomerular cyclic GMP content after in vivo CsA injection was prevented by in vivo treatment with L-NAME (10 mg kg-1) or by in vitro calcium deprivation of the incubation medium. 4. The stimulating effects of CsA on glomerular cyclic GMP content were inhibited by in vivo administration of the ETB receptor antagonist BQ-788 (2 mg kg-1) but not by the ETA receptor antagonist BQ-123 (2 mg kg-1). 5. The maximum increase in glomerular cyclic GMP content induced in vitro by acetylcholine (100 microM) and by ET-3 (100 nM) was slightly lower (approximately by 20-25%; P < 0.05) in glomeruli from CsA-treated rats than in glomeruli from untreated rats. In contrast, the maximum increase achieved with 1 microM sodium nitroprusside was similar in both groups. 6. A single subcutaneous injection of CsA did not significantly alter the glomerular mRNA expression of constitutive endothelial NO synthase (eNOS), as evaluated by RT-PCR, whereas the mRNA expression of the inducible NO synthase (iNOS), which follows pretreatment with lipopolysaccharide, was prevented. 7. These results indicate that in vivo administration of a single dose of cyclosporine A transiently increases the cyclic GMP content of freshly isolated glomeruli, and that activation of ETB receptors and stimulation of the NO pathway are involved in this process. Furthermore, a single administration of CsA does not impair eNOS mRNA expression and only slightly reduces NO-dependent glomerular cyclic GMP production.     

Primary culture and expression of cytokine mRNAs by lipopolysaccharide in bovine Kupffer cells

To clarify the mechanisms of the antiepileptic activity of phenytoin (PHI), the effects of PHT on extracellular and total levels of monoamines (dopamine and serotonin), in rat striatum and hippocampus were studied. The plasma concentrations of PHT associated with therapeutic activity did not affect striatal and hippocampal extracellular levels of monoamines, whereas supratherapeutic concentrations of PHT decreased striatal and hippocampal extracellular levels of monoamines, in a concentration dependent manner. Toxic concentrations of PHT produced generalized seizures 'paradoxical intoxication' and an initial drastic decrease in striatal and hippocampal extracellular levels of monoamines before seizure onset, whereas the extracellular monoamines levels increased after seizures. In addition, the therapeutic concentrations of PHT did not affect monoamine turnover, whereas supratherapeutic concentrations of PHT inhibited monoamine turnover. These results suggest that monoaminergic transmission may not be involved in the antiepileptic mechanism of action of PHT, and that dysfunction of monoaminergic transmission can produce generalized tonic-clonic convulsions. Thus, the present study suggests that 'Paradoxical Intoxication' induced by toxic concentrations of PHT, at least partially, can be mediated by hypo-monoaminergic function in the brain.     

Convulsions with meningiomas: incidence and significance

In a study of a consecutive series of 127 surgically treated meningiomas, it was found that 29% of the patients had reported with convulsions as their initial symptom. In this group, surgical excision of the meningioma stopped the convulsions in about half of the patients, but the others continued to have seizures after their operations. Among those patients with meningiomas who did not have preoperative convulsions, about one-sixth (15 patients) developed postoperative seizures. Patients in both groups required prolonged anticonvulsant medication. Factors predisposing to the occurrence of postoperative seizures were the site of the tumor, faulty surgical technique, and a preoperative history of seizures.     

Anatomical localization and time course of Fos expression following soman-induced seizures

Soman (pinacolymethylphosphonofluoridate), a highly potent, irreversible inhibitor of cholinesterase, causes intense convulsions, neuropathology and, ultimately, death. There is evidence that certain brain structures are selectively vulnerable to the pathological consequences of soman-induced seizures. A working hypothesis is that central nervous system (CNS) structures with the earliest and most severe signs of neuropathology may be key sites for the initiation of the seizures. Fos, the immediate-early gene product, increases rapidly in several animal seizure models. Thus, we reasoned that the earliest brain regions to express Fos might be involved in the initiation and maintenance of soman-induced convulsions. To assess this, rats were injected with a single, convulsive dose of soman (77.7 micrograms/kg, i.m.). The animals were euthanized and processed for immunocytochemical analysis at several time points. Robust Fos expression was seen in layer II of the piriform cortex and the noradrenergic nucleus locus coeruleus within 30-45 minutes. One hour following soman injection, staining was more intense in the piriform cortex layer II and in the locus coeruleus. In addition, Fos was evident in the piriform cortex layer III, the entorhinal cortex, the endopiriform nucleus, the olfactory tubercle, the anterior olfactory nucleus and the main olfactory bulb. By 2 hours, Fos staining was present throughout the cerebral cortex, thalamus, caudate-putamen and the hippocampus. At 8 hours and beyond, Fos expression returned to control levels throughout the CNS except for the piriform cortex and the locus coeruleus which still had robust labeling. By 24 hours, neuropathology was evident throughout the rostral-caudal extent of layer II of the piriform cortex. The rapid induction of Fos in the piriform cortex and the locus coeruleus, taken together with previous anatomical, eletrophysiological and neurochemical studies, suggests that prolonged, excessive exposure to synaptically released acetylcholine and norepinephrine triggers the production of soman-induced seizures initially in the piriform cortex and subsequently in other cortical and subcortical structures.     

NMDA receptor complex blockade by oral administration of magnesium: comparison with MK-801

The ion channel of the N-methyl-D-aspartate (NMDA) receptor complex is subject to a voltage-dependent regulation by Mg2+ cations. Under physiological conditions, this channel is supposed to be blocked by a high concentration of magnesium in extracellular fluids. A single dose of magnesium organic salts (i.e., aspartate, pyroglutamate, and lactate) given orally to normal mice rapidly increases the plasma Mg2+ level and reveals a significant dose-dependent antagonist effect of magnesium on the latency of NMDA-induced convulsions; this effect is similar to that seen after administration of the dizocilpine (MK-801) channel blocker. An anticonvulsant effect of Mg2+ treatment is also observed with strychnine-induced convulsions but not with bicuculline-, picrotoxin-, or pentylenetetrazol-induced convulsions. In the forced swimming test, Mg2+ salts reduce the immobility time in a way similar to imipramine and thus resemble the antidepressant-like activity of MK-801. This activity is masked at high doses of magnesium by a myorelaxant effect that is comparable to MK-801-induced ataxia. Potentiation of yohimbine fatal toxicity is another test commonly used to evaluate putative antidepressant drugs. Administration of Mg2+ salts, like administration of imipramine strongly potentiates yohimbine lethality in contrast to MK-801, which is only poorly active in this test. Neither Mg2+ nor MK-801 treatment can prevent reserpine-induced hypothermia. These data demonstrate that oral administration of magnesium to normal animals can antagonize NMDA-mediated responses and lead to antidepressant-like effects that are comparable to those of MK-801. This important regulatory role of Mg2+ in the central nervous system needs further investigation to evaluate the potential therapeutic advantages of magnesium supplementation in psychiatric disorders.     

Roles of anoxia and noise-induced hearing loss in the postictal refractory period for audiogenic seizures in mice.

Three experiments with 188 Ss demonstrated a postictal refractory period for audiogenic seizures in DBA/2J mice, which was not related to hearing loss but apparently was related to anoxia. Exp I controlled for the effects of noise exposure upon hearing sensitivity and demonstrated reduced susceptibility to subsequent audiogenic seizures for at least 1 hr after initial clonic-tonic convulsions. The postictal refractory period resulted from the occurrence of seizures per se, not from noise exposure alone. Exp II demonstrated deficiencies of sensorimotor functions that accompanied reduced postictal seizure susceptibility. The 2 phenomena had similar time courses of recovery, which suggested a common mechanism, probably anoxia, associated with the initial convulsions. In support of this view, Exp III shows that recovery from both phenomena was expedited by allowing Ss to breathe increased O-sub-2. The role of anoxia in fatal convulsions is suggested by the finding that Ss experiencing clonic-tonic convulsions in a high-O-sub-2 environment survived without exception. In contrast, seizures of air-breathing controls were almost always fatal. The data indicate that the postictal reduced susceptibility to audiogenic seizures was closely related to metabolic depletion (in particular, anoxia). The pattern of recovery of susceptibility further suggests that the effects of anoxia impair the spread of seizure activity through the CNS, although the initiation of seizures is also affected for a short time. (44 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Development of a novel rat mutant with spontaneous limbic-like seizures

A new epileptic rat mutant with spontaneous seizures was developed by successive mating and selection from an inherited cataract rat. The procedures for developing the mutant and the symptomatology, electroencephalographic correlates, and neuropathology of the mutant are reported. It is possible that this rat stain will provide a useful animal model for human temporal lobe epilepsy. The seizures of the rat usually begin with face and head myoclonus, followed by rearing, and generalized clonic and tonic convulsions, all of which are symptomatologically the same as limbic seizures. Electrographic recording during generalized convulsive seizures demonstrated that sustained spike discharges emerged at the hippocampus and then propagated to the neocortex. Seizures occurred spontaneously without any artificial stimuli. Furthermore, external stimuli such as auditory, flashing light, or vestibular stimulations could not elicit epileptic attacks. Almost all of the male animals had generalized convulsions, mostly from 5 months after birth, and the frequency of the seizures increased with aging. Generalized convulsions developed in approximately 20% of the female rats. Microdysgenesis, such as abnormal neuronal clustering, neuronal disarrangement, or interruption of pyramidal neurons in the hippocampal formation, was found in the young rats that had not yet had generalized seizures. This microdysgenesis, which is though to be genetically programmed, was very interesting from the aspect of the relationship between structural abnormalities and epileptogenesis in this mutant. In addition to microdysgenesis, there was sprouting of mossy fibers into the inner molecular layer of the dentate gyrus in those adult rats that had repeated generalized convulsions. An increase of glial-fibrillary-acidic-protein-positive astrocytes with thickened and numerous processes, ie, astrogliosis, was also found in the cerebral cortex, amygdala region, and hippocampus of these adult animals. Judging from the characteristics of the symptomatology, electroencephalographic correlates, and neuropathology, this epileptic mutant can be expected to be a useful animal model for studying human temporal lobe epilepsy.     

Alterations of lidocaine and pentylenetetrazol-induced convulsions by manipulation of brain monoamines

The thresholds for pentylenetetrazol and lidocaine-induced clonic convulsions were significantly influenced by manipulation of brain biogenic amines. Pretreatment with inhibitors of monoamine synthesis, alpha-methyl-p-tyrosine and p-chlorophenylalanine, caused significant decreases in brain monoamine contents and pentylenetetrazol seizure threshold, while the threshold for lidocaine-induced convulsions was significantly increased by either treatment. Moreover, the inhibitor of dopamine-beta-hydroxylase, disulfiram, caused significant decrease in brain noradrenaline (NA) and significant increase in brain dopamine (DA) contents. The threshold for pentylenetetrazol-induced convulsions was decreased by treatment with disulfiram, while that of lidocaine was increased by the same treatment. Furthermore, treatment with L-dihydroxyphenylalanine (L-DOPA) caused significant increase in brain DA contents, while 5-hydroxytryptophan (5-HTP) treatment caused significant increase in brain 5-hydroxytryptamine (5-HT) contents, but the thresholds for lidocaine and pentylenetetrazol-induced convulsions were not influenced by either treatment. These results may suggest that the brain monoaminergic systems, different from their ability to inhibit control of pentylenetetrazol seizures, act to potentiate lidocaine-induced convulsions.     

Low sodium levels in serum are associated with subsequent febrile seizures

Fever plays an important role in causing disturbances in fluid and electrolyte balance. Hyponatraemia has been thought to enhance the susceptibility to seizures associated with febrile illnesses in childhood. We have studied serum electrolyte levels in children with simple and complicated febrile convulsions. Sodium levels were lower in those children with complicated convulsions in comparison with those having simple convulsions (136.07 +/- 3.06 mmoll-1, mean +/- SD, n = 42, and 137.62 +/- 2.63 mmoll-1, n = 71, respectively; p < 0.01, Student's t-test). The sodium concentrations were lowest in children with repeated seizures (134.20 +/- 2.30 mmoll-1, n = 15) compared with children having simple (p < 0.01, ANOVA, Duncan's test) or other complicated types of febrile convulsions: focal seizures (137.08 +/- 3.82 mmoll-1, n = 12, p < 0.01), seizures lasting longer than 15 minutes (138.00 +/- 2.45 mmoll-1, n = 5, p < 0.05) and children over 5 years (136.70 +/- 2.06 mmoll-1, n = 10, p < 0.05). Serum potassium levels showed no statistically significant differences between the patient groups. Our results show that hyponatraemia may increase the risk for multiple convulsions during the same febrile illness.     

Alterations in GABAA receptor alpha 1 and alpha 4 subunit mRNA levels in thalamic relay nuclei following absence-like seizures in rats

Modification of GABAA receptor mRNA levels by seizure activity can regulate general neuronal excitability. The possibility of absence seizure-induced alteration in GABAA receptor alpha 1, alpha 4, beta 2, and gamma 2 subunit gene expression in thalamic relay nuclei was studied in a rat model of absence seizures induced by gamma-hydroxybutyric acid (GHB). We observed a marked increase in alpha 1 mRNA and a corresponding decrease in alpha 4 mRNA in thalamic relay nuclei 2-4 h after the onset of GHB-induced absence seizures (when the seizures were terminating). These changes were selective to these alpha isoforms as neither beta 2 nor gamma 2 mRNA changed following seizures and occurred only in thalamic relay nuclei but not in hippocampus, a structure from which absence seizures do not evolve. The alterations in alpha 1 and alpha 4 mRNA persisted until about 12 h, and by 24 h after the seizure-onset the mRNA levels normalized. Blocking GHB-seizures produced no change in the levels of alpha 1 and alpha 4 mRNA in thalamic relay nuclei, suggesting that seizures themselves were responsible for mRNA alterations. In order to determine if absence seizure-induced changes in alpha 1 and alpha 4 mRNA had any physiological significance, GHB was readministered in rats 6 and 24 h after the onset of seizures. The total duration of GHB-seizures was found to be significantly decreased when GHB was readministered at 6 h but not 24 h after the seizure-onset. These results suggest that absence seizures regulate GABAA receptor alpha 1 and alpha 4 gene expression in thalamic relay nuclei as a compensatory mechanism by which absence seizures are terminated.     

Pancreatic cancer cells selectively stimulate islet beta cells to secrete amylin

The goal of the studies described was to evaluate the role of NMDA receptor-mediated glutamate excitotoxicity in the pathogenesis of selective neuronal loss due to thiamine deficiency. Administration of the central thiamine antagonist pyrithiamine to adult male rats resulted in a sequence of neurological symptoms including ataxia and loss of righting reflex followed by convulsions. Prior to the onset of convulsions, neuropathologic evaluation revealed significant neuronal loss in the ventral posterior medial thalamic nucleus. However, in vivo cerebral microdialysis at preconvulsive stages did not demonstrate significant increases of extracellular glutamate in this region and pretreatment with the NMDA receptor antagonist MK801 (1 mg/ kg/12 h, i.p.) did not afford significant neuroprotection. Following the onset of convulsions, microdialysate glutamate concentrations were increased fivefold (P > 0.05) and MK801 treatment resulted in significant attenuation of neuronal loss in some thalamic nuclei. A comparable degree of neuroprotection was afforded by pretreatment with an anticonvulsant dose of diazepam (10 mg/kg/12 h, i.p.) a compound whose action is not NMDA receptor mediated. These findings suggest that NMDA receptor-mediated excitotoxicity is not responsible for early selective neuronal loss in this model of thiamine deficiency encephalopathy and that the neuroprotective effect of MK801 at later stages are at least in part a consequence of its anticonvulsant properties.     

Effects of physostigmine and electrical stimulation on the acetylcholine content of the guinea-pig ileum

Incubation with physostigmine (7.7 muM) caused an approximately 2 fold increase in the acetylcholine content of the myenteric plexus--longitudinal muscle preparation of the guinea-pig ileum. This effect was due mainly to an increase in 'free' acetylcholine, which was directly assayable in either the homogenate after removal of cell debris or the supernatant fraction (100,000 g for 60 min) after subcellular fractionation. Acetylcholine output during stimulation at 0.017, 0.1 or 1 Hz was maintained for 60 min at a rate 2--4 times greater than the non-stimulated output; there was no change in content. At 10 HZ, output was high at the start of stimulation and then decreased continuously; there was a proportionate loss of mainly 'free' acetylcholine from the tissue. Mn2+, hexamethonium, morphine and noradrenaline, which depressed acetylcholine output during stimulation at 0.1 HZ, had no effect on the acetylcholine content nor did they affect the increase in acetylcholine content during incubation with physostigmine.