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Biomedical subjects

N Y Walton

Publications and source records attributed to N Y Walton.

At least 19 recordsLinked to original sources
PubMed1999

Changes in electrocortical power and coherence in response to the selective cholinergic immunotoxin 192 IgG-saporin.

Changes in brain electrical activity in response to cholinergic agonists, antagonists, or excitotoxic lesions of the basal forebrain may not be reflective entirely of changes in cholinergic tone, in so far as these interventions also involve noncholinergic neurons. We examined electrocortical activity in rats following bilateral intracerebroventricular administration of 192 IgG-saporin (1.8 microg/ventricle), a selective cholinergic immunotoxin directed to the low-affinity nerve growth factor receptor p75. The immunotoxin resulted in extensive loss of choline acetyl transferase (ChAT) activity in neocortex (80%-84%) and hippocampus (93%), with relative sparing of entorhinal-piriform cortex (42%) and amygdala (28%). Electrocortical activity demonstrated modest increases in 1- to 4-Hz power, decreases in 20- to 44-Hz power, and decreases in 4- to 8-Hz intra- and interhemispheric coherence. Rhythmic slow activity (RSA) occurred robustly in toxin-treated animals during voluntary movement and in response to physostigmine, with no significant differences seen in power and peak frequency in comparison with controls. Physostigmine significantly increased intrahemispheric coherence in lesioned and intact animals, with minor increases seen in interhemispheric coherence. Our study suggests that: (1) electrocortical changes in response to selective cholinergic deafferentation are more modest than those previously reported following excitotoxic lesions; (2) changes in cholinergic tone affect primarily brain electrical transmission within, in contrast to between hemispheres; and (3) a substantial cholinergic reserve remains following administration of 192 IgG-saporin, despite dramatic losses of ChAT in cortex and hippocampus. Persistence of a cholinergically modulated RSA suggests that such activity may be mediated through cholinergic neurons which, because they lack the p75 receptor, remain unaffected by the immunotoxin.

Analysis of Variance↗
PubMed1999

Phenytoin penetration into brain after administration of phenytoin or fosphenytoin.

PURPOSE: This study was designed to measure the brain penetration of phenytoin (PHT) after intravenous (i.v.) administration of either standard PHT or fosphenytoin (FPHT), a PHT prodrug. The study was formulated to answer the question whether the time required for FPHT to be converted to PHT in the bloodstream would delay the accumulation of PHT in brain. METHODS: Four rats were sampled at various times after intravenous infusion of 30 mg/kg PHT i.v. or 30 mg/kg PHT equivalents of FPHT i.v. PHT was measured in serum, protein-free ultrafiltrate, and in brain, by using high-performance liquid chromatography. RESULTS: Although the initial PHT-free fraction was significantly higher for FPHT-treated rats than it was for PHT-treated rats, brain PHT levels were significantly reduced after infusion of FPHT. CONCLUSIONS: When FPHT is used for treatment of generalized status epilepticus, it should be anticipated that lower initial brain PHT levels will be achieved than are typically found with standard PHT.

Animals↗
PubMed1998

A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group.

BACKGROUND AND METHODS: Although generalized convulsive status epilepticus is a life-threatening emergency, the best initial drug treatment is uncertain. We conducted a five-year randomized, double-blind, multicenter trial of four intravenous regimens: diazepam (0.15 mg per kilogram of body weight) followed by phenytoin (18 mg per kilogram), lorazepam (0.1 mg per kilogram), phenobarbital (15 mg per kilogram), and phenytoin (18 mg per kilogram). Patients were classified as having either overt generalized status epilepticus (defined as easily visible generalized convulsions) or subtle status epilepticus (indicated by coma and ictal discharges on the electroencephalogram, with or without subtle convulsive movements such as rhythmic muscle twitches or tonic eye deviation). Treatment was considered successful when all motor and electroencephalographic seizure activity ceased within 20 minutes after the beginning of the drug infusion and there was no return of seizure activity during the next 40 minutes. Analyses were performed with data on only the 518 patients with verified generalized convulsive status epilepticus as well as with data on all 570 patients who were enrolled. RESULTS: Three hundred eighty-four patients had a verified diagnosis of overt generalized convulsive status epilepticus. In this group, lorazepam was successful in 64.9 percent of those assigned to receive it, phenobarbital in 58.2 percent, diazepam plus phenytoin in 55.8 percent, and phenytoin in 43.6 percent (P=0.02 for the overall comparison among the four groups). Lorazepam was significantly superior to phenytoin in a pairwise comparison (P=0.002). Among the 134 patients with a verified diagnosis of subtle generalized convulsive status epilepticus, no significant differences among the treatments were detected (range of success rates, 7.7 to 24.2 percent). In an intention-to-treat analysis, the differences among treatment groups were not significant, either among the patients with overt status epilepticus (P=0.12) or among those with subtle status epilepticus (P=0.91). There were no differences among the treatments with respect to recurrence during the 12-hour study period, the incidence of adverse reactions, or the outcome at 30 days. CONCLUSIONS: As initial intravenous treatment for overt generalized convulsive status epilepticus, lorazepam is more effective than phenytoin. Although lorazepam is no more efficacious than phenobarbital or diazepam plus phenytoin, it is easier to use.

Aged↗
PubMed1998

Effects of cholinergic deafferentation and NGF on brain electrical coherence.

Rats received unilateral lesions of the nucleus basalis and were infused intracerebroventricularly (i.c.v.) over 3 weeks with nerve growth factor (NGF) or vehicle. Electrocortical coherence was assessed at postoperative days 4, 7, 14, and 21 from all possible pairs of eight epidural electrodes in the delta (1-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), beta-1 (12-20 Hz), and beta-2 (20-28 Hz) bands. On day 21 choline acetyltransferase (ChAT) activity was measured in cortical tissue underlying each electrode site. Lesions resulted in losses of interhemispheric, as well as bilateral intrahemispheric coherence in the theta band (F1,21 = 28.61, p < 0.0001, F1,21 = 4.30, p < 0.05), with no significant differences seen in other bands. Changes were accentuated during immobility compared with walking and exploratory behavior. Intrahemispheric changes were greatest within the lesioned hemisphere (F1,21 = 6.97, p < 0.01) in long connections between electrode pairings connecting frontal to posterior brain regions. Nerve growth factor (NGF) attenuated losses in ChAT (F1,21 = 21.31, p < 0.0001) and intrahemispheric coherence (F1,21 = 9.66, p < 0.005), whereas interhemispheric coherence showed no significant response. Intact animals receiving NGF showed increases in intrahemispheric coherence, as well as modest increases in ChAT. Increases in coherence in response to NGF occurred within 4-7 days following brain lesions, with no significant change during the 2 weeks thereafter. Our results suggest that coherence is sensitive to cholinergic deafferentation, particularly of long corticocortical connections. NGF differentially restores coherence within hemispheres, as opposed to between hemispheres. Our study suggests that brain function in Alzheimer's disease related to damage of transcallosal fiber tracts may not be responsive to cholinergic treatments. Future studies may wish to evaluate the cognitive relevance of NGF's effects on intact brain.

Afferent Pathways↗
PubMed1998

Altered residual ATP content in rat brain cortex subcellular fractions following status epilepticus induced by lithium and pilocarpine.

Changes in residual ATP concentrations were investigated following subcellular fractionation of rat brain cortex after a prolonged period of status epilepticus induced by sequential administration of lithium and pilocarpine. After 2 h of continuous high-amplitude rapid spiking on EEG, we found significantly decreased levels of residual ATP in the homogenate and mitochondria fractions from status epilepticus rat brains compared to matched controls. No difference in residual ATP level was observed in the synaptosomal preparations of status epilepticus animals compared to controls. Inorganic phosphate concentration in the status animals was higher than controls in the cytosolic fraction only. F1-ATPase activity, an enzymatic indicator of mitochondrial ATP synthesis rate, was significantly higher in the status brains, whereas other mitochondrial enzymes were not different in the status and control rat groups. These findings, together with our earlier report of reduced synaptosomal ecto-ATPase activity, suggest that either the corresponding in vivo ATP concentrations were reduced as a result of status epilepticus or other biochemical changes had occurred that facilitated the hydrolysis of ATP following decapitation. Controls for and measurement of such other changes failed to provide an explanation for the observed changes in residual ATP.

Adenosine Triphosphate↗
PubMed1997

Changes in cortical EEG and cholinergic function in response to NGF in rats with nucleus basalis lesions.

We examined whether recovery of cholinergic function in response to nerve growth factor (NGF) results in restoration of electrocortical activity. Rats received unilateral lesions of the nucleus basalis and were infused intracerebroventricularly (i.c.v.) over 3 weeks with NGF or vehicle. Cortical electrical activity was assessed at postoperative days 4, 7, 14, and 21 from 8 epidural electrodes. On day 21, choline acetyl transferase (ChAT) activity was measured in cortical tissue underlying each electrode site. Lesions resulted in increases in slow-wave (delta) power and decreases in high-frequency (beta 2) power in the lesioned, as well as the non-lesioned hemisphere. Changes correlated topographically and in magnitude with losses of ChAT activity and suggested that regional electrocortical function was affected by cholinergic activity originating in the ipsilateral, as well as the contralateral hemisphere. NGF attenuated changes in cholinergic and electrocortical function bilaterally, though in the lesioned hemisphere, function did not return to control levels. Likewise, intact animals receiving NGF showed increases in beta 2-power, as well as modest increases in ChAT activity. Changes in brain electrical activity in response to NGF occurred within 4-7 days without significant changes during the 2 weeks thereafter. Our results suggest that outcomes of future animal and human trials-using unilateral i.c.v. infusions of NGF need to consider the reciprocal influences of hemispheric cholinergic function, as well as possible effects of NGF on intact brain.

Animals↗
PubMed1997

Reduced cortical ecto-ATPase activity in rat brains during prolonged status epilepticus induced by sequential administration of lithium and pilocarpine.

Considerable evidence indicates that ATP, acting intracellularly of as a neurotransmitter, can influence nerve cell physiology in a variety of ways. Defects in the functioning of ATP-metabolizing enzymes could therefore lead to disturbances in neurotransmission and creation of sustained neuronal discharges characteristic of status epilepticus. In this study we investigated synaptosomal ATPase changes in rat brains during lithium/pilocarpine-induced status epilepticus. After 2 h of continuous electroencephalographic spiking, both Mg(2+)- and Ca(2+)-dependent ecto-ATPases were significantly decreased in freshly prepared synaptosomal preparations from the status rats. The intracellularly acting Ca2+Mg(2+)-ATPase (Ca-pump) was also decreased, but no changes occurred in synaptosomal Na+K(+)-ATPase activity. The difference between ecto-ATPase activities of the control and status rat brains was not affected by repeated freezing-thawing and lengthy storage. Possible involvement of reduced synaptosomal divalent cation-dependent ATPases in the pathophysiology of status epilepticus is discussed.

Adenosine Triphosphatases↗
PubMed1996

High-performance liquid chromatographic determination of midazolam in rat brain.

A high-performance liquid chromatography method for the determination of midazolam in rat brain is described. Midazolam and the internal standard halazepam were extracted with toluene and analyzed isocratically on a reversed-phase column with a mobile phase consisting of methanol, acetonitrile and potassium phosphate buffer. Detection was monitored by ultraviolet absorption at 240 nm. The standard curves were linear over the range of 25-350 ng midazolam per 50 mg brain tissue. The day-to-day coefficient of variation ranged from 1.7 to 6.9%. The limit of quantification was 80 ng/g brain tissue. The method is rapid, simple and reproducible for brain analysis.

Animals↗
PubMed1996

Lamotrigine vs. phenytoin for treatment of status epilepticus: comparison in an experimental model.

The newly introduced antiepileptic drug, lamotrigine, has been reported to have a mechanism of action similar to that of phenytoin. Because phenytoin is a standard clinical treatment for convulsive status epilepticus, we compared the efficacy of lamotrigine to that of phenytoin in a model of secondarily generalized convulsive status epilepticus in rats that responds to drug concentrations similar to those that have been reported to be clinically useful for this purpose. Status epilepticus was induced in rats with actively epileptogenic cortical cobalt lesions by administration of homocysteine thiolactone. While phenytoin-controlled generalized tonic clonic seizures in this model with a median effective dose of 100.5 mg/kg (16.0 micrograms/ml in serum), lamotrigine was ineffective at doses ranging from 10 to 100 mg/kg, with serum drug concentrations (2.5-43.5 micrograms/ml) within or above the reported 'therapeutic' concentration for LTG treatment of chronic epilepsy. Lamotrigine also failed to prevent the onset of generalized tonic clonic seizures when given prior to homocysteine, while phenytoin was effective in this test. Studies of lamotrigine kinetics in serum and brain revealed that the drug was well-absorbed following i.p. injection and that it entered brain rapidly enough to have exerted an anti-status effect in these experiments. These results suggest that lamotrigine and phenytoin have differences in their mechanisms of anticonvulsant action, leading to very different abilities to control status epilepticus.

Animals↗
PubMed1995

Cardiac hypertrophy secondary to status epilepticus in the rat.

Status epilepticus was induced in rats by sequential injections of lithium and pilocarpine. Seizure activity was aborted by a combination of MK-801 and diazepam, with status duration ranging from 3 to 180 min. When the hearts were examined 8-12 days later, rats that had experienced an episode of status epilepticus had significantly heavier hearts than did controls. The nature of the cardiac tissue changes was not examined, and deserves further study.

Animals↗
PubMed1994

Treatment of experimental status epilepticus with the GABA uptake inhibitor, tiagabine.

The potential clinical efficacy of tiagabine for control of status epilepticus was evaluated in an experimental model. Tiagabine was administered to cobalt-lesioned rats in which status epilepticus was induced by injection of homocysteine thiolactone. Tiagabine was effective in controlling status epilepticus in this model; the median effective dose for control of generalized tonic-clonic seizures in the model was 8.3 mg/kg. Tiagabine administration produced an abnormal, hypo-reactive behavioral state which was accompanied by an EEG pattern of high-amplitude, frontally dominant, rhythmic, 3-5-Hz spike-wave activity. This EEG and behavioral syndrome could be reproduced by administration of tiagabine to normal, non-epileptic rats. The exact nature of this syndrome remains unclear, but whether it is an epileptic or encephalopathic phenomenon, further study is clearly required before this drug should be considered for use in the treatment of human status epilepticus.

Animals↗
PubMed1993

Systemic effects of generalized convulsive status epilepticus.

Generalized convulsive status epilepticus (GCSE) is accompanied by a marked increase in plasma catecholamines. This produces a number of changes in general systemic physiology including hypertension, tachycardia, cardiac arrhythmias, hyperglycemia, acidosis, and hyperpyrexia. If SE is stopped quickly, these changes are self-correcting and do not produce an increased risk of neuropathology. However, if seizures continue, many of the early physiologic changes reverse, and late status epilepticus is marked by hypotension, hypoglycemia, pulmonary edema and a continued acidosis and elevation of body temperature. Prevention of serious hypoglycemia, maintenance of adequate systemic blood pressure to provide adequate cerebral perfusion, and normalizing the body temperature will minimize or prevent neuropathologic sequelae to SE of extended duration.

Arrhythmias, Cardiac↗
PubMed1992

Valproic acid treatment of experimental status epilepticus.

The efficacy of valproic acid (VPA) in control of generalized convulsive status epilepticus was tested in a rat model. Rats with cortical cobalt lesions were injected with homocysteine thiolactone to induce secondarily generalized tonic-clonic seizures (GTCS). The median effective dose (ED50) for control of GTCS was 211.9 mg/kg (270 micrograms/ml in serum 30 min post dose) when treatment was given intraperitoneally after the second GTCS. VPA entered both serum and brain very rapidly after injection, with little change in concentration from 5 to 30 min post dose. In earlier experiments with phenytoin, phenobarbital, diazepam and lorazepam in this model, we found that the serum concentrations produced by the ED50s versus GTCS were very similar to those which have been reported to be effective in treating human status epilepticus. If this same relationship holds true for VPA, we would predict that a serum concentration of around 270 micrograms/ml VPA would be required for control of generalized convulsive status epilepticus in human patients. The safety of this high a concentration of VPA has not been tested.

Animals↗
PubMed1991

Motor and electroencephalographic response of refractory experimental status epilepticus in rats to treatment with MK-801, diazepam, or MK-801 plus diazepam.

Pharmacologic control of refractory status epilepticus has been little-studied in experimental models. In this experiment, rats in status epilepticus induced by lithium and pilocarpine were treated with MK-801 alone, diazepam alone or MK-801 plus diazepam, with treatment begun at a time when this model of status is refractory to anticonvulsant drugs. EEG samples were digitized before and for two hours after treatment, and the digitized samples subjected to computerized frequency analysis. MK-801 plus diazepam halted all manifestations of status epilepticus. Although neither MK-801 alone nor diazepam alone stopped the ongoing electrographic status epilepticus, both drugs diminished motor seizures and total EEG power. MK-801 treatment prevented the progression of changes in EEG pattern which normally occurs in this model of status epilepticus, while diazepam did not. MK-801, with and without diazepam, allowed the rats to survive the episode of status epilepticus, but rats treated with MK-801 alone required several days to recover completely, while the MK-801 plus diazepam rats appeared normal the next day. MK-801 may be a useful agent for treatment of human refractory status epilepticus, because of its neuroprotective action as well as its ability to potentiate GABAergic drugs.

Animals↗
PubMed1990

High-performance liquid chromatographic determination of selected amino acids in rat brain by precolumn derivatization with phenylisothiocyanate.

We describe here a simple, sensitive, selective and reproducible assay method for quantitative determination of aspartate, glutamate, serine, glutamine, glycine and gamma-aminobutyric acid in rat brain using reversed-phase high-performance liquid chromatography. The method is based upon formation of phenylthiocarbamyl derivatives of the amino acids. Good resolution of the six amino acids and the internal standard norvaline is achieved within 40 min. Other amino acids which have been reported to be present in rat brain do not interfere with the analysis. Standard curves for each of the amino acids exhibited good linearity (r greater than 0.9993) over the range 0.5-20 nmol. The coefficient of variation for the intra-day and inter-day determinations ranged from 0.4% at the highest to 11% at the lowest concentration limit. Storage of whole brains at -0 degrees C for up to 8 weeks did not affect mean concentrations of the six amino acids.

Amino Acids↗