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W McIntyre Burnham

Publications and source records attributed to W McIntyre Burnham.

11 recordsLinked to original sources
PubMed2003

The effect of the 'classic' ketogenic diet on animal seizure models.

Bough et al. have recently demonstrated anticonvulsant effects of the 'classic' ketogenic diet (KD) in the pentylenetetrazol infusion model in rats. Proconvulsant effects were seen, however, when the 'classic' diet was tested against maximal electroshock (MES) seizures. These differing results may reflect the fact that the two models involve different kinds of epileptogenic stimulus, or, as Bough et al. note that the two tests involve different stimulation paradigms. The pentylenetetrazol infusion paradigm is a threshold test, whereas the MES test employs a stimulus which is well above threshold. The present experiments were designed to test the effects of the 'classic' KD against seizures triggered in rats by both threshold and suprathreshold levels of electricity and pentylenetetrazol. The threshold tests employed were the pentylenetetrazol infusion test, and the threshold electroconvulsive shock (ECS) test. The subcutaneous pentylenetetrazol (scMET) test was also included, since it is sometimes considered to be a 'threshold' test. The suprathreshold tests employed were the maximal pentylenetetrazol test (MMT) and the maximal electroshock test (MES). The KD failed to suppress seizures in either of the tests involving suprathreshold stimulation (MMT and MES), although there was a significant increase in latency in the MMT test. Small but significant threshold elevations (15-20%) were seen, however, in both the pentylenetetrazol infusion test and the ECS threshold test. No seizure suppression was seen in the scMET test, which actually employs a suprasthreshold stimulus. These data indicate that the KD has significant anticonvulsant effects against both chemically and electrically triggered seizures, but that they consist of small elevations in threshold which will be seen only when threshold measures are used.

Animals↗
PubMed2003

Anticonvulsant properties of acetone, a brain ketone elevated by the ketogenic diet.

The ketogenic diet (KD), a treatment for drug-resistant epilepsy, elevates brain acetone. Acetone has been shown to suppress experimental seizures. Whether elevation of acetone is the basis of the anticonvulsant effects of the KD and whether acetone, like the KD, antagonizes many different types of seizures, however, is unknown. This study investigated the spectrum of the anticonvulsant effects of acetone in animal seizure models. Rats were injected with acetone intraperitoneally. Dose-response effects were measured in four different models: (1) the maximal electroshock test, which models human tonic-clonic seizures; (2) the subcutaneous pentylenetetrazole test, which models human typical absence seizures; (3) the amygdala kindling test, which models human complex partial seizures with secondary generalization; and (4) the AY-9944 test, which models chronic atypical absence seizures, a component of the Lennox-Gastaut syndrome. Acetone suppressed seizures in all of the models, with the following ED(50)'s (expressed in mmol/kg): maximal electroshock, 6.6; pentylenetetrazole, 9.7; generalized kindled seizures, 13.1; focal kindled seizures, 26.5; AY-9944, 4.0. Acetone appears to have a broad spectrum of anticonvulsant effects. These effects parallel the effects of the KD. Elevation of brain acetone therefore may account for the efficacy of the KD in intractable epilepsy.

Acetone↗
PubMed2002

The effects of ACTH and adrenocorticosteroids on seizure susceptibility in 15-day-old male rats.

Infantile spasms are generalized convulsive seizures seen in the first year of life. They respond poorly to conventional anticonvulsants, but are often controlled by adrenocorticotropic hormone (ACTH) therapy. Other childhood seizures are also responsive to ACTH. The present study tested the effects of ACTH and related adrenocorticosteroids in prepubertal, 15-day-old rats. Compounds were tested against minimal (scMET) and maximal (MMT) pentylenetetrazol seizures, maximal electroconvulsive shock (MES) seizures, and hippocampal kindled seizures. ACTH had no significant anticonvulsant effects against any type of seizure. Several of the adrenocorticoid hormones, however, had strong anticonvulsant effects. Deoxycorticosterone (DOC) and progesterone (P4) both significantly suppressed scMET, MMT, and MES seizures 15 min after s.c. injection. DOC and P4 also shortened hippocampal discharge duration in the kindling model, and DOC, but not P4, suppressed the kindled convulsion. Aldosterone and corticosterone were effective against scMET seizures, and aldosterone was effective against MMT seizures. Dexamethasone and dihydroepiandrosterone had no anticonvulsant activity. These findings indicate that the adrenal steroid precursors, DOC and P4, have a broad spectrum of anticonvulsant activity in animal seizure models. They may play a role in mediating the anticonvulsant effects of ACTH in human infants.

Adrenocorticotropic Hormone↗
PubMed2002

Dose-, time-, age-, and sex-response profiles for the anticonvulsant effects of deoxycorticosterone in 15-day-old rats.

Recently, we have shown that a single high dose of the adrenal steroid precursor hormone deoxycorticosterone (DOC) has potent anticonvulsant effects in 15-day-old rats. To better define the actions of DOC, the present study established dose-, time-, age-, and sex-response curves for the anticonvulsant actions of DOC. Methods. Dose- and time-response studies were done using two different seizure models: (1) maximal pentylenetetrazol seizures (MMT) and (2) maximal electroconvulsive shock (MES) seizures. Subsequently, age- and sex-response studies were done using MMT seizures and two different DOC doses, one low (nonsedating) and one high (sedating). Results. In dose-response studies, DOC suppressed MMT seizures with an ED(50) of about 5 mg/kg (sc). Higher doses were necessary to suppress MES seizures, where the ED(50) was about 20 mg/kg. In time-response studies, DOC's effects were rapid in onset. Complete suppression of seizures was seen by 5 min in the MES model and by 15 min in the MMT model. In developmental studies, both a low nonsedating and a high sedating dose of DOC suppressed MMT seizures in neonatal, infant, weanling, and juvenile rats of either sex. The suppressive effects of low-dose DOC were lost after puberty, however. The suppressive effects of high-dose DOC also declined after puberty, especially in males. Conclusion. DOC has significant anticonvulsant actions that occur in prepubertal, but not postpubertal subjects. DOC might have clinical importance in the future treatment of childhood seizure disorders.

Age Factors↗
PubMed2002

Prenatal stress alters seizure thresholds and the development of kindled seizures in infant and adult rats.

Stressful events during gestation and in the neonatal period have important effects on the later physical and mental health of the offspring. The present study tested the hypothesis that pre- and/or postnatal stress would affect seizure susceptibility in infant and adult rats, using the hippocampal kindling model. Prenatal stress consisted of daily restraint of the dam under bright light (for 45 min, 3 x / day) during either early gestation or mid/late gestation. Pups were compared to pups born to unstressed dams. Postnatal stress (administered on Days 4 and 5 after birth) consisted of either separation from the dam and placement in the bedding of a strange male for 1 h or injection of dexamethasone. Pups were compared to nonstressed siblings of the same litter. Both early and mid/late-gestation prenatal stress significantly lowered the after-discharge threshold (ADT) in infant, 14-day-old rat offspring, as compared to nonstressed control offspring. This effect on ADT was lost by adulthood. Mid/late-gestation stress increased the rate of kindled seizure development in infant rats and in their adult male, but not female, siblings. Postnatal stress had no significant effect on ADT or kindling rate. These findings indicate that prenatal stress, particularly during the latter half of pregnancy, may play an important role in increasing seizure vulnerability in the unborn offspring. These effects are more pronounced in infancy, but can also extend to adulthood.

Aging↗
PubMed2002

Ketogenic diet: does acetone stop seizures?

BACKGROUND: The mechanism of action of the ketogenic diet, a therapy for refractory epilepsy, is unknown. Our hypothesis is that acetone, one of three ketones elevated by the ketogenic diet, is directly responsible for the diet's anticonvulsant effects. This study examined the basic concepts of this hypothesis. MATERIAL/METHODS: Rats were acutely injected with acetone intraperitoneally at doses of 1 or 10 mmol/kg, or received acetone chronically in drinking water (1% v/v) for 10 days before being injected with a 1 mmol/kg dose of acetone. Controls consumed regular water and were injected with vehicle. A pentylenetetrazole seizure test was administered 15 min after the injections. Following the test, acetone was measured in the cerebrospinal fluid. RESULTS: A 10 mmol/kg injection of acetone suppressed seizures in 60% of rats (P<0.05). A chronic administration of acetone followed by a 1 mmol/kg injection suppressed seizures in 47% of rats (P<0.05). The acetone concentrations in these rats were 10.3I2.3 and 1.0I0.2 mmol/L, respectively. The effect of the acute 1 mmol/kg injection (without acetone pretreatment) was not statistically significant. This dose elevated acetone to 1.1I0.1 mmol/L in the cerebrospinal fluid. CONCLUSIONS: Our findings suggest that acetone is an anticonvulsant and that chronic administration may enhance its action. Linking acetone to the effects of the ketogenic diet requires further research. In particular, it will be important to confirm that the ketogenic diet generates relevant concentrations of acetone.

Acetone↗
PubMed2001

Perforant pathway kindling transiently induces the mRNA expression of GABA-B receptor subtypes R1A and R2 in the adult rat hippocampus.

We examined the gene expression responses of GABA-B R1A, R1B and R2 receptor subtypes in the hippocampus of perforant pathway-kindled rats at 24 h and 28 days after 15 consecutive daily stimulations. We found R1A expression, but not R1B expression, to be significantly induced in the dentate gyrus at 24 h. No change in the expression of R1A or R1B was observed at 28 days. R2 expression was induced throughout the hippocampus at 24 h, but also returned to control levels by 28 days. Thus, our results show that kindling induces a transient increase in GABA-B receptor mRNA in the hippocampus.

Age Factors↗
PubMed2000

Diazepam-potentiated [3H]phenytoin binding is associated with peripheral-type benzodiazepine receptors and not with voltage-dependent sodium channels.

In the presence of diazepam, [3H]phenytoin binds with high affinity to brain membranes. The present experiments examined whether this high affinity [3H]phenytoin-binding site co-localized with the standard [3H]phenytoin-binding site on the voltage-dependent sodium channel (VDSC). Veratridine, a pharmacological activator of the voltage-dependent sodium channel, that inhibits standard [3H]phenytoin binding, failed to affect the high affinity diazepam-potentiated [3H]phenytoin binding in brain membranes, suggesting that the potentiated binding interaction resides at a site distinct from the voltage-dependent sodium channel. This possibility was confirmed by anion exchange chromatography of digitonin-solubilized rat brain membranes, as diazepam-potentiated high affinity [3H]phenytoin binding eluted in column fractions that were distinct from [3H]saxitoxin-defined voltage-dependent sodium channels. To examine whether diazepam-potentiated [3H]phenytoin binding might be associated with other 'classic' benzodiazepine receptor sites, we tested whether specific ligands for benzodiazepine receptors would either produce or block potentiated [3H]phenytoin binding. Neither agonists, nor antagonists, of the high affinity central-type benzodiazepine receptor affected potentiated [3H]phenytoin binding, suggesting that the high affinity potentiated binding site is not likely associated with central benzodiazepine receptors. Peripheral-type benzodiazepine receptor agonists, however, did potentiate [3H]phenytoin binding, and a specific receptor antagonist (PK11195) attenuated the potentiation seen with diazepam. Overall, these data illustrate that [3H]phenytoin interacts with a novel site in brain membranes that is distinct from the voltage-dependent sodium channel and is allosterically revealed by peripheral-type, but not central-type, benzodiazepine receptor agonists.

Animals↗
PubMed1999

Mossy fiber sprouting induced by repeated electroconvulsive shock seizures.

The elicitation of repeated focal seizures (kindling) induces mossy fiber sprouting in the hippocampus of the rat. The present study investigated whether repeated generalized seizures also induce mossy fiber sprouting. Human psychiatric patients receive repeated generalized seizures during electroconvulsive therapy (ECT). Male Long-Evans rats received a course of eight electroconvulsive shock (ECS) seizures administered on a 48-h schedule over a course of 2 1/2 weeks. Control subjects received matched handling, but no stimulation. Fourteen days after the last ECS trial, all subjects were sacrificed and their brains subjected to Timm staining. Cell counts and area measures were also taken in the hilus. Significant sprouting, but not significant cell loss, was seen in the fascia dentata of the subjects that had received ECS.

Animals↗