Biomedical subjects

W M Burnham

Publications and source records attributed to W M Burnham.

At least 19 recordsLinked to original sources

PubMed2006

The anticonvulsant effects of allopregnanolone against amygdala-kindled seizures in female rats.

It has long been known that the steroid hormone progesterone has anticonvulsant actions. These have been documented both in animals and humans. In 2003, we reported that progesterone's first metabolite, 5alpha-dihydroprogesterone (5alpha-DHP), has strong anticonvulsant effects in amygdala-kindled female rats. These occur without sedation, and involve suppression of the kindled amygdala focus, as well as the secondarily generalized kindled seizure. The purpose of this study was to investigate the anticonvulsant actions of progesterone's secondary metabolite, allopregnanolone, in the amygdala kindling model. Adult female Wistar rats were implanted with chronic indwelling electrodes in the right amygdala, and kindled to 30 stage 5 seizures. Varying doses of allopregnanolone were then administered to each subject in randomized order, and the effects on the kindled amygdala focus and the secondarily generalized kindled seizure were observed. Immediately before each drug trial, ataxia was rated using the Löscher scale. Complete suppression of the generalized kindled convulsion was seen in all subjects, with an ED(50) of 1.1 mg/kg. Ataxia--scored as Löscher stage 2 or higher--was seen at higher doses, with a TD(50) of 8.6 mg/kg. The therapeutic index for suppression of the generalized convulsion was 7.8. Even at the highest doses tested, however, there was no suppression of the kindled amygdala focus. Allopregnanolone has anticonvulsant effects--and a good therapeutic index--against the secondarily generalized component of amygdala-kindled seizures.

Amygdala↗

PubMed2006

A ketogenic diet and diallyl sulfide do not elevate afterdischarge thresholds in adult kindled rats.

INTRODUCTION: Acetone has been shown to have broad-spectrum anticonvulsant actions in animal seizure models and has been hypothesized to play a role in the anticonvulsant mechanism of the ketogenic diet (KD). The present study examined the ability of a KD to elevate amygdaloid afterdischarge thresholds (ADT) in fully kindled rats. The effects of the KD were studied in the presence and absence of diallyl sulfide (DAS), an inhibitor of acetone metabolism. METHODS: Twenty-four adult male rats were kindled to 30 stage 5 seizures. Afterdischarge thresholds (ADT) were determined. Subjects were then administered one of the following diets: (1) KD+V (vehicle; KD+V); (2) KD+DAS; (3) control diet+V (CD+V); (4) CD+DAS. They were stimulated every second day. Blood sampling was performed every second day--on non-stimulating days--to determine levels of glucose, beta-hydroxybutyrate, acetoacetate, and acetone. After 20 days, ADTs were re-determined. RESULTS: Blood acetone concentrations were significantly higher in the KD+DAS group as compared to the other groups, although they did not reach "therapeutic levels". None of the treatments, however, elevated ADTs. CONCLUSIONS: The KD was unable to elevate amygdaloid ADTs in fully kindled rats. Although subjects in the KD+DAS group achieved significant elevations of blood acetone, these concentrations (e.g. 0.2 mM) were much lower than those (>2.0 mM) previously shown to confer anticonvulsant activity. There appears to be large difference between humans and rats in their ability to produce elevated blood acetone levels on the KD. These data suggest that adult rats are not ideal subjects for modeling the anticonvulsant actions of the KD.

3-Hydroxybutyric Acid↗

PubMed2006

The ketogenic diet causes a reversible decrease in activity level in Long-Evans rats.

Individuals with epilepsy also often exhibit symptoms of attention deficit hyperactivity disorder (ADHD). The ketogenic diet, which is a high fat, low protein, and low carbohydrate diet used in the treatment of intractable epilepsy, also appears to improve symptoms of ADHD in individuals with both disorders. Previous research suggests that the diet decreases the activity level of rats. The purpose of the present research was to further investigate the effects of the ketogenic diet on activity level, using an animal model. Two experiments were conducted. The first experiment examined the time frame and reversibility of the effect of the diet on activity level. The second experiment examined the relationship between activity level and anxiety level. In both experiments, adult male Long-Evans rats were placed on either a ketogenic diet or a control diet. The results of the first experiment show that the ketogenic diet can cause a decrease in activity level within 24 h and that the results are reversible. The results of Experiment 2 show that the decrease in activity level is not linked to a change in anxiety level. The ketogenic diet may be of use in the treatment of ADHD.

Animals↗

PubMed2006

Deoxycorticosterone's anticonvulsant effects in infant rats are blocked by finasteride, but not by indomethacin.

Deoxycorticosterone (DOC) is a steroid hormone that suppresses seizures in both humans and animals. At higher doses, DOC's anticonvulsant actions are accompanied by sedation and ataxia. The mechanism of DOC's anticonvulsant actions is not known, although it has been suggested that they may relate to DOC's secondary metabolite 3-alpha-5-alpha-tetrahydrodeoxycorticosterone (THDOC). The present study was designed to study the relation of DOC's anticonvulsant actions to its primary and secondary metabolites in 15-day-old rats. It was found that DOC's anticonvulsant and ataxic effects were suppressed by finasteride, which blocks the formation of DOC's primary metabolite, 3-alpha-5-alpha-dehydrodeoxycorticosterone (DHDOC). They were not suppressed by indomethacin (INDO), which blocks the conversion of DHDOC into THDOC. The direct anticonvulsant effects of DHDOC and THDOC were also tested. DHDOC and THDOC were both potent anticonvulsants in 15-day old rats. Both also caused ataxia at high doses. DHDOC had a therapeutic index (TI) of 3.2, however, which was better than either DOC (TI = 1.2) or THDOC (TI = 1.5). It appears that DOC itself is not anticonvulsant, but that its anticonvulsant effects may relate to both its primary and secondary metabolites. DOC's primary metabolite, DHDOC--with its good TI--deserves a test in the treatment of childhood seizures.

Animals↗

PubMed2006

Kindled seizures enhance young neuron survival in the adult rat dentate gyrus.

New neurons continue to be generated throughout adulthood in the dentate gyrus of mammals. This process of neurogenesis is believed to play a role in some forms of learning and memory. Hippocampal-dependent learning tasks have been shown to specifically enhance the survival of new granule neurons. The present study examined the effects of kindled seizures in rats on the survival of young neurons born before the kindling began. Kindled seizures within the perforant path input to the dentate gyrus triggered between 1 and 2 weeks following the injection of bromodeoxyuridine (BrdU), were found to increase the number of BrdU and NeuN co-labeled cells in the granule cell layer by 128% 1 month later. The number of co-labeled cells was not correlated with measures of seizure severity. These results demonstrate that kindled seizures enhance the survival of new born neurons in the adult rat dentate gyrus which may reflect the actions of an activity-dependent mechanism normally involved in hippocampal-dependent learning and memory.

Animals↗

PubMed2004

The antidepressant properties of the ketogenic diet.

BACKGROUND: The ketogenic diet is used to treat epilepsy refractory to anticonvulsant medication. Individuals with epilepsy often have behavioral problems and deficits in attention and cognitive functioning. The ketogenic diet has been found to effect improvements in these domains. It has also been suggested that the ketogenic diet may act as a mood stabilizer. METHODS: The present research used the Porsolt test, an animal model of depression, to determine whether the ketogenic diet has antidepressant properties. Porsolt test scores of rats on the ketogenic diet were compared with those of rats on a control diet. RESULTS: The rats on the ketogenic diet spent less time immobile, suggesting that rats on the ketogenic diet, like rats treated with antidepressants, are less likely to exhibit "behavioral despair." CONCLUSIONS: It is concluded that the ketogenic diet may have antidepressant properties.

3-Hydroxybutyric Acid↗

PubMed2003

The effect of kindled seizures on the locomotory behavior of Long-Evans rats.

The incidence of attention deficit hyperactivity disorder (ADHD) is higher in children with epilepsy than in the general childhood population. The origin of the symptoms of ADHD seen in children with epilepsy is unknown. This experiment used an animal model to investigate whether seizures could be a cause of the hyperactivity sometimes associated with epilepsy. Sixteen male Long-Evans rats were implanted with electrodes, and 8 of them were kindled until generalized stage 5 seizures were elicited. Eight subjects were handled, but not kindled. The behavior of the rats in the two groups was compared in an open field test. The time spent in four behaviors was measured: exploratory behavior, immobility, eating, and grooming. Rats were tested after 5 stage 5 seizures, after 10 stage 5 seizures, after 15 stage 5 seizures, after a 2-week rest period, and after 5 more stage 5 seizures. Data were analyzed using the Mann-Whitney rank sum test. Twenty-four hours after a seizure, the kindled rats displayed a greater level of exploratory behavior than did the controls. They were not found to differ on any other measure. After a 2-week rest period, the group difference in behavior disappeared. When kindling was reinitiated, the kindled rats again showed increased exploratory behavior. The findings suggest that the increased exploratory behavior found in the kindled rats resulted from recent seizure activity. It may be that the hyperactivity seen in some children with epilepsy also results from recent seizure activity.

Animals↗

PubMed2002

Kindling induces the mRNA expression of methyl DNA-binding factors in the adult rat hippocampus.

We have investigated the gene expression responses of a family of methyl CpG-binding domain-containing factors (MeCP2, MBD1, MBD2, and MBD3) in the hippocampus of electrically kindled rats. Expression was examined in both amygdala- and partial perforant-pathway-kindled subjects, 24 h and 28 days following the final stimulation. In general, the responses of MBDs 2 and 3 paralleled each another, both temporally and spatially. The expression of both genes was significantly elevated in all hippocampal subfields at 24 h following either the fifth stage 5 seizure (amygdala kindling) or the 15th stimulation of the perforant pathway. This induced expression was transient, however, as the expression of both genes returned to control levels by 28 days. This pattern of response contrasted to that observed for MeCP2 and MBD1. MeCP2 displayed no change in expression either 24 h or 28 days after amygdala kindling, but did display a late-developing, significant increase in expression in the dentate gyrus at 28 days following perforant-pathway kindling. The expression of MBD1 was unchanged by partial perforant-pathway kindling, but was induced in the dentate gyrus 28 days after amygdala kindling. These results demonstrate that electrical kindling alters the hippocampal expression of methyl DNA-binding factors, but does not affect each factor equivalently. The responsive patterns observed suggest that this family of transcriptional regulators can be differentially altered in the hippocampus by seizure activity.

Amygdala↗

PubMed2001

Gonadectomy unmasks an inhibitory effect of progesterone on amygdala kindling in male rats.

Previous studies have suggested that the effects of progesterone on kindling in rats may be sexually differentiated, significant effects of physiological levels of progesterone being observed only in females. The present study demonstrates that this difference results from the hormones secreted by the testes. Thus, in orchidectomized males, progesterone induces a delay in the onset of amygdala-kindled seizures similar to that observed in females.

Amygdala↗

PubMed2001

Lipid and fatty acid profiles in rats consuming different high-fat ketogenic diets.

High-fat ketogenic diets are used to treat intractable seizures in children, but little is known of the mechanism by which these diets work or whether fats rich in n-3 polyunsaturates might be beneficial. Tissue lipid and fatty acid profiles were determined in rats consuming very high fat (80 weight%), low-carbohydrate ketogenic diets containing either medium-chain triglyceride, flaxseed oil, butter, or an equal combination of these three fat sources. Ketogenic diets containing butter markedly raised liver triglyceride but had no effect on plasma cholesterol. Unlike the other fats, flaxseed oil in the ketogenic diet did not raise brain cholesterol. Brain total and free fatty acid profiles remained similar in all groups, but there was an increase in the proportion of arachidonate in brain total lipids in the medium-chain triglyceride group, while the two groups consuming flaxseed oil had significantly lower arachidonate in brain, liver, and plasma. The very high dietary intake of alpha-linolenate in the flaxseed group did not change docosahexaenoate levels in the brain. Our previous report based on these diets showed that although ketosis is higher in rats consuming a ketogenic diet based on medium-chain triglyceride oil, seizure resistance in the pentylenetetrazol model is not clearly related to the degree of ketosis achieved. In combination with our present data from the same seizure study, it appears that ketogenic diets with widely differing effects on tissue lipids and fatty acid profiles can confer a similar amount of seizure protection.

Animals↗

PubMed2001

The impact of corticosteroids on the developing animal.

Infants are subjected to both endogenous and exogenous corticosteroids in the pre- and postnatal periods. Stress to the mother before birth, or to the child postpartum, can give rise to high, chronic endogenous corticosteroid levels caused by activation of the hypothalamic-pituitary-adrenal (HPA) axis. Physician-administered exogenous corticosteroids are also used in the management of a wide spectrum of pre- and postnatal conditions. The long-term effects of corticosteroids in developing humans are not well known. Studies in animals, however, indicate that both natural stress and exogenous corticosteroids can have long-lasting and deleterious effects on the body, brain, behavior, and hypothalamic-pituitary-adrenal axis of developing infants. These data suggest that exogenous corticosteroids should be administered with caution, after careful benefit/risk analyses, and that, as far as possible, the developing brain should be protected against the effects of pre- and postnatal stress.

Adrenal Cortex Hormones↗

PubMed2000

The MCT ketogenic diet: effects on animal seizure models.

Male Wistar rat pups were weaned at 20 days of age and placed on either a control diet or a ketogenic diet containing medium-chain triglyceride (MCT) oil. After 10 days on the diets, they were subjected to one of four seizure tests-maximal electric shock, threshold electroconvulsive shock, threshold pentylenetetrazol, or maximal pentylenetetrazol. After testing, subjects were sacrificed and blood samples were analyzed for beta-hydroxybutyrate concentration. It was found that the MCT diet produced blood levels of beta-hydroxybutyrate that were comparable to or higher than those commonly reported in clinical studies. However, no anticonvulsant effects were seen in any of the seizure tests. In fact, the tests involving maximal seizures actually showed proconvulsant effects. It appears that clinical levels of ketones may be present in the bloodstream without suppressing seizures.

3-Hydroxybutyric Acid↗

PubMed2000

Neurogenesis in the dentate gyrus of the rat following electroconvulsive shock seizures.

Electroconvulsive shock (ECS) seizures provide an animal model of electroconvulsive therapy (ECT) in humans. Recent evidence indicates that repeated ECS seizures can induce long-term structural and functional changes in the brain, similar to those found in other seizure models. We have examined the effects of ECS on neurogenesis in the dentate gyrus of the adult rat using bromodeoxyuridine (BrdU) immunohistochemistry, which identifies newly generated cells. Cells have also been labeled for neuronal nuclear protein (NeuN) to identify neurons. One month following eight ECS seizures, ECS-treated rats had approximately twice as many BrdU-positive cells as sham-treated controls. Eighty-eight percent of newly generated cells colabeled with NeuN in ECS-treated subjects, compared to 83% in sham-treated controls. These data suggest that there is a net increase in neurogenesis within the hippocampal dentate gyrus following ECS treatment. Similar increases have been reported following kindling and kainic acid- or pilocarpine-induced status epilepticus. Increased neurogenesis appears to be a general response to seizure activity and may play a role in the therapeutic effects of ECT.

Animals↗

PubMed2000

The effect of seizures and kindling on reproductive hormones in the rat.

Reproductive dysfunction and endocrine disorders are common among both women and men with epilepsy, and, in particular, with temporal lobe epilepsy. In clinical studies, it is hard to separate the effects of seizures from the effects of medication and life style. Studies in rodents, however, suggest that seizures per se can contribute to reproductive dysfunction. In female rats, generalized seizures disrupt normal ovarian cyclicity in adults, and repeated electroshock seizures delay the onset of puberty in juveniles. Right amygdala kindling in adult female rats causes acyclicity, the development of polycystic ovaries and premature aging of the hypothalamic-pituitary neuroendocrine axis, leading to chronic anovulation and continuous estrogen exposure. In adult male rats, repeated electroshock seizures result in transient hypogonadism, characterized by decreased serum testosterone levels and lowered gonadal tissue weight. In contrast, right amygdala kindling increases serum testosterone, estradiol levels and gonadal weight. These findings suggest that reproductive dysfunction in women and men with epilepsy may result from recurrent seizure activity, due to seizure-related interference with the normal functions of the hypothalamic-pituitary-gonadal axis.

Animals↗

PubMed2000

Dietary fat, ketosis, and seizure resistance in rats on the ketogenic diet.

PURPOSE: Fat is the major component of the ketogenic diet (KD), yet no studies have examined whether the type of fat used in the diet can be optimized to provide additional benefits. The purpose of the present experiments was to compare the efficiency of different fats in inducing ketosis and affording seizure resistance. METHODS: The effects of KDs that incorporate lard, butter, medium-chain triglycerides (MCT), or flaxseed oil or a mixture of the latter three fats were examined in rats fed KD for up to 98 days. The maximal electroshock (MES) or pentylenetetrazole (PTZ) threshold tests were used to assess seizure susceptibility in two separate experiments. RESULTS: The rank order of induced ketosis was MCT > mixture > or = flaxseed oil > or = lard = butter > or = control. MES failed to reveal anticonvulsant effects, but the PTZ test indicated that up to 50% of rats fed the KD were seizure protected (p < 0.05). The measures of seizure protection, seizure incidence and score, did not correlate, however, with the level of ketosis in the range of 0. 7-5.2 mmol/L for beta-hydroxybutyrate. In the long-term study, flaxseed oil KD maintained stable ketosis throughout 98 days, whereas ketones declined with lard and butter KD to the control level. CONCLUSIONS: Seizure protection with the versions of the KD did not improve with the higher level of ketosis. The focus of the KD improvement, therefore, is not the achievement of higher ketosis per se but rather designing a diet that provides steady ketosis, exploits advantages of certain fats for neurological development or seizure protection via a nonketogenic mechanism, and is nutritionally balanced.

Age Factors↗

PubMed1999

Ketamine and phenobarbital do not reduce the evoked-potential enhancement induced by electroconvulsive shock seizures in the rat.

Electroconvulsive shock (ECS) seizures provide an animal analog of electroconvulsive therapy (ECT). Repeated ECS seizures cause a long-lasting, and perhaps permanent, enhancement of entorhinal-dentate evoked potentials (EPs) in the rat. Recently it has been reported that ketamine protects against ECS-induced EP enhancement. The present study was designed to replicate these findings and to extend them by incorporating a phenobarbital group (to control for ketamine's partial diminution of seizures) and an animal test of antidepressant activity (the Porsolt test). Unexpectedly, we found that neither ketamine nor phenobarbital protected against ECS-induced enhancement of EPs. Both, however, diminished the 'therapeutic' effects of ECS, as modeled by the Porsolt test. These data suggest that the use of ketamine would not eliminate the unwanted effects of ECT and that it might diminish ECT's therapeutic benefits.

Animals↗

PubMed1999

Steroid hormones affect limbic afterdischarge thresholds and kindling rates in adult female rats.

UNLABELLED: Catamenial epileptics show particular vulnerability to seizures during menstruation and at the time of ovulation, when circulating estradiol (E(2))/progesterone (P(4)) ratios are high. The present study tested the hypothesis that alterations in neuronal excitability induced by E(2) and P(4) affect thresholds and the development of secondary generalization in kindled rats. METHODS: The effects of endogenous hormones secreted during the estrous cycle, and of exogenous exposure to E(2) and P(4) after ovariectomy (OVX), with and without adrenalectomy (ADX), were tested. Kindling electrodes were implanted in the basolateral amygdala or dorsal hippocampus in adult female rats. The anticonvulsive effects of P(4) on amygdala kindled seizures were also determined in intact subjects. RESULTS: In intact females, afterdischarge thresholds (ADTs) in the amygdala were significantly lower (306+/-48 microA; peak to peak) at mid-day proestrus, just prior to ovulation, when serum E(2) is elevated. ADTs were more than twofold higher (808+/-95 microA) during metestrus, coincident with peak ovarian P(4) secretion. In OVX females, amygdala thresholds were lowest with E(2) replacement and highest with P(4) replacement. Hippocampal ADT was unaffected by hormone replacement after OVX. The rates of both amygdala and hippocampal kindling were significantly accelerated by E(2) and slowed by P(4). E(2) replacement significantly increased serum corticosterone (CORT) levels. In ADX rats, CORT replacement increased kindling rates, synergizing with the effects of E(2). In fully kindled animals, P(4) administration suppressed motor seizures in approximately 60% of cases. CONCLUSIONS: E(2) lowers amygdala ADTs and facilitates kindling. This effect may involve both direct E(2) effects and indirect effects mediated via increased levels of circulating corticosterone. P(4) raises amygdala ADTs, slows kindling development and suppresses fully kindled seizures. Hence, P(4) may have potential therapeutic value for women with catamenial epilepsy.

Amygdala↗

PubMed1999

Testosterone and its metabolites affect afterdischarge thresholds and the development of amygdala kindled seizures.

UNLABELLED: In boys with epilepsy, pubertal increases in seizure frequency may be associated with rising androgen levels. The present study tested the hypothesis that testosterone (T) and/or its metabolites might affect amygdala seizure thresholds and the development of secondary generalization from amygdala foci (kindling). Afterdischarge thresholds and kindling rate were measured in gonadectomized (GDX) male rats, with or without T replacement therapy. Drugs that block either androgen or estradiol (E(2)) receptor-mediated responses were also tested. METHODS: Kindling electrodes were implanted in the basolateral amygdala of adult male Wistar rats. In Experiment 1, subjects were GDX and implanted with a silastic capsule containing either: cholesterol (control); T; 5% E(2) in cholesterol; or 5alpha-dihydrotestosterone (DHT). In Experiment 2, intact subjects were treated with daily injections of vehicle (control); daily injections of flutamide (an androgen receptor antagonist); or Silastic implants containing 1,4,9-androstatriene 3,17-dione (ATD; an aromatase inhibitor). RESULTS: In Experiment 1, initial afterdischarge (AD) thresholds were significantly lowered by E(2) treatment, as compared to cholesterol controls, and remained low throughout the kindling paradigm. In T replaced males, AD threshold significantly decreased over the kindling period, a response that was not observed in DHT treated rats. Rates of kindling were significantly faster as a result of T, E(2) and DHT treatment, as compared to cholesterol controls. E(2) treated males kindled the fastest of all 3 groups. In Experiment 2, initial AD thresholds were significantly lowered by flutamide treatment, as compared to cholesterol controls, and remained low throughout the kindling paradigm. AD threshold significantly decreased over the kindling period in intact males, a response that was blocked by ATD treatment. Both flutamide and ATD significantly slowed the rate of kindling, as compared to intact controls. ATD had the most dramatic inhibitory effect on kindling rate. CONCLUSIONS: In males, T and its two metabolites, E(2) and DHT, all appear to enhance the development of amygdala-kindled seizures. E(2) has the most potent epileptogenic effect. Antagonism of E(2) mediated effects in the brain may have potential therapeutic value for males with epilepsy.

Amygdala↗