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Biomedical subjects

W McIntyre Burnham

Publications and source records attributed to W McIntyre Burnham.

At least 19 recordsLinked to original sources
PubMed2006

Afterdischarge threshold reduction in the kindling model of epilepsy.

Female Wistar rats were implanted with electrodes in the right amygdala, and initial--pre-kindling--afterdischarge thresholds (ADT's) were determined 1, 2, 4, and 8 weeks after electrode implantation. Pre-kindling ADT's were highest 1 week after implantation, lower at 2 weeks, and lowest at 4 weeks. This drop in non-stimulated thresholds had largely disappeared by 8 weeks post-implantation. Half of each group was then kindled, while the other half was "sham" kindled. ADTs were re-measured 1 week after the 10th Stage 5 seizure. When kindling was begun 1 or 2 weeks after implantation (when non-stimulated thresholds were dropping), no effect of kindling on ADT's could be seen. When kindling was begun 4 or 8 weeks after implantation (when non-stimulated thresholds were rising), however, kindling clearly lowered thresholds.

Amygdala↗
PubMed2006

The anticonvulsant effects of progesterone and its metabolites on amygdala-kindled seizures in male rats.

Progesterone is a neurosteroid that modulates neuronal excitability. The anticonvulsant effects of progesterone are largely mediated by the actions of its metabolites. The purpose of this study was to measure the anticonvulsant effects of progesterone, 5alpha-dihydroprogesterone, and allopregnanolone against amygdala-kindled seizures in male rats. The amygdala kindling model is a model of human complex partial seizures with secondary generalization. A bipolar electrode was chronically implanted in the right amygdala of male Wistar rats. All subjects were kindled to 30 stage 5 seizures and stability tested. Multiple doses of progesterone, 5alpha-dihydroprogesterone, or allopregnanolone were administered in separate dose-response studies. The antiseizure effects of each compound were determined. A progesterone time-response study was also conducted. At 30 min after injection, progesterone had an ED50 of 65.3 mg/kg against the secondarily generalized seizure and an ED50 of 114 mg/kg against the focal seizure. 5alpha-dihydroprogesterone had a low ED50 of 6.2 mg/kg against both the generalized component of the amygdala-kindled seizure and the focal seizure. Allopregnanolone had an ED50 of 15.2 mg/kg against the secondarily generalized seizure and was not effective against the focal seizure. Progesterone is an effective anticonvulsant against the secondarily generalized component of amygdala-kindled seizures in male rats. Progesterone is only effective against the focal seizure at high ataxic doses. 5alpha-dihydroprogesterone is a potent anticonvulsant against both the kindled amygdala focal discharge and the secondarily generalized seizure. Allopregnanolone is an effective anticonvulsant against the secondarily generalized component of the seizure, but not against the amygdala focal discharge.

Amygdala↗
PubMed2006

Lack of benefit of linoleic and alpha-linolenic polyunsaturated fatty acids on seizure latency, duration, severity or incidence in rats.

BACKGROUND: Polyunsaturated fatty acids have been reported to increase seizure threshold and to reduce seizure duration and severity in rats. OBJECTIVE: The purpose of the present study was to test the anticonvulsant effects of an essential fatty acid mixture containing linoleic and alpha-linolenic acids at a 4:1 ratio (SR-3 compound), using the pentylenetetrazol seizure model in Long-Evans hooded rats. RESULTS: There were no significant effects of SR-3 on seizure latency, duration or severity (P>0.05). There were also no significant differences in the incidence of myoclonic jerks, forelimb and hindlimb clonus, forelimb and hindlimb tonus or running fits in rats that received SR-3, as compared to control rats (P>0.05). CONCLUSION: Linoleic and alpha-linolenic polyunsaturated fatty acids have no beneficial effects on seizure latency, duration, average severity or incidence.

Animals↗
PubMed2006

GABAB receptor antagonism abolishes the learning impairments in rats with chronic atypical absence seizures.

Chronic atypical absence seizures are a component of the Lennox-Gastaut syndrome, a disorder invariably associated with severe cognitive impairment in children. However, the cause of this intellectual delay remains unclear. The AY9944 model of chronic atypical absence seizures in rats reliably reproduces the electrographic, behavioral, pharmacological and cognitive features of clinical atypical absence. Using this model, we tested the hypothesis that the cognitive impairment associated with this disorder involves a gamma-aminobutyric acid B (GABA(B)) receptor-mediated mechanism. Therefore, we examined the effect of a specific, high affinity GABA(B) receptor antagonist, CGP35348, on the atypical absence seizures, the working memory deficits, and the altered long-term potentiation that we have observed in the AY9944 model. CGP35348 blocked atypical absence seizures, restored long-term potentiation to normal level, and reversed the cognitive deficit in the AY9944-treated animals. However, dose-response studies showed that lower doses of CGP35348 that failed to influence atypical absence seizure activity, completely reversed the spatial working memory deficit. These data suggest that GABA(B) receptor-mediated mechanisms are responsible for the cognitive dysfunction in the AY9944 model of chronic atypical absence seizures and further, that their cognitive impairment is independent of the seizure activity. The data raise the possibility that GABA(B) receptor antagonists may have therapeutic potential for the treatment of cognitive impairment in epilepsy syndromes where atypical absence seizures are a component.

Animals↗
PubMed2006

Visuospatial function in the beagle dog: an early marker of cognitive decline in a model of human aging and dementia.

Visuospatial learning and memory impairments are an early marker for age-related cognitive decline and Alzheimer's disease. Similar to humans, aged dogs show visuospatial learning and memory deficits (). One hundred and nine beagle dogs ranging between 0.25 and 11.99 years were tested on a visuospatial delayed non-matching to position (DNMP) task to better characterize the progression of visuospatial deficits in the dog. Age predicted 48.2% of the variability in learning the DNMP, with dogs ranging from 1 to 11.99 years generally making more errors with increasing age. By contrast, puppies (<1 year) likely were showing developmental deficits, possibly due to an immature prefrontal cortex. Mild visuospatial deficits were detected by 6 years, which precedes the typical onset of amyloid-beta (Abeta) accumulation in the dog brain by two years, and can serve as an early marker for cognitive decline in the dog. These findings suggest that (1) age-related changes in visuospatial function in the dog models that seen in humans, further validating the dog as a model for human aging and dementia; and (2) other mechanisms, such as oxidative stress, soluble Abeta oligomers or cholinergic deficits, are likely contributing to the early impairment.

Aging↗
PubMed2006

G-protein-coupled receptors and asthma endophenotypes: the cysteinyl leukotriene system in perspective.

Genetic variation in specific G-protein coupled receptors (GPCRs) is associated with a spectrum of respiratory disease predispositions and drug response phenotypes. Although certain GPCR gene variants can be disease-causing through the expression of inactive, overactive, or constitutively active receptor proteins, many more GPCR gene variants confer risk for potentially deleterious endophenotypes. Endophenotypes are traits, such as bronchiole hyperactivity, atopy, and aspirin intolerant asthma, which have a strong genetic component and are risk factors for a variety of more complex outcomes that may include disease states. GPCR genes implicated in asthma endophenotypes include variants of the cysteinyl leukotriene receptors (CYSLTR1 and CYSLTR2), and prostaglandin D2 receptors (PTGDR and CRTH2), thromboxane A2 receptor (TBXA2R), beta2-adrenergic receptor (ADRB2), chemokine receptor 5 (CCR5), and the G protein-coupled receptor associated with asthma (GPRA). This review of the contribution of variability in these genes places the contribution of the cysteinyl leukotriene system to respiratory endophenotypes in perspective. The genetic variant(s) of receptors that are associated with endophenotypes are discussed in the context of the extent to which they contribute to a disease phenotype or altered drug efficacy.

Aspirin↗
PubMed2006

Intractable epilepsy, hormonal and reproductive problems: human and animal studies.

Both women and men with epilepsy run significant risks of reproductive dysfunction. These problems are seldom addressed, however, either by the medical profession or by lay organizations. Many physicians are not even aware of these health risks. Increased awareness of--and treatment of--these problems are important goals for the future.

Animals↗
PubMed2005

Charting epilepsy by searching for intelligence in network space with the help of evolving autonomous agents.

The problem of demarcating neural network space is formidable. A simple fully connected recurrent network of five units (binary activations, synaptic weight resolution of 10) has 3.2 *10(26) possible initial states. The problem increases drastically with scaling. Here we consider three complementary approaches to help direct the exploration to distinguish epileptic from healthy networks. [1] First, we perform a gross mapping of the space of five-unit continuous recurrent networks using randomized weights and initial activations. The majority of weight patterns (>70%) were found to result in neural assemblies exhibiting periodic limit-cycle oscillatory behavior. [2] Next we examine the activation space of non-periodic networks demonstrating that the emergence of paroxysmal activity does not require changes in connectivity. [3] The next challenge is to focus the search of network space to identify networks with more complex dynamics. Here we rely on a major available indicator critical to clinical assessment but largely ignored by epilepsy modelers, namely: behavioral states. To this end, we connected the above network layout to an external robot in which interactive states were evolved. The first random generation showed a distribution in line with approach [1]. That is, the predominate phenotypes were fixed-point or oscillatory with seizure-like motor output. As evolution progressed the profile changed markedly. Within 20 generations the entire population was able to navigate a simple environment with all individuals exhibiting multiply-stable behaviors with no cases of default locked limit-cycle oscillatory motor behavior. The resultant population may thus afford us a view of the architectural principles demarcating healthy biological networks from the pathological. The approach has an advantage over other epilepsy modeling techniques in providing a way to clarify whether observed dynamics or suggested therapies are pointing to computational viability or dead space.

Action Potentials↗
PubMed2005

Propagation of amygdala-kindled seizures to the hippocampus in the rat: electroencephalographic features and behavioural correlates.

BACKGROUND: The propagation of amygdala-kindled seizures to the dorsal and ventral hippocampus was examined, in rats. The relation of contralateral seizure propagation to the onset of generalized convulsions was also studied. METHODS: In all subjects, electrodes were implanted in the amygdala. Two additional electrodes were implanted (bilaterally) in the dorsal (n = 6) or ventral (n = 8) hippocampus. Kindling stimulations were delivered twice daily (interval 4 h). RESULTS: Initially, triggered after-discharges (ADs) were recorded only in the amygdala. With repeated stimulation, the AD propagated to the hippocampus. Rates of propagation were as follows (mean # of stimulations +/- SEM): ipsilateral ventral hippocampus, 4.0 +/- 0.9; ipsilateral dorsal hippocampus, 6.2 +/- 1.4; contralateral dorsal hippocampus, 7.5 +/- 1.4; contralateral ventral hippocampus, 8.5 +/- 1.0. AD propagation to contralateral sites was significantly slower than to ipsilateral sites. Ipsilateral hippocampal recruitment occurred between stages 1 and 2 (partial seizures), whereas contralateral hippocampal recruitment occurred between stages 2 and 3 (transition to generalized seizures). SUMMARY: These results indicate that during amygdala-kindling, it takes several stimulations before discharge propagates to the hippocampus. The close link between contralateral hippocampus involvement and seizure generalization warrants further study, and may lead to a better understanding of the pathways involved in seizure spread.

Amygdala↗
PubMed2005

Might astrocytes play a role in maintaining the seizure-prone state?

The amygdala-kindling model is used to study complex partial epilepsy with secondary generalization. The present study was designed to (A) quantify astrocytic changes in the piriform cortex of amygdala-kindled subjects over time and (B) investigate the role that astrocytes might play in maintaining the seizure-prone state. In Study A, once the experimental subjects reached five stage 5 seizures, stimulation was stopped, and both kindled and control rats were allowed to survive for the interval appropriate to their group (7, 18, 30, or 90 days). Following each interval, the kindled and control animals were given 10 intraperitoneal injections of bromodeoxyuridine (BrdU) and sacrificed 24 h following the last injection. Significantly higher numbers of dividing astrocytes (identified by co-labeling for BrdU and to one of the astrocytic intermediate filament proteins glial fibrillary acidic protein or vimentin) were found in the kindled brains. All kindled groups had significantly higher numbers of double-labeled cells on the side contralateral to the stimulation site, except for those in the 90 day survival group. In Study B, rats were implanted with chemotrodes, were kindled as in Study A, and were subsequently infused with either saline or with L alpha-AA (to lesion astrocytes) during a further 25 stimulations (1/day). L alpha-AA infused rats had significantly diminished levels of behavioral seizures, higher after discharge thresholds, lower after discharge durations, and decreased numbers of double-labeled astrocytes in piriform cortex than did saline infused rats. Together, the data indicate that astrocytes may play a role in maintaining the seizure-prone state.

2-Aminoadipic Acid↗
PubMed2005

The G protein-coupled receptors: pharmacogenetics and disease.

Genetic variation in G-protein coupled receptors (GPCRs) is associated with a wide spectrum of disease phenotypes and predispositions that are of special significance because they are the targets of therapeutic agents. Each variant provides an opportunity to understand receptor function that complements a plethora of available in vitro data elucidating the pharmacology of the GPCRs. For example, discrete portions of the proximal tail of the dopamine D1 receptor have been discovered, in vitro, that may be involved in desensitization, recycling and trafficking. Similar in vitro strategies have been used to elucidate naturally occurring GPCR mutations. Inactive, over-active or constitutively active receptors have been identified by changes in ligand binding, G-protein coupling, receptor desensitization and receptor recycling. Selected examples reviewed include those disorders resulting from mutations in rhodopsin, thyrotropin, luteinizing hormone, vasopressin and angiotensin receptors. By comparison, the recurrent pharmacogenetic variants are more likely to result in an altered predisposition to complex disease in the population. These common variants may affect receptor sequence without intrinsic phenotype change or spontaneous induction of disease and yet result in significant alteration in drug efficacy. These pharmacogenetic phenomena will be reviewed with respect to a limited sampling of GPCR systems including the orexin/hypocretin system, the beta2 adrenergic receptors, the cysteinyl leukotriene receptors and the calcium-sensing receptor. These developments will be discussed with respect to strategies for drug discovery that take into account the potential for the development of drugs targeted at mutated and wild-type proteins.

Drug Resistance↗
PubMed2005

Increased seizure susceptibility of the hippocampus compared with the neocortex of the immature mouse brain in vitro.

PURPOSE: The temporal lobe seems particularly susceptible to seizure activity. Mesial temporal lobe structures, including the hippocampus, have the lowest seizure thresholds in the brain. Conversely, thresholds in the frontal neocortex are significantly higher. The development of intact, isolated preparations of hippocampus and neocortex in vitro allows for study into mechanisms governing seizure threshold. METHODS: Epileptiform discharges in isolated mouse neocortical blocks were compared with the contralateral intact hippocampus, isolated from the same brain, by using the low-Mg2+, 4 aminopyridine (4-AP), and low-Ca2+ in vitro seizure models. The pharmacology of low Mg(2+)-induced ictal-like events (ILEs) generated in the hippocampus and neocortex was then compared by using glutamatergic antagonists DL-2-amino-5-phosphonovaleric acid (APV) and 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX), and the Ca2+ channel antagonist, nifedipine. RESULTS: Neocortical blocks generated both recurrent, spontaneous ILEs and interictal-like events under low-Mg2+ artificial CSF (aCSF) perfusion, distinct from those generated in the hippocampus. ILEs from the hippocampus displayed lower thresholds and longer durations as compared with isolated neocortical blocks. Similar results were obtained during 4-AP perfusion. Perfusion with low-Ca2+ ACSF did not produce stereotypical ILEs in the neocortical block, producing instead recurrent, slow depolarizations. Both ILEs and recurrent, slow depolarizations were produced in the hippocampus. Application of APV and nifedipine exacerbated low Mg(2+)-induced ILEs in the hippocampus but not the neocortex, indicating a distinct pharmacology for partial seizures of different brain regions. CONCLUSIONS: The developing mouse hippocampus demonstrates increased ictogenesis compared with the developing neocortex in vitro, consistent with clinical observations and in vivo experimental models.

2-Amino-5-phosphonovalerate↗
PubMed2005

The acute anticonvulsant effects of deoxycorticosterone in developing rats: role of metabolites and mineralocorticoid-receptor responses.

PURPOSE: The mechanisms that mediate the acute anticonvulsant effects of deoxycorticosterone (DOC) were investigated in young rats. METHODS: Fifteen-day-old rats were pretreated with a variety of compounds, including (a) agonists of the receptors that bind DOC (mineralocorticoid receptors); (b) the DOC 5alpha- and 5alpha-3alpha-reduced metabolites, plus agonists that bind the receptors of the 5alpha-reduced metabolite of DOC (progesterone receptors); and (c) DOC itself in the presence and absence of metabolism and receptor blockers. Fifteen minutes later, pentylenetetrazol (PTZ) was administered, and maximal pentylenetetrazol (MMT) seizure responses were scored. RESULTS: Agonists of mineralocorticoid receptors increased the latency to forelimb flexion in PTZ seizures and sometimes suppressed the seizures completely. At low, nonconvulsant doses, spironolactone (a mineralocorticoid-receptor antagonist) blocked the anticonvulsant effects of a nonsedating, but not a sedating, dose of DOC. These data suggest the possible direct involvement of mineralocorticoid receptors in the anticonvulsant effects of DOC. At low, nonconvulsant doses, finasteride (which blocks the metabolism of DOC) partially blocked the protective effects of DOC, suggesting the contribution of metabolites to the anticonvulsant actions of DOC. Dihydrodeoxycorticosterone (DHDOC)-the first metabolite of DOC, an agonist at progesterone receptors, and an allosteric modulator of the gamma-aminobutyric acid (GABA)(A) receptor-and tetrahydrodeoxycorticosterone, a secondary metabolite of DOC and an allosteric modulator of the GABA(A) receptor, both blocked MMT seizures. CONCLUSIONS: These findings suggest that both DOC and its metabolites may contribute to the anticonvulsant effects seen in young rats, perhaps acting via interactions with several different receptors.

Animals↗
PubMed2005

A comparison of the ability of a 4:1 ketogenic diet and a 6.3:1 ketogenic diet to elevate seizure thresholds in adult and young rats.

PURPOSE: The pentylenetetrazol (PTZ) infusion test was used to compare seizure thresholds in adult and young rats fed either a 4:1 ketogenic diet (KD) or a 6.3:1 KD. We hypothesized that both KDs would significantly elevate seizure thresholds and that the 4:1 KD would serve as a better model of the KD used clinically. METHODS: Ninety adult rats and 75 young rats were placed on one of five experimental diets: (a) a 4:1 KD, (b) a control diet balanced to the 4:1 KD, (c) a 6.3:1 KD, (d) a standard control diet, or (e) an ad libitum standard control diet. All subjects were seizure tested by using the PTZ infusion test. Blood glucose and beta-hydroxybutyrate (beta-OHB) levels were measured. RESULTS: Neither KD elevated absolute "latencies to seizure" in young or adult rats. Similarly, neither KD elevated "threshold doses" in adult rats. In young rats, the 6.3:1 KD, but not the 4:1 KD, significantly elevated threshold doses. The 6.3:1 KD group showed poorer weight gain than the 4:1 KD group when compared with respective controls. The most dramatic discrepancies were seen in young rats. CONCLUSIONS: "Threshold doses" and "latency to seizure" data provided conflicting measures of seizure threshold. This was likely due to the inflation of threshold doses calculated by using the much smaller body weights found in the 6.3:1 KD group. Ultimately, the PTZ infusion test in rats may not be a good preparation to model the anticonvulsant effects of the KD seen clinically, especially when dietary treatments lead to significantly mismatched body weights between the groups.

3-Hydroxybutyric Acid↗
PubMed2004

Effect of the ketogenic diet on the activity level of Wistar rats.

Children, adolescents, and adults with epilepsy often also show symptoms associated with attention-deficit/hyperactivity disorder (ADHD). The ketogenic diet, which is administered to children with epilepsy refractory to drug therapy, seems to improve behavior in individuals with symptoms of ADHD. The basis for this improvement is unknown, although it seems to be unrelated to seizure control. The present research was designed to investigate the effect of two ketogenic diets on the behavior of normal adult male rats. Two experiments were conducted. In experiment 1, 36 subjects were placed on one of three diets: a control diet, a 6.3:1 ketogenic diet, and a 4:1 ketogenic diet. In experiment 2, 20 subjects were placed either on a control diet or on a 4:1 ketogenic diet. The activity level of each subject was measured using an open field test. Time spent immobile, grooming, and in exploratory behavior was measured for 600 s. Subjects were tested once before initiation of the diets and once while on the diets. No significant group differences were found in activity level before initiation of the diets. After initiation of the diets, subjects in both ketogenic groups showed a significantly lower activity level than the rats on the control diet. The ketogenic diet decreases activity level in an animal model. This behavioral change may relate to the improved behavior seen when children with symptoms of ADHD are placed on the diet.

Adolescent↗
PubMed2004

Astrocytic proliferation in the piriform cortex of amygdala-kindled subjects: a quantitative study in partial versus fully kindled brains.

Complex partial epilepsy is a seizure disorder in which attacks frequently arise from foci located in the temporal lobes. The amygdala-kindling model is a widely used model of complex partial epilepsy with secondary generalization. The present study was designed to quantitatively assess astrocytic changes in the rat piriform cortex in the amygdala-kindling model of epilepsy. Bromodeoxyuridine-injected subjects were sacrificed 24 h after the first stage 1 or fifth stage 5 seizure. Brain sections were prepared and examined quantitatively. A significantly higher number of dividing astrocytes (identified by co-labeling with antibodies to bromodeoxyuridine and to one of the astrocytic intermediate filament proteins glial fibrillary acidic protein or vimentin) was found in both partially kindled (stage 1) and fully kindled (stage 5) brains. The partially kindled brains had a significantly higher number of double-labeled cells on the side ipsilateral to stimulation. The opposite trend was observed in the fully kindled brains. Differences between the ipsilateral and contralateral sides of the kindled brain may suggest different role(s) for astrocytes in the development and progression of the seizure-prone state.

Amygdala↗
PubMed2004

Variants of the orexin2/hcrt2 receptor gene identified in patients with excessive daytime sleepiness and patients with Tourette's syndrome comorbidity.

The orexin-2/hypocretin-2 (OX2R) receptor gene is mutated in canine narcolepsy and disruption of the prepro-orexin/hypocretin ligand gene results in both an animal model of narcolepsy and sporadic cases of the human disease. This evidence suggests that the structure of the OX2R gene, and its homologue, the OX1R gene, both members of the G protein-coupled receptor (GPCR) family, and the gene encoding the peptide ligands, the prepro-orexin/hypocretin gene, may be variables in the etiology of sleep disorders. We report a single stranded conformational polymorphism (SSCP) analysis of the coding regions of these genes in idiopathic sleep disorder patients diagnosed with excessive daytime sleepiness (EDS) (n = 28), narcolepsy (n = 28), Tourette's syndrome/chronic vocal or motor tic disorder (n = 70), and control subjects (n = 110). Two EDS patients showed a Pro11Thr change. One Tourette's syndrome patient was found to have a Pro10Ser alteration. The Pro10Ser and Pro11Thr variants were not found in non-disease populations. Analysis of the ability of the mutant receptors to mobilize calcium compared to the wild-type receptor in response to orexin agonists indicated that they resulted in decreased potency at high (etaM) concentrations of orexin ligands. Further work is warranted to study the variability of the orexin/hypocretin system in a variety of disorders characterized by EDS.

Amino Acid Sequence↗