Biomedical subjects

W M Burnham

Publications and source records attributed to W M Burnham.

At least 37 records · Page 2Linked to original sources

PubMed1999

Kindling induces an asymmetric enhancement of N-type Ca2+ channel density in the dendritic fields of the rat hippocampus.

The mechanisms underlying epilepsy are largely unknown. Recent genetic, pharmacological and electrophysiological data indicate a significant, but poorly understood, role for voltage-dependent calcium channels (VDCCs). Since the contribution of ion channels to nerve function depends on their cell surface distribution, we hypothesized that epilepsy might alter VDCC surface densities. To test this idea we mapped the expression and distribution of fluorescent-labeled hippocampal N-type VDCCs (N-VDCCs) in an animal model of epilepsy, amygdala kindling. Image analysis demonstrated that kindling induced a 21-40% increase in N-VDCC expression in CA1 but not CA3. This increase occurred in the stratum radiatum and was twice as high in tissues contra- versus ipsi-lateral to the stimulating electrode. These data rationalize recent electrophysiology and argue that a persistent alteration in N-VDCC trafficking in dendrites or nerve termini may contribute to seizure-induced synaptic plasticity.

Animals↗

PubMed1999

Neuroprotective effects of acetylsalicylic acid in an animal model of focal brain ischemia.

Recent studies have shown neuroprotective effects of acetylsalicylic acid (ASA) in cell cultures and hippocampal slices. The present study demonstrates similar effects in a whole-animal modal of focal ischemic stroke. Focal cortical ischemia was produced in Wistar rats by ligation of the common carotid and middle cerebral arteries. Subjects were sacrificed 8 days after ligation, and infarct volume was assessed via automated densitometry. Significant reductions in infarct volume were seen with i.p. ASA doses of 15 mg/kg and above. Reductions occurred when ASA was injected 2 h or 30 min before ligation, but not when it was injected 8 or 24 h before, or 30 min after ligation.

Animals↗

PubMed1999

Kindling induces a long-term enhancement in the density of N-type calcium channels in the rat hippocampus.

How seizures arise and recur in epilepsy is unknown. Recent genetic, pharmacological and electrophysiological data indicate a significant but undisclosed role for voltage-dependent calcium channels. Since the contribution such channels make to nerve function reflects the targeting of discrete subtypes to distinct cellular regions, we hypothesized that epilepsy reflects alterations in their spatiotemporal patterns of expression at the cell surface. To test this possibility, we examined the expression and distribution of hippocampal N-type calcium channels in an animal seizure model: kindling. Confocal microscopy of N-type calcium channels labeled with a new fluorescent ligand, coupled with a novel technique for analysing multiple images, revealed a 20-40% increase in their expression in CA1 and CA3 within 24 h post-seizure. These increases persisted in the dendritic fields of CA1, but had dissipated in CA3 by 28 days post-seizure. Such changes correlate poorly with cell number or synaptogenesis, but are consistent with increased N-type calcium channel expression on presynaptic terminals or, more likely, dendrites. These data rationalize recent electrophysiology and in situ hybridization data, and suggest that kindling alters N-type calcium channel trafficking mechanisms to cause a persistent, local, remodeling of their distributions in CA1 dendrites. The persistent induction of N-type calcium channels may be part of a mechanism for, and a hallmark of, synaptic plasticity, in which kindling represents a reinforcement of synapses en masse.

Animals↗

PubMed1999

Limbic seizures alter reproductive function in the female rat.

PURPOSE: Reproductive dysfunction and endocrine disorders are common among women with temporal lobe epilepsy. This study used the kindled rat model to test the hypothesis that limbic seizures directly contribute to reproductive dysfunction. METHODS: Kindling electrodes were implanted in the basolateral amygdala in adult female rats. Females were kindled by either brief, daily, suprathreshold stimulations with a bipolar electrode or sham-kindled (controls). Electrographic and behavioral seizures were monitored. Estrous cycles also were monitored with daily vaginal smears. RESULTS: Seizures arrested ovarian cyclicity in all (n = 42) kindled animals, the rats exhibiting persistent vaginal cornification (PVC). In these animals PVC was associated with high serum estradiol, increased pituitary weight, and polyfollicular ovaries consisting of many cystic follicles, as well as follicles in various stages of growth and atresia. In 93% of females, this effect occurred after the development of stage 5 motor seizures, when focal seizures had secondarily generalized. In contrast, only five (21%) of 24 sham-kindled controls exhibited PVC. A single injection of progesterone (P4) temporarily restored cyclicity in five (18%) of 28 kindled females exhibiting PVC. In contrast, P4 administration restored cyclicity in all five sham-kindled controls that had spontaneously stopped cycling. P4 treatment to kindled females in PVC resulted in a different endocrine profile than that in non-P4-treated, kindled rats in PVC. P4-treated rats had high serum estradiol, testosterone, and prolactin levels; they showed an increase in pituitary weight; and their ovaries contained numerous corpora lutea and cystic follicles surrounded by markedly overdeveloped thecal cell layers. CONCLUSIONS: Seizures initiated in the amygdala result in impairment of the hypothalamic-pituitary axis, resulting in loss of ovarian cyclicity.

Amygdala↗

PubMed1999

Partial and generalized seizures affect reproductive physiology differentially in the male rat.

PURPOSE: Reproductive dysfunction and endocrine disorders occur frequently among men with epilepsy. This study tested the hypothesis that focal limbic seizures and generalized seizures may both contribute to reproductive dysfunction. METHODS: The rat kindling model was used to mimic focal limbic seizures. Kindling electrodes were placed in the basolateral amygdala. Male rats were either intact, gonadectomized (GDX) or GDX + testosterone (T) replaced and then kindled. Controls were left intact and sham-kindled. Maximal electroconvulsive shock (MES) treatment was used to model generalized seizures, by using eight stimulations, one every other day, for 2.5 weeks. Animals were killed either 3 h or 6 weeks after MES treatment to determine short- and long-term effects. RESULTS: Kindled seizures resulted in an increase in serum testosterone, estradiol, and prolactin in intact males, accompanied by a significant increase in testis, epididymis, and pituitary weight, as well as a significant decrease in prostate weight. MES treatment caused a short-term reduction in serum testosterone and testis, epididymis, and prostate weight. All parameters were restored to control values within 6 weeks of the last MES seizure, with the exception of pituitary weight and serum prolactin, which remained significantly elevated 6 weeks after MES treatment. CONCLUSIONS: Our results indicate that both focal limbic (amygdaloid) seizures and generalized MES seizures disturb normal reproductive physiology in the male rat. Amygdaloid-kindled seizures have mixed effects on different parameters of reproductive function, whereas MES seizures induce a transient hypogonadal state. These results suggest that reproductive dysfunction in men with epilepsy may result from seizure-related interference with the normal functions of the hypothalamic-pituitary-testicular axis.

Amygdala↗

PubMed1998

Amygdala-kindled and electroconvulsive seizures alter hippocampal expression of the m1 and m3 muscarinic cholinergic receptor genes.

Expression of m1 and m3 muscarinic cholinergic receptors mRNAs was examined in rat hippocampus following either: (1) kindling to five Stage 5 amygdala-kindled seizures; or (2) eight electroconvulsive shock (ECS) seizures. Twenty-four hours after the last seizure of either type, there was a significant decrease in both m1 and m3 mRNAs in CA1, CA3 and the dentate gyrus subfields of the hippocampus. Twenty-eight days after the last seizure of either type, there was a significant increase in m1 mRNAs in CA1, CA3, and the dentate gyrus; for m3 mRNAs, there was a significant increase in CA3 28 days after the last ECS seizure, and in CA1 and CA3 28 days after the last kindled seizure. These results suggest that seizures alter the cholinergic system in the hippocampus, and that some of the alterations are very long-lasting.

Amygdala↗

PubMed1998

Kindling-induced neurogenesis in the dentate gyrus of the rat.

Kindling, a form of neuronal plasticity produced by repeated low intensity electrical brain stimulation, leads to epileptic seizures. To address possible causes of this phenomenon, we have prepared amygdala-kindled animals and measured neurogenesis, by bromodeoxyuridine incorporation. Early, when focal seizures were present, there was no evidence of a change in the rate of hippocampal neurogenesis. In contrast, during the later phases of kindling, when secondary generalization was well established and motor seizures were present, neurogenesis was enhanced by 75-140%, depending on the hippocampal region. Double labelling with the neuron-specific marker TOAD-64 demonstrated the presence of numerous new-born granule neurons in the kindled animals. We propose that the newly-born neurons contribute to the cellular changes and behavioral symptoms associated with this type of epileptiform brain plasticity.

Animals↗

PubMed1997

Kainic acid-induced generalized seizures alter the regional hippocampal expression of the rat Kv4.2 potassium channel gene.

Potassium channels play a key role in the regulation of membrane excitability. We investigated the gene expression response of the Kv4.2 subtype of potassium channel, in the rat hippocampus, to a brief (5 min) episode of kainic acid-induced seizures. Our results demonstrate that Kv4.2 expression is reduced in the granule cell layer of the dentate gyrus at 3 h post-seizure, while no significant changes in expression are observed in other hippocampal subfields. At 6 h post-challenge, expression in both dentate hilar cells and granule cells is reduced, while no other significant changes are observed. At 24 h post-challenge, expression levels for Kv4.2 in the dentate granule cells have rebounded to levels greater than control, while expression levels are significantly reduced in the CA3 and CA4 subfields. No significant changes in Kv4.2 expression are observed in kainic acid-administered animals that fail to seize, indicating that the changes in gene expression result from seizure activity and not from the direct actions of the administered kainic acid. These results demonstrate that brief kainic acid-induced epileptiform activity promotes alterations in the expression levels for the Kv4.2 subtype of potassium channel gene.

Animals↗

PubMed1997

Long-term enhancement of entorhinal-dentate evoked potentials following 'modified' ECS in the rat.

Electroconvulsive therapy (ECT) is widely used as a treatment for drug-resistant depression. The animal analogue of ECT is electroconvulsive shock (ECS) seizures. We have recently shown that repeated ECS seizures cause a long-lasting, perhaps permanent, enhancement in entorhinal-dentate evoked potentials in the rat. Our study, however, involved 'unmodified' ECS, whereas in clinical practice ECT is now usually given in its 'modified' form (with near-threshold currents, a short-acting barbiturate, muscle relaxant and oxygen). We have therefore repeated our experiments using modified ECS. Entorhinal-dentate evoked potentials were measured in Long-Evans rats before and after: (1) eight modified ECS seizures; or (2) eight sham modified ECS trials. Despite the use of the modified procedure, a significant and long-lasting enhancement in population spike amplitude was seen in the ECS group. We conclude that the modified procedure does not protect rats against the long-lasting enhancement of evoked potentials. Similar changes may be occurring in the brains of patients subjected to modified ECT.

Animals↗

PubMed1997

Infantile spasms: seasonal onset differences and zeitgebers.

The health records of 76 infants with infantile spasms (IS) were reviewed retrospectively. The distribution of seizure onset was examined with respect to calendar month, annual changes in day length (photoperiod), and global solar radiation (GSR). IS onset was more frequent during the months with low GSR and short photoperiods. The greatest frequency of IS onset was in December and January (22 cases, 29%); the lowest was in April and May (8 cases, 10.5%). IS onset frequency (f) was more than twice as great in the months with a short photoperiod (10Light-14Dark) and a low GSR (f = 11) as compared with months with a long photoperiod (16Light-8Dark) and a high GSR (f = 5). IS onset frequency was 2.2-fold greater in months with a short photoperiod and a low GSR. This finding suggests that environmental photoperiodic factors (zeitgebers) may play a role in the onset of IS.

Environment↗

PubMed1997

Kainic acid-induced generalized seizures alter the regional hippocampal expression of the rat m1 and m3 muscarinic acetylcholine receptor genes.

We investigated the gene expression responses using in situ hybridization with radiolabelled riboprobes for the m1 and m3 subtypes of muscarinic cholinergic receptors in the rat hippocampus following a brief (5-min) kainic acid-induced behavioral seizure. The kainic acid was intraperitoneally administered, and the ensuing generalized convulsive seizure terminated with diazepam. Our results demonstrate that the expression of the m1 subtype was significantly reduced in the CA1, CA3 and the dentate granule cells by 3 h after the administration of kainic acid while no significant change was observed in any hippocampal subfield for the m3 subtype. By 6 h post challenge, the m1 subtype was still decreased in all hippocampal subfields examined, while the m3 subtype remained unchanged from vehicle injected control. At 24 h post challenge, both the m1 and m3 subtypes were significantly reduced in the CA1 and CA3 subfields; the expression of the m1 subtype in the dentate granule cells, however, had recovered to levels indistinguishable from vehicle-injected control. These results demonstrate that epileptiform activity induced by kainic acid administration promotes alterations in the expression levels for both the m1 and m3 muscarinic receptor genes, and suggest that the activity of this neuromodulatory system in the hippocampus may be altered through activity-dependent mechanisms at early times following seizures.

Animals↗

PubMed1996

Brain region-specific and time-dependent decreases of G alpha i2 in amygdala-kindled rats.

Immunoreactivity levels of G protein alpha-subunits, Galphas (45 and 52 kDa), Galphai1, and Galphai2, were determined in plasma membranes prepared from ipsilateral amygdala-pyriform cortex (AM/PC), contralateral AM/PC, dorsal hippocampus (DH), and ventral hippocampus (VH) in amygdala-kindled rats 24 h, 1 month, and 3 months after the last seizure. Relative to sham controls, immunoreactivity levels of Galphai2 were significantly reduced in ipsilateral AM/PC and DH, with maximal decreases observed, respectively, at 24 h (26% form control levels) and 1 month (18% from control levels) postseizure. No significant alterations in the levels of Galphai1 or either of the Galphas isoforms were observed. The reduction in Galphai2 levels was, however, not accompanied by measurable changes in Galphai-mediated inhibition of adenylyl cyclase, as estimated by GppNHp modulation of forskolin-activated adenylyl cyclase activity. The present findings add support to the hypothesis that long-term changes in brain functioning following kindling may involve altered expression and/or function of components of the transmembrane signalling cascade, including G proteins.

Adenylyl Cyclases↗

PubMed1996

Amygdala-kindled convulsions in suspended rats.

Amygdala-kindled Long-Evans rats were suspended in a harness--with all four feet off the ground--and their convulsions were triggered, videotaped, and scored. In the suspended subjects, it was found that kindled convulsions involve the hindlimbs as well as the forelimbs and that they involve tonus as well as clonus. These data contradict the commonly held view that kindled convulsions consist only of face and forelimb clonus. They suggest that kindled convulsions resemble the generalized, whole-body convulsions observed in the maximal electroshock model and other "maximal" seizure models.

Amygdala↗

PubMed1995

Long-term changes in entorhinal-dentate evoked potentials induced by electroconvulsive shock seizures in rats.

Entorhinal-dentate evoked potentials were measured in rats before and after: (1) eight electroconvulsive shock (ECS) seizures, or (2) matched handling. In animals that received ECS, evoked potentials were significantly enhanced, as evidenced by a long-lasting increase in the amplitude of the population spike. This increase in population-spike amplitude lasted for at least 3 months after the last ECS trial. No evoked-potential changes were observed in the subjects that received matched handling. These data suggest that ECS seizures produce long-lasting, perhaps permanent, changes in the brain.

Analysis of Variance↗

PubMed1995

Alterations in the brain GABAA/benzodiazepine receptor-chloride ionophore complex in a genetic model of paroxysmal dystonia: a quantitative autoradiographic analysis.

Dystonia is a relatively common syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures. The most frequent type of dystonia is idiopathic generalized dystonia, whose pathophysiology is largely unknown. In this respect, mutant animal strains with inborn dystonia may be helpful to elucidate the pathophysiological defects involved in idiopathic dystonia. The genetically dystonic (dtsz) hamster is an animal model of paroxysmal dystonia that displays attacks of generalized dystonia either spontaneously or in response to mild environmental stimuli. In the present study, a quantitative autoradiographic analysis of ligand binding to different sites of the GABAA/benzodiazepine receptor-chloride ionophore complex was carried out in 123 brain areas from genetically dystonic mutant hamsters and age-matched control hamsters. Animals were killed 2 weeks after their last dystonic attack. Analysis of the GABA-binding site of the receptor complex, using the ligand [3H]muscimol, and the benzodiazepine site labelled with [3H]flunitrazepam revealed no significant alterations in the binding of either ligand in any of the brain regions examined. In contrast, widespread changes were observed in binding densities of [35S]t-butylbicyclophosphorothionate ([35S]t-butylbicyclophosphorothionate), which labels the picrotoxinin site of the GABAA receptor-chloride ionophore complex. Significantly increased [35S]t-butylbicyclophosphorothionate binding was found in several parts of the thalamus, cortex, and hippocampus as well as in the red nucleus, the subthalamic nucleus, and the granular layer of the cerebellum. Since high-affinity [35S]TBPS binding is thought to represent the closed conformation of the GABA-gated chloride ionophore, increased TBPS binding would indicate an impaired GABAergic function. The study is consistent with the concept that dystonia is caused by impaired connections between the basal ganglia, the thalamus, and frontal association areas. The data on increased [35S]TBPS binding are the first evidence implicating alterations in the GABA-gated chloride ion channel function in a movement disorder, i.e. idiopathic generalized dystonia.

Animals↗

PubMed1994

Decreased voluntary ethanol selection in amygdala-kindled rats.

Kindled and control rats were exposed to either ethanol or dextrose solutions in the limited access paradigm, a paradigm that allows access to the test solution for only 1 h each day. Limited access trials were initiated either 24 h or 30 days after the fifth stage 5 seizure had been elicited in the kindled subjects. As previously reported, increased voluntary ethanol selection was observed in the limited access paradigm. Kindled subjects, however, ingested significantly less ethanol than controls. This difference was found both when limited access trials were started 24 h after the last seizure and when they were started 30 days after the last seizure. Kindled and control subjects did not differ in their intake of dextrose solutions.

Alcohol Drinking↗

PubMed1994

The effect of anticonvulsant drugs on GABA-stimulated chloride uptake.

Eight anticonvulsant drugs-including clonazepam, diazepam and phenobarbital-were tested for their effects on GABA-stimulated chloride uptake in rat cerebral cortical microsacs (unfiltered synaptoneurosomes). "Mid" and "high" therapeutic concentrations were screened, and, if significant enhancement was found, full concentration-response tests were done. In the initial screens, enhancement of GABA-stimulated uptake was found only with phenobarbital, clonazepam and diazepam. In subsequent concentration-response tests, the effects of phenobarbital were found to occur throughout the range of normal, anticonvulsant concentrations, whereas the effects of clonazepam and diazepam were observed only above the concentrations normally used for the chronic control of seizures or anxiety. These data suggest that phenobarbital's anticonvulsant effects are mediated via the GABAA receptor complex, but that the low-dose effects of the benzodiazepines may be mediated via some other mechanism.

Animals↗

PubMed1993

Brain cytochrome oxidase activity after kindled seizures: a quantitative histochemical mapping study.

Quantitative histochemistry was used to analyze changes in cytochrome oxidase (CO) activity in 93 brain regions after entorhinal cortex kindling. Rats were kindled to at least six stage-5 seizures and sacrificed either 24 h or 28 days after the last convulsion. Regional brain CO activity was quantitated in histological sections using calibrated densitometric standards. No statistically significant differences in regional CO activity between kindled and control brains were seen either 24 h or 28 days after the last convulsion. These results suggest that the brain changes underlying the kindling state are not reflected in localized alterations in mitochondrial respiratory capacity. They also indicate that long-lasting changes in regional brain CO activity recently found after electroconvulsive shock are not common to all types of seizures.

Animals↗