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Biomedical subjects

L James Willmore

Publications and source records attributed to L James Willmore.

9 recordsLinked to original sources
PubMed2005

Molecular regulation of glutamate and GABA transporter proteins by clobazam during epileptogenesis in Fe(+++)-induced epileptic rats.

To assess the molecular effects of the antiepileptic drug clobazam (CLB, 1,5-benzodiazepine), a benzodiazepine effective in the management of epilepsy, we performed a series of experiments using rats with chronic, spontaneous recurrent seizures induced by amygdalar injection of FeCl(3). Experimental animals were treated for 14 days with CLB. We then measured the expression of glutamate and GABA transporter proteins and evaluated the changes that occurred in these proteins using both experimental and control animals. CLB treatment was associated with an increase in the production of GLT-1 in the contra-lateral hippocampus of animals receiving amygdalar FeCl(3) and CLB treatment. CLB treatment up-regulated the GABA transporter GAT3 in the contra-lateral hippocampus of animals with chronic, recurrent seizures. In contrast, CLB had no effect on the expression of EAAC1 and GAT1 in the hippocampus or the cortex in control animal groups. Chronic epileptogenesis may be associated with down-regulation of the production of glial excitatory amino acid transporters, GLAST and GLT-1, proteins that cause increase in the basal extracellular concentrations of glutamate. Elevated GABA transporter expression results in increased reverse transport of GABA to the extracellular space during periods of excitation. In addition to allosteric activation of GABA(A) receptors, this study suggests that CLB might exhibit its antiepileptic action by increasing GLT-1 expression and GAT3 in the hippocampus of rats with chronic seizures.

Amino Acid Transport System X-AG↗
PubMed2005

Antiepileptic drugs and neuroprotection: current status and future roles.

There has been a growing interest in the use of antiepileptic drugs (AEDs) for neuroprotection, and in the possible role of AEDs in disease modification (i.e., antiepileptogenesis). Increased understanding of the mechanisms underlying brain injury has led to advances in the study of neuroprotection. However, defining the clinical paradigm and selecting appropriate outcomes to detect neuroprotective effects present challenges to clinicians studying the neuroprotective properties of drugs. Established AEDs, such as phenytoin, phenobarbital, and carbamazepine, have shown neuroprotective activity in an ischemic/hypoxic model of neuronal injury. Animal model studies also have suggested that newer AEDs, such as levetiracetam, topiramate, and zonisamide, may have neuroprotective or antiepileptogenic properties. However, the prevention of epileptogenesis by an AED has yet to be demonstrated in clinical trials. The future of neuroprotection may involve established and newer AEDs, as well as other compounds, such as immunophilins, caspase inhibitors, endocannabinoids, and antioxidants.

Animals↗
PubMed2004

MRI-based high-dimensional hippocampal mapping in mesial temporal lobe epilepsy.

MRI-based evaluation of the hippocampus is important in the assessment and treatment of patients with mesial temporal lobe epilepsy (MTLE). Using MRI-based large-deformation high-dimensional mapping (HDM-LD), which allows structural evaluation of regions of the hippocampus, we document the HDM-LD-defined pattern of hippocampal deformation in MTLE patients compared with matched controls. In 30 subjects with MTLE and confirmed medial temporal lobe sclerosis (MTS), we performed measurements of intracranial area, brain parenchymal volume and deformation-based hippocampal segmentations, and then grouped patients into right and left MTS groups (resulting in 15 subjects in each group). Using HDM-LD techniques, we compared the right and left MTS groups with a group of 15 matched controls. Analysis included both the MTS and contralateral hippocampi, and covariance for changes in brain parenchymal volume. Final results were interpreted using a segmentation showing normal hippocampal surface subfield anatomy. Comparing the MTS groups with controls, after covarying with brain parenchymal volume, the MTS hippocampi showed significant volume loss (P < 0.0001), contralateral hippocampi showed no significant volume loss. HDM-LD techniques showed significant shape changes, with marked inward deviation in the Sommer sector of the MTS hippocampi. In the contralateral hippocampi, the inferior surface of the hippocampal body showed inward deformation in the medial aspect of the subiculum, with minimal involvement of the Sommer sector. HDM-LD shows involvement of subregions of the hippocampus which are consistent with MTS histopathology. Contralateral hippocampi show different HDM-LD changes, suggesting that the underlying disease process in the contralateral hippocampi is different from MTS.

Adult↗
PubMed2004

Natural antioxidants may prevent posttraumatic epilepsy: a proposal based on experimental animal studies.

Head injury or hemorrhagic cortical infarction results in extravasation of blood and breakdown of red blood cells and hemoglobin. Iron liberated from hemoglobin, and hemoglobin itself, are associated with the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). ROS and RNS have been demonstrated to be involved in the mechanism of seizures induced by iron ions in the rat brain, an experimental animal model for posttraumatic epilepsy (PTE). ROS are responsible for the induction for peroxidation of neural lipids, i.e., an injury of neuronal membranes, and also could induce disorders in the excitatory and inhibitory neurotransmitters. Antioxidants, such as a phosphate diester of vitamin E and C (EPC-K1) and antiepileptic zonisamide, have been known to prevent the epileptogenic focus formation, or to attenuate seizure activities in the iron-injected rat brain. Natural antioxidants, such as alpha-tocopherol, and condensed tannins, including (-)-epigallocatechin and (-)-epigallocatechin-3-O-gallate, adenosine and its derivative, melatonin, uyaku (Lindera Strychnifolia), fermented papaya preparations, Gastrodia elata BI., and Guilingji, have been demonstrated to scavenge ROS and/or RNS and to be prophylactic for the occurrence of epileptic discharge in the iron-injected rat brain.

Animals↗
PubMed2003

Effect of zonisamide on molecular regulation of glutamate and GABA transporter proteins during epileptogenesis in rats with hippocampal seizures.

Epileptiform discharges and behavioral seizures may be the consequences of excess excitation associated with the neurotransmitter glutamate, or from inadequate inhibitory effects associated with gamma-aminobutyric acid (GABA). Synaptic effects of these neurotransmitters are terminated by the action of transporter proteins that remove amino acids from the synaptic cleft. Excitation initiated by the synaptic release of glutamate is attenuated by the action of glial transporters glutamate-aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1), and the neuronal transporter excitatory amino-acid carrier-1 (EAAC-1). GABA is removed from synaptic regions by the action of the transporters proteins GABA transporter-1 (GAT-1) and GABA transporter-3 (GAT-3). In this experiment, albino rats with chronic, spontaneous recurrent seizures induced by the amygdalar injection of FeCl3 were treated for 14 days with zonisamide (ZNS) (40 mg/kg, i.p.). Control animals underwent saline injection into the same amygdalar regions. Treatment control for both groups of intracerebrally injected animals was i.p. injection of equal volumes of saline. Western blotting was used to measure the quantity of glutamate and GABA transporters in hippocampus and frontal cortex. ZNS caused increase in the quantity of EAAC-1 protein in hippocampus and cortex and down regulation of the GABA transporter GAT-1. These changes occurred in both experimental and ZNS treated control animals. These data show that the molecular effect of ZNS, with up-regulation of EAAC-1 and decreased production of GABA transporters, should result in increased tissue and synaptic concentrations of GABA. Although many antiepileptic drugs have effects on ion channels when measured in vitro our study suggests that additional mechanisms of action may be operant. Molecular effects on regulation of transporter proteins may aid in understanding epileptogenesis and inform investigators about future design and development of drugs to treat epilepsy.

Amino Acid Transport System X-AG↗
PubMed2003

Divalproex and epilepsy.

Valproic acid, a branched chain carboxylic acid, has a broad spectrum of action as an antiepilepsy drug. While effective in myoclonus syndromes and absence epilepsy, the drug has efficacy for patients with generalized convulsive and partial seizures as well. Mechanisms of action are similar to other drugs used to treat epilepsy, in that valproate limits sustained repetitive firing by actions on the voltage sensitive sodium channel. However, the drug facilitates the removal of glutamate from synaptic regions by up regulating glial glutamate transporters while prolonging the action of GABA by limiting production of inhibitory transmitter transporter proteins. Adverse effects include hepatotoxicity that requires informing patients and establishing clinical monitoring plans. Teratogenicity occurs with valproate and requires informing patients and careful monitoring in women during pregnancy.

Anticonvulsants↗
PubMed2002

Genetics of epilepsy.

Understanding the molecular biology of epilepsy is a challenge for modern science. Epilepsy results from alternations in fundamental mechanisms of brain and membrane function. Although an understanding of the mode of inheritance and the etiology of genetic epilepsy syndromes forms the basis for genetic counseling, the development of specific therapies will come from knowing the basic mechanisms of epilepsy. Defining the genes causing epilepsy requires an unambiguous definition of seizure phenotype, along with the stability of that trait, an unremitting clinical course, and an abundance of clinical material. This article reviews the task of defining the genetics of epilepsy and discusses genetic methodology, idiopathic generalized and localization-related partial epilepsies, neuronal migration disorders, progressive myoclonus epilepsies, molecular biology of epileptogenesis, and future research.

Child↗
PubMed2002

Molecular biology and genetics of epilepsy.

Genetic and molecular biological methodologies are being applied to the study of patients with epilepsy at an ever-increasing pace. Accurate classification of epilepsy within large families has allowed identification of genes through linkage analysis and then isolation of gene products. Mutations causing ion channel abnormalities coupled with clinical patterns of focal epilepsy syndromes are beginning to change our thinking about the etiology of recurrent seizures in all patients. Molecular methodology is beginning to have impact on understanding of the mechanisms of actions of drugs used to treat epilepsy and will have an impact on how future treatments are designed.

Adolescent↗