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PubMed1999

Amygdala enlargement in dysthymia--a volumetric study of patients with temporal lobe epilepsy.

BACKGROUND: Previous studies indicated an important role of the amygdala for emotional information processing. We investigated a possible relationship between amygdala volumes, aggressive behavior, and dysthymia, in patients with temporal lobe epilepsy (TLE). METHODS: Patients with TLE with and without aggression or dysthymia and healthy volunteers were assessed using quantitative MRI. Amygdala volumes were measured in a blinded fashion and corrected for total brain volumes. RESULTS: There was a highly significant enlargement of left and right amygdala volumes in patients with dysthymia (right side, p < .000; left side, p = .001). We found a significant positive correlation between left amygdala volumes (p = .02) and a trend towards positive correlation between right amygdala volumes and depression (p = .06), as measured with the Beck Depression Inventory. Amygdala volumes of females were significantly larger than those of males (left side: p = .005; right side: p = .06). CONCLUSIONS: This is the second report of a relationship between amygdala volumes and depressed mood, confirming an earlier finding in patients with bipolar disease, and the first study reporting a correlation between amygdala volumes and depression. Increased processing of emotional information might increase amygdala blood flow and subsequently, result in amygdala enlargement.

Adolescent↗

PubMed1990

Mapping of collision frequencies for stearic acid spin labels by saturation-recovery electron paramagnetic resonance.

Short pulse saturation-recovery electron paramagnetic resonance methods have been used to measure interactions of 14N:15N stearic acid spin label pairs in multilamellar liposomal dispersions composed of dimyristoyl-phosphatidylcholine (DMPC) and dielaidoylphosphatidylcholine (DEPC). Pairs consisting of various combinations of [14N]-16-, [14N]-12- or [14N]-5-doxylstearate, and [15N]-16-, [15N]-12-, or [15N]-5-doxylstearate were studied. SR experiments were performed at 27 degrees and 37 degrees C, and recovery signals were analyzed for initial conditions and multiexponential time constants by computer fitting using a damped least-squares approach. The time constants contain combinations of the electron spin lattice relaxation time, Tle, for each member of the spin-label pair, and the Heisenberg exchange rate constant, Kx. Spin-lattice relaxation times for each of the 14N and 15N stearic acid spin labels were determined, and it is noted that Tle for a given 15N-SASL was always slightly greater than that of the corresponding 14N-SASL. From Kx the bimolecular collision frequency was calculated, providing a detailed picture of molecular interactions. For both lipid systems the bimolecular collision rates were ordered as 12:5 less than 16:5 less than 5:5 less than 16:12 less than 12:12 less than 16:16. For all spin-label pairs studied, interaction frequencies were greater in DMPC than in DEPC. For the 16:16, 12:12, and 16:12 pairs, Kx was approximately 30% greater in DMPC than in DEPC, a significantly greater difference than is observed by conventional EPR methods. Further confirmation of the existence of vertical fluctuation of nitroxide moieties that are at the 16- (or 12) position toward the polar surfaces was obtained, with the frequency of 16:5 (or 12:5) interactions ~40% of the 16:16 (or 12:12) interaction frequency. In both DMPC and DEPC, Kx for homogeneous pairs increases as the doxyl moiety is moved further down the alkyl chain (i.e.,5:5 < 12:12 < 16:16), suggesting that steric effects or the local rotational mobility of the nitroxide group influence the frequency at which spin exchange occurs.

Cyclic N-Oxides↗

PubMed1997

Metabolic and pathological effects of temporal lobe epilepsy in rat brain detected by proton spectroscopy and imaging.

The goal of these experiments was to test the hypothesis that in an animal model of temporal lobe epilepsy (TLE), magnetic resonance spectroscopic measurement of N-acetylaspartate (NAA) and other metabolites, together with magnetic resonance imaging, provides a sensitive in vivo method to localize and monitor the progression of neuronal cell death and gliosis. Seizures were induced in rats by unilateral hippocampal injection of kainate. Magnetic resonance measurements were made from 1 to 84 days using proton spectroscopic imaging (1H-MRSI), T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI). The results were compared with findings on histological sections. Decreased NAA and creatine levels and increased apparent diffusion coefficient of water were found in the ipsilateral hippocampus after 14 days where neuronal loss and gliosis were observed. In the contralateral hippocampus a significant increase of choline level was observed. These results suggest that 1H-MRSI is a useful in vivo method for localizing neuronal loss and may also indicate additional pathological and metabolic alterations. In addition, DWI may be a useful method for in vivo detection of tissue alterations due to TLE.

Animals↗

PubMed1999

Analysing metabotropic glutamate group III receptor mediated modulation of synaptic transmission in the amygdala-kindled dentate gyrus of the rat.

Metabotropic glutamate receptors (mGluRs) provide a powerful control of synaptic transmission in the hippocampus and may serve as a target for drug development in human temporal lobe epilepsies. Agonists and antagonists at these receptors influence the development and propagation of seizures in some animal models of epilepsy. Experimental seizures can change the level of expression of mGluRs in the rat hippocampus. In the human dentate gyrus of patients suffering from temporal lobe epilepsy (TLE), group III mGluR mediated inhibition of synaptic transmission is almost lost in the sub-group with Ammon's horn sclerosis. We tested the modulation of synaptic transmission by the group III mGluR specific agonist L(+)-2-amino-4-phosphonobutyric acid (L-AP4) in the dentate gyrus outer molecular layer in control and amygdala-kindled rats, a common model for TLE. Extracellular field potential recordings upon subthreshold stimulation of lateral perforant path fibers were measured simultaneously in the outer molecular layer and granule cell layer. Analysis of 'paired-pulse' characteristics in the absence and presence of L-AP4 and group III mGluR mediated inhibition of synaptic transmission in the lateral perforant path revealed no significant alterations in fully kindled rats. Since there is no evidence of altered L-AP4 responses, a loss of group III mGluR function, particularly that of subtype mGluR8, seems not necessary for the kindling epilepsy.

Amygdala↗

PubMed1998

An evaluation of how MRI is used as a pre-operative screening investigation in patients with temporal lobe epilepsy.

AIMS: A retrospective analysis was carried out of how magnetic resonance imaging (MRI) is used as a pre-operative screening investigation in patients with a clinical diagnosis of medically intractable temporal lobe epilepsy (TLE). Up to 65% of such patients are said to have hippocampal sclerosis (HS). MATERIALS AND METHODS: Forty-six patients in a 26-month period underwent MR examination on a 1.5 T scanner according to a routine protocol. Each patient had coronal T1-weighted and oblique coronal T2-weighted scans performed. Hippocampal volume was calculated from the T1-weighted images, the T2-weighted images being assessed for relative hippocampal signal intensity. Each individual patient's medical records were audited. RESULTS: Thirty per cent of patients in our study had a diagnosis of HS made on their MR scan. No patient had a diagnosis of HS made without prior clinical evidence of seizure lateralization. Sixty-eight per cent of patients with clinical evidence of a unilateral seizure focus had HS diagnosed by MR scanning. Forty-three per cent of patients did not have clinical evidence of an unilateral seizure focus. It was found that over 25% of patients referred to the unit did not fit the criteria of having medically intractable TLE. Nine per cent of patients had previously stated that they did not want epilepsy surgery. CONCLUSION: The lower than expected diagnostic rate of HS in this patient population reflects the broad criteria used in referring patients for imaging studies. This is likely to mirror the initial investigation of these patients outside specialist units where more extensive investigation prior to MRI is available. However, when MRI is used as an initial screening investigation, this study indicates that implementation of simple clinical criteria should significantly reduce the number of unnecessary scans.

Adolescent↗

PubMed2002

Effect of phenytoin on sodium and calcium currents in hippocampal CA1 neurons of phenytoin-resistant kindled rats.

About 20-30% of patients with epilepsy continue to have seizures despite carefully monitored treatment with antiepileptic drugs. The mechanisms explaining why some patients' respond and others prove resistant to antiepileptic drugs are poorly understood. It has been proposed that pharmacoresistance is related to reduced sensitivity of sodium channels in hippocampal neurons to antiepileptic drugs such as carbamazepine or phenytoin. In line with this proposal, a reduced effect of carbamazepine on sodium currents in hippocampal CA1 neurons was found in the rat kindling model of temporal lobe epilepsy (TLE), i.e. a form of epilepsy with the poorest prognosis of all epilepsy types in adult patients. To address directly the possibility that neuronal sodium currents in the hippocampus play a crucial role in the pharmacoresistance of TLE, we selected amygdala-kindled rats with respect to their in vivo anticonvulsant response to phenytoin into responders and nonresponders and then compared phenytoin's effect on voltage-activated sodium currents in CA1 neurons. Furthermore, in view of the potential role of calcium current modulation in the anticonvulsant action of phenytoin, the effect of phenytoin on high-voltage-activated calcium currents was studied in CA1 neurons. Electrode-implanted but not kindled rats were used as sham controls for comparison with the kindled rats. In all experiments, the interval between last kindled seizure and ion channel measurements was at least 5 weeks. In kindled rats with in vivo resistance to the anticonvulsant effect of phenytoin (phenytoin nonresponders), in vitro modulation of sodium and calcium currents by phenytoin in hippocampal CA1 neurons did not significantly differ from respective data obtained in phenytoin responders, i.e. phenytoin resistance was not associated with a changed modulation of the sodium or calcium currents by this drug. Compared to sham controls, phenytoin's inhibitory effect on sodium currents was significantly reduced by kindling without difference between the responder and nonresponder subgroups. Further studies in phenytoin-resistant kindled rats may help to elucidate the mechanisms that can explain therapy resistance.

Animals↗

PubMed2001

Amygdala lesion in temporal lobe epilepsy subjects impairs associative learning of emotional facial expressions.

To investigate the role of unilateral amygdala lesions on processing emotions, 22 drug-resistant temporal lobe epilepsy (TLE) subjects (12 with left-sided and ten with right-sided focus) were tested, after anterior temporal lobectomy or selective amygdalo-hippocampectomy on two associative learning tasks containing emotional and neutral facial expressions, respectively. Volumetric lesion analysis was performed on the basis of 3-D MR images. No effects of lesion side were found in TLE subjects. Taken the extent of amygdala damage into account, an interaction effect could be shown between task (learning of neutral facial expressions versus emotional facial expressions) and group (subjects with little versus considerable amygdala damage), indicating worse performance of subjects with considerable amygdala damage in learning emotional facial expressions. Subjects with considerable amygdala damage were also significantly impaired in learning emotional facial expressions when compared with control subjects.

Adult↗

PubMed1997

Spatial memory deficits in patients with unilateral damage to the right hippocampal formation.

Patients with unilateral temporal lobe damage resulting from intractable temporal lobe epilepsy (TLE, n = 30) or from temporal lobe resection (temporal lobectomy, TLR, n = 47) were investigated on the Nine-box Maze. The task, analogous to the radial arm maze, was designed to compare spatial mapping and working memory theories of the functions of the hippocampus. The task provides measures of spatial, object, working and reference memory, incorporated into a within subjects design. The spatial component was designed to encourage the formation of allocentric rather than egocentric spatial representations. Spatial memory deficits were found (across working and reference memory components) in both TLE and TLR patients with right temporal lobe damage, with intact spatial memory in patients with corresponding left temporal lobe damage. Performance on the matched non-spatial (object) working memory component was equal to healthy controls for all groups. However all patient groups showed a deficit on object reference memory. These findings are discussed in relation to the underlying temporal lobe pathology and particularly atrophy of the hippocampal formation. Overall, the results support the cognitive mapping theory of hippocampal function, with the demonstration of a selective (and probably allocentric) spatial memory deficit in patients with right hippocampal damage.

Adolescent↗

PubMed1998

A test of spatial memory and its clinical utility in the pre-surgical investigation of temporal lobe epilepsy patients.

Deficits in memory for figurative detail, spatial composition and the spatial location of objects in a scene have been reported postoperatively in right temporal lobectomy patients. The aim of this study was to examine whether these deficits can be used as a sign of lateralised dysfunction in pre-surgical temporal lobe epilepsy (TLE) patients. Sixty-nine patients with lateralised TLE (27 right, 42 left) were assessed on a battery of neuropsychological tests, including tests of general intellectual functioning and psychomotor speed and standardised memory tests involving the learning and recall of verbal and non-verbal material. A new task, the "Aspects of Spatial Memory Test" (AoSMT), based on the experimental tasks developed by Pigott and Milner [39] was also administered. The RTLE and LTLE groups did not differ in their overall level of intellectual function or on measures of cognitive and motor speed. On the AoSMT the LTLE group recognised significantly more figurative detail changes than the RTLE group. In addition, the RTLE group took significantly longer than the LTLE group to identify changes in orientation, figurative detail and filled/unfilled spaces. Poor scores on the AoSMT were significantly correlated with quantitative MRI measures of right hippocampal pathology. The clinical and theoretical implications of these findings are discussed.

Adult↗

PubMed2002

Functional genomics in experimental and human temporal lobe epilepsy: powerful new tools to identify molecular disease mechanisms of hippocampal damage.

The human genome project is a milestone for molecular genetic studies on complex, sporadic disorders in the human central nervous system (CNS). Functional analysis and tissue-/cell-specific expression profiles will be of particular importance anticipating the magnitude of expressed genes in the brain and their dynamic epigenetic modifications. The recent progress in microarray technologies allows expression studies for a large number of genes. In combination with laser-microdissection and quantitative reverse transcription-polymerase chain reaction technologies, such large-scale expression analyses can be successfully addressed in well-defined tissue specimens or cellular subpopulations. Complex, sporadic diseases, such as temporal lobe epilepsy (TLE), are challenging for functional genomics. Issues of particular importance in this field include molecular mechanisms of neurodevelopmental abnormalities, neuronal plasticity and hyperexcitability as well as neuronal cell damage in affected CNS areas. The availability of anatomically well-preserved surgical specimens, i.e. hippocampus obtained from epilepsy patients with Ammon's horn sclerosis or focal lesions not affecting the hippocampus proper as well as comparisons with experimental TLE models may help to elucidate specific molecular-pathological mechanisms during epileptogenesis and in chronic conditions of the disease.

Animals↗

PubMed2002

Proton magnetic resonance spectroscopic imaging suggests progressive neuronal damage in human temporal lobe epilepsy.

Whether temporal lobe epilepsy (TLE) is the result of an isolated, early injury or whether there is ongoing neuronal damage due to seizures is often debated. We attempted to examine the long-term effect of seizures using proton magnetic resonance spectroscopic imaging (1H-MRSI), which can quantify neuronal loss or dysfunction based on reduced signals from the neuronal marker N-acetylaspartate (NAA). We performed 1H-MRSI in 82 consecutive patients with medically intractable, non-foreign-tissue TLE to determine whether there was a correlation between seizure frequency, type or duration of epilepsy and NAA to creatine ratios (NAA/Cr). Spectroscopic resonance intensities were categorized as to whether they were measured from the temporal lobe ipsilateral or contralateral to the predominant EEG focus. Ipsilateral and contralateral NAA/Cr was negatively correlated with duration of epilepsy. Furthermore, patients with frequent generalized tonic-clonic seizures had lower NAA/Cr than patients with no or rare generalized tonic-clonic seizures. The results suggest that although an early injury may cause asymmetric temporal lobe damage that is present at the onset of epilepsy, generalized seizures may induce additional neuronal damage that progresses over the course of the disease.

Cross-Sectional Studies↗

PubMed1996

Functional activity of new C-terminal cyclic-neurotensin fragment analogs.

Neurotensin (NT, pGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu) is a tridecapeptide that displays a wide spectrum of biological actions. Cyclic derivatives of a hexapeptide NT [(8-13)] (N alpha MeArg-Lys-Pro-Trp-Tle-Leu, Tle = tert-leucine) were designed and prepared by a combination of solution and solid-phase peptide synthetic methodologies. As reported previously, several analogs possessed nanomolar binding affinities for NT receptors in newborn (10-day-old) mouse brain membrane preparations. In this study, we determined the functional ability of these analogs to mobilize intracellular free calcium, [Ca2+]i, in HT-29 cells (human colonic adenocarcinoma). Of greatest interest were the cyclic compounds 2, 6 and 9 that had Ki values of 0.19, 3.50 and 4.18 microM for [3H]NT labeled receptors in the HT-29 cell membrane assay, respectively. In the functional assay, compounds 2 and 6 mobilized [Ca2+] with EC50 values of 0.13 and 20 microM, respectively. In comparison, Compound 9 blocked the NT-induced mobilization of [Ca2+]i, with an IC50 of 1.70 microM. The present findings indicate that small molecule cyclic analogs, that possess functional activity, can be designed and may have therapeutic utility in the treatment of schizophrenia and possibly other neurological disorders.

Amino Acid Sequence↗

PubMedDate not supplied

Functional transitions and active life expectancy for older Japanese living in a community.

We examined functional transitions in both the activities of daily living (ADL), and instrumental activities of daily living (IADL), over a 1-year interval among older Japanese living in a community, then estimated their physically active life expectancy (PALE) and instrumentally active life expectancy (IALE). In 1992, all residents aged 65 or older who lived in Saku City, Nagano, Japan, were followed-up over the 1-year interval. A self-administrated questionnaire, which involved age, sex, five ADL items, and five IADL items, was used for each survey in both 1992 and 1993. Of the baseline cohort (n=10,098), we received 9533 analyzable questionnaires at the follow-up survey in 1993. During the follow-up, 92 and 87% of subjects who were initially independent in ADL and IADL remained independent, respectively. PALE for men and women were estimated to be 16.0 and 18.9 at 65 years of age, respectively. IALE for men and for women were estimated to be 12.8 and 14.6 at the age of 65, respectively. Proportions of the PALE to total life expectancy (TLE) at any age did not greatly differ between men and women; however, men had a slightly larger proportion of IALE to TLE at any given age than women.

Journal Article↗

PubMed2000

Quantitative magnetic resonance imaging in consecutive patients evaluated for surgical treatment of temporal lobe epilepsy.

We present the results of quantitative Magnetic Resonance Imaging (MRI) in 55 consecutively referred patients with clinical evidence of temporal lobe epilepsy (TLE). The Cavalieri method was used in combination with point counting to provide unbiased estimates of the volume of the left and right hippocampus, amygdala, temporal lobe, lateral ventricles and cerebral hemisphere, and pixel by pixel maps of the T2 relaxation time were computed for both central and anterior sections of the hippocampus. The 99th centiles of hippocampal volume, hippocampal volume asymmetry and T2 relaxation times in 20 control subjects provided limits which identified the presence of MTS. The results of the quantitative MRI were compared with the results of conventional diagnostic MRI, foramen ovale (FO) recording and the WADA test. Thirty-one patients were found to have unilateral MTS (17 left and 14 right) and 7 bilateral MTS. No evidence of MTS was detected in 16 patients. Of the 31 patients diagnosed with unilateral MTS on the basis of hippocampal volume and T2 measurement, 74% and 77% would respectively have received the same diagnosis on the basis of hippocampal volume and T2 measurements alone. In comparison to FO recording, quantitative MRI has a sensitivity of 55% and a specificity of 86%, while conventional diagnostic MRI has a sensitivity of 42% and a specificity of 80% for detection of MTS. Unilateral abnormalities were detected by FO recording in 30% cent of patients who appeared normal on quantitative MRI. WADA test results were available for 40 patients. The findings were consistent with quantitative MRI showing reduced memory function ipsilateral to unilateral MTS in 18 patients, but reduced memory function contralateral to unilateral MTS in two patients, and reduced memory function without MR abnormality in seven patients. WADA testing revealed unilateral memory impairments where MRI found bilateral pathology in 4 patients and in 4 patients in whom quantitative MRI detected unilateral MTS there was no evidence of reduced memory during WADA testing of the corresponding cerebral hemisphere. In the patients with unilateral right MTS a highly significant negative correlation (p = 0.0003) was observed between age of onset and the volume of the contralateral temporal lobe. Quantitative MR imaging of the hippocampus (i.e. volume and T2 measurement) is preferable to conventional radiological reporting for providing objective evidence of the presence of MTS on which to base the referral of patients for surgery, and since it has associated morbidity FO recording is now only being used in selected patients. Furthermore, stereology provides a convenient method for estimating the volume of other brain structures, which is relevant to obtaining a better understanding of the effects of laterality and age of onset of TLE.

Adolescent↗

PubMed2002

Diffusion tensor MRI in temporal lobe epilepsy.

The purpose of this study was to investigate the diffusion characteristics of white matter in patients with focal temporal lobe epilepsy (TLE). Diffusion tensor imaging (DTI) was applied to patients and normal controls. Rotationally invariant mean diffusivity and diffusion anisotropy maps were calculated for all subjects. Comparisons between the two groups were performed for several white matter structures. Mean diffusivity and diffusion anisotropy of each selected structure were tested for correlations with age at onset and duration of epilepsy. Significantly lower diffusion anisotropy, and higher diffusivity in directions perpendicular to the axons, was detected in several white matter structures of the patients when compared to the controls. These structures were not located in the temporal lobes. No significant difference in mean diffusivity was detected between the selected structures from the two groups. Diffusion anisotropy was significantly correlated with age at onset of epilepsy in the posterior corpus callosum. Duration of epilepsy was not significantly correlated with the diffusion indices from any of the selected structures. The results of this study suggest that diffusion anisotropy may reveal abnormalities in patients with focal TLE. In addition, these abnormal changes are not necessarily restricted to the temporal lobes but might extend in other brain regions as well. Furthermore, the age at onset of epilepsy may be an important factor in determining the extent of the effect of epilepsy on white matter.

Adult↗

PubMed1999

Automatic detection of hippocampal atrophy on magnetic resonance images.

An automatic method for identifying hippocampal atrophy on magnetic resonance (MR) images obtained from patients with clinical evidence of temporal lobe epilepsy (TLE) is described. The method is based on the analysis of image intensity differences between patients and controls within a volume of interest (VOI) centred on the hippocampus. The core of the method is a fully automatic signal intensity-based inter-subject image registration technique. In particular, a global affine registration to a reference image is performed, followed by a local affine registration within the VOI. A mask produced by manual segmentation of the mean hippocampus for 30 control subjects enabled investigations to be restricted to a specified region of the VOI approximately corresponding to the hippocampus. Normal variations of hippocampal signal intensity were computed from images obtained for the 30 control subjects. The manual method of hippocampal volumetry, currently an important component of the pre-surgical evaluation of patients with clinical evidence of medically intractable TLE, is used to determine the lower 1st percentile limits of normal hippocampal volume. Hippocampi with volumes below this limit are defined as atrophic. We investigated whether the automatic method can correctly distinguish between 15 patients with significant hippocampal atrophy according to absolute volumes and a further 14 controls. ROC curves enabled evaluation of sensitivity and specificity in respect of an intensity threshold. 100% specificity is required when determining suitability of patients for neurosurgery, resulting in levels of 50% and 70% sensitivity in detecting atrophy in the right and left hippocampus, respectively. We propose that the method can be developed as an automatic screening procedure.

Adolescent↗

PubMed2000

The effects of an alpha-2 adrenergic agonist, guanfacine, on rCBF in human cortex in normal controls and subjects with focal epilepsy.

Alpha-2 noradrenergic agonists may have wide applicability in the treatment of pre-frontal cortex deficits in primates and behavioral dysfunction in man. We have undertaken this study to determine the effect of an alpha-2 agonist, guanfacine, on regional cerebral blood flow (rCBF) in humans. Three subject groups were evaluated: normal controls, subjects with frontal lobe epilepsy (FLE), and subjects with temporal lobe epilepsy (TLE). All underwent a number of PET scans using 15O-water, with half before and half after a single dose of guanfacine. A wide area of increased rCBF was seen in the frontal lobe, maximal at the central region, following guanfacine in controls and subjects with TLE. Smaller areas of decrease in rCBF were seen in the posterior temporal-occipital cortex. In the FLE group a decrease in rCBF was seen in the dorsal prefrontal cortex on the epileptogenic side with only small increases seen in the mid- to anterior temporal perisylvian areas. The ability of alpha-2 agonists to enhance performance of tasks reliant on prefrontal cortex, without improving tasks believed to rely on intact temporal-hippocampal function, may be explained by these results. Epileptogenic zones appear to create both direct and indirect changes in patterns of drug response. Further studies on the cognitive properties of these agents in humans should be encouraged.

Adrenergic alpha-2 Receptor Agonists↗

PubMed2001

Vigabatrin protects against hippocampal damage but is not antiepileptogenic in the lithium-pilocarpine model of temporal lobe epilepsy.

In temporal lobe epilepsy (TLE), the nature of the structures involved in the development of the epileptogenic circuit is still not clearly identified. In the lithium-pilocarpine model, neuronal damage occurs both in the structures belonging to the circuit of initiation and maintenance of the seizures (forebrain limbic system) as well as in the propagation areas (cortex and thalamus) and in the circuit of remote control of seizures (substantia nigra pars reticulata). In order to determine whether protection of some brain areas could prevent the epileptogenesis induced by status epilepticus (SE) and to identify the cerebral structures involved in the genesis of TLE, we studied the effects of the chronic exposure to Vigabatrin (gamma-vinyl-GABA, GVG) on neuronal damage and epileptogenesis induced by lithium-pilocarpine SE. The animals were subjected to SE and GVG treatment (250 mg/kg) was initiated at 10 min after pilocarpine injection and maintained daily for 45 days. These pilo-GVG rats were compared with rats subjected to SE followed by a daily saline treatment (pilo-saline) and to control rats not subjected to SE (saline-saline). GVG treatment induced a marked, almost total neuroprotection in CA3, an efficient protection in CA1 and a moderate one in the hilus of the dentate gyrus while damage in the entorhinal cortex was slightly worsened by the treatment. All pilo-GVG and pilo-saline rats became epileptic after the same latency. Glutamic acid decarboxylase (GAD67) immunoreactivity was restored in pilo-GVG rats compared with pilo-saline rats in all areas of the hippocampus, while it was increased over control levels in the optical layer of the superior colliculus and the substantia nigra pars reticulata. Thus, the present data indicate that neuroprotection of principal cells in the Ammon's horn of the hippocampus is not sufficient to prevent epileptogenesis, suggesting that the hilus and extra-hippocampal structures, that were not protected in this study, may play a role in the genesis of spontaneous recurrent seizures in this model. Furthermore, the study performed in non-epileptic rats indicates that chronic treatment with a GABAmimetic drug upregulates the expression of the protein GAD67 in specific areas of the brain, independently from the seizures.

Animals↗