Biomedical subjects

I Najm

Publications and source records attributed to I Najm.

At least 37 records · Page 2Linked to original sources

PubMed1999

Selective coexpression of NMDAR2A/B and NMDAR1 subunit proteins in dysplastic neurons of human epileptic cortex.

NR1 and NR2 are the two gene families for the NMDA receptor. In vitro studies show that while NR2 alone is nonfunctional, NR1 alone produces weak currents to glutamate or NMDA. We previously showed by immunocytochemistry (ICC) that in normal appearing, nonepileptic human cortical neurons, only NR1 and not NR2 proteins were expressed, in contrast to the presence of both NR1 and NR2 in normal rat cortical neurons. We also showed, in dysplastic epileptic cortex, that both NR1 and NR2 were highly expressed using ICC on adjacent 30-microm sections. However, the relative coexpressions of NR1 and NR2 proteins in single neurons in single sections of human epileptic cortex were unknown. In this study, we used double-labeled immunofluorescence and confocal microscopy to examine the distribution and coexpression of subunit proteins for NR1 and NR2A/B in both nondysplastic (control comparison) and dysplastic regions of human brain resected for the treatment of intractable epilepsy (11 patients). In nondysplastic regions, cortical neurons did not have immunoreactivity (ir) for NR2A/B, whereas NR1-ir was abundant. By contrast, dysplastic neurons in the regions with epileptic cortical dysplasia showed intense NR2A/B-ir in the somata and their dendritic processes. These same NR2A/B-ir dysplastic neurons were colabeled by NR1. These results demonstrate directly that dysplastic neurons express both NR2A/B and NR1 proteins, whereas nondysplastic cortical neurons express only NR1 proteins. Selective coexpression of NR2A/B and NR1 in dysplastic neurons suggests that NR2A/B may form heteromeric NR1-NR2 coassemblies and hyperexcitability in dysplastic neurons that could contribute to focal seizure onset.

Animals↗

PubMed1999

Hippocampal volumetry in children 6 years or younger: assessment of children with and without complex febrile seizures.

PURPOSE: To study the relationship of complex febrile seizures (CFS) in the evolution of mesial temporal sclerosis. METHODS: We studied five children 22-68 (mean 44) months old with MRI volumetry 2 days-46 months after their first CFS, and compared total hippocampal volumes and right to left hippocampal volume ratios to those of 11 controls, 15-83 (mean 55) months old, who had MRI for complaints which turned out to be neurologically insignificant. RESULTS: In control children, total hippocampal volumes increased linearly with age, while right to left hippocampal volume ratios tended to decrease with age. In children with CFS total hippocampal volumes tended to be smaller than in controls. Right to left ratios were greater than 1 in all five children with CFS compared to seven of 11 controls. Hippocampal asymmetry was noted in only one child, with the right to left volume ratio exceeding two standard deviations from the control mean. The MRI of this child also demonstrated a subarachnoid cyst in the left frontocentral region, ipsilateral to the smaller hippocampus. Visual inspection of the remaining patients revealed no definite structural cortical abnormalities. None of the children developed subsequent afebrile seizures during the brief follow-up period. CONCLUSIONS: Hippocampal volumetry in controls revealed a linear increase in total hippocampal volumes and a statistically nonsignificant trend toward reduced right larger than left hippocampal ratios between 17 and 83 months old. The tendency for smaller total hippocampal volumes and larger right to left hippocampal volume ratios in children with CFS compared to controls could suggest a developmental abnormality, injury during CFS, or be age-related. The significant hippocampal asymmetry in a single child with CFS suggests that age may not be a factor in every case. Further studies are needed to collect control data in young children as well as prospectively follow children with CFS with serial imaging to better understand the relationship between CFS and the evolution of hippocampal atrophy.

Aging↗

PubMed1999

Interictal epileptiform discharges in temporal lobe epilepsy due to hippocampal sclerosis versus medial temporal lobe tumors.

PURPOSE: It remains controversial whether a specific pattern of interictal epileptiform activity exists that may help to differentiate temporal lobe epilepsy (TLE) due to hippocampal sclerosis (HS) from other forms of TLE. In this study, we characterized the distribution of interictal epileptiform discharges in TLE due to HS as compared with those in patients with tumors restricted to the medial temporal lobe structures. METHODS: The study included 21 adult patients with unilateral HS who remained seizure free (>1 year) after anterior temporal lobectomy with amygdalohippocampectomy. Patients with "dual pathology" were excluded. The comparison group consisted of nine patients with tumors restricted to the amygdala and hippocampus. All patients underwent video-EEG monitoring preoperatively by using 39 scalp electrodes (including the 10-10 system over both temporal regions) and bilateral sphenoidal electrodes. RESULTS: The HS patient group showed a significantly higher percentage of ipsilateral epileptiform discharges maximal at anterior temporal electrodes (median, 97.0%; sphenoidal electrode alone, 88.1%), as compared with the tumor group (median, 72.1%; p<0.001; sphenoidal electrode alone, 24.8%; p<0.001). The HS group had significantly fewer extratemporal spikes/sharp waves (median, 0.0), as compared with the tumor group (10.0%; p<0.001). At least 90% of the interictal discharges were located in the anterior temporal region in 20 (95.2%) of 21 HS patients, but in none of the tumor patients (p<0.001). Bilateral temporal discharges were found in nine (42.9%) of 21 patients with HS and in two (22.2%) of nine tumor patients (p = 0.42). CONCLUSIONS: We conclude that ipsilateral interictal epileptiform discharges outside the anterior temporal region are rare (<10%) in adults with intractable TLE due to unilateral HS. Frequent posterior or extratemporal sharp waves may detract from the certainty of this diagnosis in complicated cases. These restricted epileptiform discharges suggest a smaller irritative zone in HS as compared with medial tumors, or a more organized activity associated with intrinsic hippocampal disease. Bilateral epileptiform discharges were not uncommon in both groups.

Adolescent↗

PubMed1999

NMDA-receptors 1 and 2A/B coassembly increased in human epileptic focal cortical dysplasia.

PURPOSE: This study was designed to quantify the relation between expressions of NMDA receptor (NMDAR) subunits (1 and 2A/B) and the epileptogenicity in human focal cortical dysplasia. METHODS: Immunoblotting and immunoprecipitation were used to quantify these receptor subunits in tissue resected from EEG-verified epileptic and distal nonepileptic frontal cortical areas in each of three patients as determined by chronic subdural electrode recordings. In each patient, adjacent sections were immunostained to verify that the numbers of dysplastic neurons were greater in epileptic than in nonepileptic cortex. RESULTS: In all patients, NMDAR2A/B expressions and their coassemblies with NMDAR1 were increased in epileptic dysplastic cortex compared with the relatively normal appearing nonepileptic cortex. For all three patients, there were no significant differences in NMDAR1 protein expressions between the two EEG groups. CONCLUSIONS: These results suggest that increased NMDAR1-NMDAR2A/B coassembly contributes to hyperexcitability in dysplastic cortical neurons and focal seizure onsets.

Adolescent↗

PubMed1999

Periictal diffusion-weighted imaging in a case of lesional epilepsy.

PURPOSE: Diffusion-weighted MR imaging (DWI) has been used for the early diagnosis of acute ischemic lesions in humans and in animal models of focal status epilepticus. We hypothesized that DWI may be a sensitive, noninvasive tool for the localization of the epileptogenic area during the periictal period. METHODS: A periictal DWI study was performed on a 35-year-old patient during focal status epilepticus with repetitive prolonged focal motor seizures originating from a lesion in the right frontal lobe. DWI results were analyzed visually and by calculating apparent diffusion coefficient (ADC) maps. RESULTS: On DWI, a single area of signal increase (decrease in ADC) was found in the region of focal electrocorticographic seizures that was mapped intraoperatively. CONCLUSIONS: Ictal/postictal DWI may be a useful technique for seizure localization in patients with lesional epilepsy.

Adult↗

PubMed1999

Hippocampal chemical anatomy in pediatric and adolescent patients with hippocampal or extrahippocampal epilepsy.

We determined whether age or seizure types were associated with hippocampal neuron loss, mossy fiber (MF) and GABAergic synaptic reorganizations or postsynaptic receptor densities. Children and adolescents were grouped into: (1) nonhippocampal sclerosis (non-HS; n = 11) and (2) hippocampal sclerosis (HS; n = 11). The most important results showed that: (1) regardless of the etiology of the seizures, there were greater cell losses in Ammon's horn with older ages in years; in the non-HS group, cell losses were greater with the older ages or with longer epilepsy durations; however, in the HS patients, the cell losses were not related to the patients' ages or epilepsy durations; (2) in both HS and non-HS, CA1 had greater cell losses than CA4; (3) in HS, CA1 and CA4 had greater cell losses than those in non-HS; (4) in non-HS, MF sprouting was greater with ages or with longer epilepsy durations; by contrast, in HS, MF sprouting was not related to the patients' age or epilepsy duration; (5) densities for AMPA GluR1, GABA-Abeta and for GABA axonal terminals were positively increased with age. These findings support the hypothesis that hippocampal cell losses and aberrant synaptic reorganizations are greater in the hippocampi of adolescents than in children, even for non-HS pathologies.

Adolescent↗

PubMed1999

Focal cortical dysplasia in children.

Cortical dysplasia (CD) is now recognized as one of the major causes of pediatric focal neocortical epilepsy, and surgical procedures have been considered early in life. However, the mechanisms involved in seizure generation and intractability in these patients are still unknown. We analyzed with immunocytochemistry for various antibodies the brain tissue from 4 children (10 months to 6 years old) with focal epilepsy due to focal CD in order to study the inhibitory and excitatory circuits in dysplastic areas. Our group had similar histopathological and clinical characteristics. In all patients we found areas of cortical disorganization with dysplastic neurons and balloon cells. We studied distributions of glial cells with glial fibrillary acidic protein (GFAP) and neurons with microtubule-associated protein 2 (MAP-2). Gliosis was present in all cases, and GFAP stained also some balloon cells. Dysplastic neurons were darkly stained by MAP-2, and we also found balloon cells weakly stained with MAP-2 in the same areas where GFAP was positive, suggesting coexpression of neuronal and glial markers in some of these cells. There was an increased expression of glutamate receptors, especially GluR2/3, but also N-methyl-D-aspartate receptors in dysplastic cortex. The inhibitory circuit does not seem to be decreased, rather we notice an increased amount of glutamate-decarboxylase-positive terminals around some of the big neurons. We discuss the possible role of these findings as mechanisms of epilepsy.

Cerebral Cortex↗

PubMed1998

Ganglioglioma and intractable epilepsy: clinical and neurophysiologic features and predictors of outcome after surgery.

PURPOSE: To review the clinical, neurophysiologic, and radiological data of patients with ganglioglioma who had undergone evaluation and surgery in our Epilepsy Program. METHODS: The medical and neurophysiologic records of 38 patients with intractable epilepsy and ganglioglioma were reviewed. Data underwent statistical analysis. RESULTS: There were 28 temporal and 10 extratemporal resections, with a mean age at seizure onset of 10.5 years and mean age at surgery of 22 years. Five tumor resections performed earlier were recorded. Twenty-nine patients had auras and 20 had secondarily generalized seizures. All 28 patients with temporal tumor had complex partial seizures. Preoperative MRI demonstrated the tumor in 36 of 36 patients: 17 of 29 demonstrated gadolinium enhancement, and 17 of 36 had mass effect. Scalp interictal sharp waves were present in 32 patients, and in 15 they were multiregional. In two patients, scalp EEG seizure onset was from the hemisphere contralateral to the tumor. Postoperatively, 79% of patients (30 of 38) were seizure-free (Engel's class I) at 6 months, 72% at 1 year (26 of 36), and 63% at 2 years (20 of 32). Excellent outcome was associated with a lower age at operation (p = 0.008), shorter duration of epilepsy (p = <0.01), absence of generalized seizures (p = <0.01), and no epileptiform discharges on a postoperative EEG (p = 0.01). CONCLUSIONS: Good surgical outcome is expected in patients with ganglioglioma despite years of medically resistant seizures. Good outcome may be achieved despite EEG findings that may conflict with tumor location, and is more likely when surgery is performed relatively soon after epilepsy onset.

Adult↗

PubMed1996

Postictal alteration of sodium content and apparent diffusion coefficient in epileptic rat brain induced by kainic acid.

PURPOSE: We studied temporal changes of brain sodium and apparent diffusion coefficient (ADC) in a temporal lobe epilepsy (TLE) rat model using kainic acid (KA). METHODS: In situ three-dimensional 23Na magnetic resonance imaging (MRI) and proton diffusion-weighted imaging (DWI) were used. KA at a dose of 10 mg/kg body weight and 12 adult Sprague Dawley rats weighing 228-318 g (268 +/- 25 g) were used. RESULTS: Twenty-four hours after KA injection, magnetic resonance (MR) visible sodium levels increased in both the pyriform cortex (+90%) and amygdala (+68%) and increased insignificantly in the hippocampus (+18%) and caudate-putamen (12%). The ADC in the pyriform cortex showed a -9% decrease at 5 h postictally, reaching -30% at 24 h, whereas in the amygdala decreases were -8 and -26% respectively. A significant decrease in ADC (-7%) in the hippocampus was also observed 24 h postically. Seven days later, sodium increases persisted, whereas ADC returned to normal level. CONCLUSIONS: The increase in MR visible sodium, associated with the decrease in ADC is consistent with the hypothesis that sequential seizures caused an increase in sodium influx and perturbation of membrane ion homeostasis, which eventually evolved into an irreversible phase of cellular edema, with increased MR visible intracellular sodium and decreased ADC. Return of ADC to near-control level and persistent high sodium level at 7 days may be explained by the increase in extracellular space and tissue necrosis.

Amygdala↗

PubMed1994

Neural tropomodulin: developmental expression and effect of seizure activity.

Tropomodulin is a 40.6 kDa tropomyosin-binding protein associated with actin filaments in muscle and the membrane cytoskeleton in erythrocytes. We have detected tropomodulin mRNA and protein in brains of rats by northern and western blot analyses. In situ hybridization of rat brain and spinal cord sections shows tropomodulin expression in the cerebellum, neocortex, hippocampus, and anterior horn of the spinal cord. Tropomodulin expression is first observed around day 15 after birth and increases through day 24. The temporal and spatial changes in tropomodulin expression during cerebellar development parallel those for brain tropomyosin. Tropomodulin mRNA increases in the dentate gyrus of the hippocampus following prolonged seizure activity induced by kainic acid administration; the increase is clearly evident 8 h after initiation of seizures and is still present 1 week later. However, Western blot analysis of tropomodulin protein level in the dentate gyrus before and after seizure induction show only slight increases in tropomodulin protein concentration, suggesting tight regulation of tropomodulin expression at the translational level. The developmental expression of tropomodulin, together with the induction of tropomodulin mRNA production in the dentate gyrus after kainic acid treatment, suggests a role for tropomodulin in neuronal organization and plasticity.

Animals↗

PubMed1994

Kainate-induced seizure activity stimulates the polyamine interconversion pathway in rat brain.

Systemic injection of kainic acid in adult rat is accompanied by a large increase in the accumulation of acetylated derivatives of spermidine and spermine in the hippocampus and piriform cortex of animals pretreated with the polyamine oxidase inhibitor, MDL 72527. Furthermore, the activity of the enzyme spermine/spermidine acetyltransferase is increased at 8 and 16 h after kainate injection in piriform cortex and hippocampus. These results indicate that the polyamine interconversion pathway is rapidly activated in limbic areas following kainate-induced seizure activity, and suggest that this pathway might participate in the resulting neuronal damage.

Acetylation↗

PubMed1993

Co-expression of HSP72 and c-fos in rat brain following kainic acid treatment.

The relationship between heat shock protein 72 (HSP72) and c-fos gene expression following systemic administration of kainic acid was investigated by combining immunocytochemistry for HSP72 with in situ hybridization for c-fos. Increased HSP72 expression was detected in adult rat hippocampus 4 h after seizure-onset. Transient co-expression of c-fos and HSP72 occurred in neurons that are resistant to kainic acid, whereas prolonged co-expression was observed in vulnerable neurons. The spatial distribution and developmental time course of kainic acid-induced HSP72 expression were similar to those of kainic acid-induced neurodegeneration. The results demonstrate a relationship between c-fos and HSP72 gene expression and suggest that prolonged co-expression of these genes plays a role in kainic acid-induced neuronal death.

Animals↗

PubMed1993

Transcriptional activation of ornithine decarboxylase in adult and neonatal hippocampal slices.

Ornithine decarboxylase (ODC) is the rate-limiting enzyme in polyamine synthesis and is regulated by both transcription-dependent and transcription-independent mechanisms. We compared the effects of asparagine, an amino acid previously shown to increase ODC activity in adult hippocampal slices, on ODC mRNA and activity in adult and neonatal hippocampal slices. In addition, we evaluated the effects of asparagine on ODC activity following seizure activity elicited by systemic administration of kainic acid (KA) in both adult and neonatal rats. Asparagine produced an increase in ODC gene expression and activity in both adult and neonatal hippocampal slices. The increase in ODC activity elicited by asparagine in hippocampal slices was the same in control animals as in animals sacrificed 16 h after KA-induced seizure activity. The asparagine-elicited increase in ODC activity in neonatal and adult hippocampal slices was blocked by the RNA synthesis inhibitor, actinomycin D. Finally, polyamines produced an inhibition of ODC activity in neonatal hippocampal slices. The results indicate that the regulation of the expression and activity of ODC is similar in neonatal and adult hippocampus.

Aging↗

PubMed1993

Seizure activity causes a rapid increase in sulfated glycoprotein-2 messenger RNA in the adult but not the neonatal rat brain.

The present study investigated the changes in sulfated glycoprotein-2 (SGP-2) messenger RNA at various times following kainic acid-induced seizure onset in adult and neonatal rat brain. Double labelling using immunostaining of the astrocyte-specific glial fibrillary acidic protein indicated that SGP-2 expression was rapidly and transiently increased in granule cells of the dentate gyrus up to 8 hours after seizure onset. Thereafter, and up to 7 days following seizure onset, the majority of cells exhibiting increased SGP-2 expression were astrocytes located in the molecular layer of the dentate gyrus and in the alveus, as well as in regions adjacent to CA3 and CA1 pyramidal cells. No increase in SGP-2 mRNA was detected in pyramidal neurons selectively damaged by KA. In addition, increased expression of SGP-2 following KA administration was not observed in neonatal rat hippocampus prior to postnatal day 21. The results argue against a role for SGP-2 in KA-induced neuronal death and demonstrate a surprisingly rapid increase in astroglial gene expression following seizure activity, thus supporting a role for SGP-2 in synaptic plasticity.

Aging↗

PubMed1993

Cycloheximide prevents kainate-induced neuronal death and c-fos expression in adult rat brain.

The present study was directed at evaluating the possible involvement of protein synthesis in excitotoxin-induced neuronal damage and prolonged expression of the proto-oncogene, c-fos. Kainic acid-induced seizure activity elicited varying degrees of neuronal damage and cell loss in selectively vulnerable regions of the adult rat limbic system. Pretreatment with cycloheximide, a protein synthesis inhibitor, did not alter behavioral seizure characteristics, but markedly attenuated damage to susceptible neuronal populations. A prolonged increase in c-fos mRNA was observed by in situ hybridization up to 16 h after the onset of seizures in regions exhibiting neuronal death. Pretreatment with cycloheximide did not affect the transient induction of c-fos observed in numerous structures, but significantly reduced the prolonged expression of c-fos mRNA in kainate-vulnerable regions. Despite producing massive seizure activity, systemic kainic acid administration during the early postnatal period did not induce any neuronal death, and did not result in prolonged c-fos expression in any brain structures. The developmental onset of selective neuronal vulnerability coincided with that of prolonged c-fos expression in susceptible neuronal populations. In adult rats, seizure activity induced by pentylenetetrazole did not produce neuronal damage nor did it produce prolonged c-fos expression. These results not only demonstrate that kainate-induced neurotoxicity and the prolonged expression of c-fos are both prevented by cycloheximide, but also strengthen idea that prolonged c-fos expression is a marker of neuronal death.

Aging↗

PubMed1992

Seizure activity-induced changes in polyamine metabolism and neuronal pathology during the postnatal period in rat brain.

Systemic injection of kainic acid (KA) does not cause neuronal pathology in limbic structures in rat brain prior to postnatal day (PND) 21. The present study tested if the development of the pathogenic response is associated with the maturation of a link between seizure activity and polyamine metabolism. Pathology was assessed with histological techniques and with the binding of [3H]Ro5-4864, a ligand for the peripheral type benzodiazepine binding sites (PTBBS), a marker of glial cell proliferation. In agreement with previous results, peripherally administered kainate at doses sufficient to induce intense behavioral seizures produced a loss of Nissl staining in hippocampus after PND 21 but not at earlier ages. The pattern of neuronal damage observed after PND 21 resembled that found in adult animals: extensive losses of Nissl staining in area CA3 of hippocampus and in piriform cortex, more modest effects in CA1 and sparing of the granule cells of the dentate gyrus. Similarly, no increase in [3H]Ro5-4864 binding as a result of KA administration was observed in hippocampus and piriform cortex until PND 21. Ornithine decarboxylase (ODC) activity and putrescine levels were high in the neonatal brain and decreased to reach adult values by PND 21. KA-induced seizure activity did not significantly alter both variables until PND 21. After PND 21, ODC activity and putrescine levels markedly increased 16 h after KA-induced seizure activity in hippocampus and piriform cortex. The magnitude of the effects increased between PND 21 and PND 30, at which point the changes in both parameters were comparable to those found in adults. Polyamines stimulate the activity of the calcium-dependent proteases calpain in brain fractions and may increase calpain-mediated proteolysis in situ. In accord with this, kainate-induced breakdown of spectrin, a preferred substrate of calpain, measured 16 h after KA injection followed a developmental curve parallel to that for kainate-induced increases in putrescine levels. These results indicate that the onset of vulnerability to seizure activity triggered by kainic acid is correlated with the development of an ODC/polyamine response to the seizures and further support a critical role for the ODC/polyamine pathway in neuronal pathology following a variety of insults.

Animals↗

PubMed1992

Absence of c-fos induction in neonatal rat brain after seizures.

Induction of the proto-oncogene c-fos is often considered to be a marker of increased neuronal activity. We have used in situ hybridization to study the pattern of c-fos expression in limbic structures following kainic acid-induced seizures during the postnatal period in the rat. Prior to postnatal day 13 (P13), seizure activity did not result in c-fos induction in any limbic structure. Between P13 and P25, a gradual increase in c-fos expression was observed in hippocampus and cortical structures. These results were corroborated by nuclear run-off transcription assay. Thus, alterations in c-fos transcription that may facilitate stimulus-transcription coupling occur during postnatal development. The possible relationship between the postnatal maturation of c-fos expression and the increase in susceptibility of specific neuronal populations to seizure-induced cell damage is discussed.

Age Factors↗

PubMed1992

Changes in polyamine levels and spectrin degradation following kainate-induced seizure activity: effect of difluoromethylornithine.

The induction of ornithine decarboxylase (ODC) in adult CNS and the resulting changes in polyamine levels are often observed under conditions associated with activation of NMDA receptors, calpain stimulation and spectrin degradation. The present study was directed at evaluating the links between these two sets of events. We measured the effects of an acute treatment of adult rats with difluoromethylornithine (DFMO), an irreversible inhibitor of ODC, on biochemical alterations following kainate-induced seizure activity. Beside ODC activity and polyamine levels, we assayed the in situ spectrin degradation and the in vitro binding of 3H-Ro5-4864, a ligand for the peripheral benzodiazepine binding sites which is a good marker of glial proliferation, at various time intervals following systemic kainic acid (KA) injection. Kainate-induced seizure activity was followed by a transient increase in ODC activity, a long-lasting increase in putrescine levels and spectrin degradation, and a delayed increase in 3H-Ro5-4864 binding, mainly in hippocampus and piriform cortex. Treatment of the animals with DFMO markedly reduced the increase in putrescine levels up to 7 days after KA injection. It also reduced the increase in spectrin breakdown observed at 16 h but not at 4 and 7 days after KA injection. Finally, it did not modify the increase in 3H-Ro5-4864 binding measured 4 and 7 days after KA injection. The levels of putrescine were positively correlated with the extent of spectrin proteolysis in KA-treated animals whether or not they were treated with DFMO, at 16 h but not at 7 days after KA injection. The results indicate that the extent of spectrin breakdown observed shortly after KA-induced seizure activity is causally related to the changes in ODC activity and putrescine levels. Although the data are consistent with the idea that putrescine could be a marker for acute pathology, they do not support a role for polyamines in delayed neurotoxicity.

Animals↗