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R Sankar

Publications and source records attributed to R Sankar.

At least 19 recordsLinked to original sources
PubMed1999

Resistance to excitotoxin-induced seizures and neuronal death in mice lacking the preprotachykinin A gene.

Epileptic seizures are associated with increases in hippocampal excitability, but the mechanisms that render the hippocampus hyperexcitable chronically (in epilepsy) or acutely (in status epilepticus) are poorly understood. Recent evidence suggests that substance P (SP), a peptide that has been implicated in cardiovascular function, inflammatory responses, and nociception, also contributes to hippocampal excitability and status epilepticus, in part by enhancing glutamate release. Here we report that mice with disruption of the preprotachykinin A gene, which encodes SP and neurokinin A, are resistant to kainate excitoxicity. The mice show a reduction in the duration and severity of seizures induced by kainate or pentylenetetrazole, and both necrosis and apoptosis of hippocampal neurons are prevented. Although kainate induced the expression of bax and caspase 3 in the hippocampus of wild-type mice, these critical intracellular mediators of cell death pathways were not altered by kainate injection in the mutant mice. These results indicate that the reduction of seizure activity and the neuroprotection observed in preprotachykinin A null mice are caused by the extinction of a SP/neurokinin A-mediated signaling pathway that is activated by seizures. They suggest that these neurokinins are critical to the control of hippocampal excitability, hippocampal seizures, and hippocampal vulnerability.

Animals↗
PubMed1999

Substance P is expressed in hippocampal principal neurons during status epilepticus and plays a critical role in the maintenance of status epilepticus.

Substance P (SP), a member of the tachykinin family, is widely distributed in the central nervous system and is involved in a variety of physiological processes including cardiovascular function, inflammatory responses, and nociception. We show here that intrahippocampal administration of SP triggers self-sustaining status epilepticus (SSSE) in response to stimulation of the perforant path for periods too brief to have any effect in control rats, and this SSSE generates a pattern of acute hippocampal damage resembling that known to occur in human epilepsy. The SP receptor (SPR) antagonists, spantide II and RP-67,580, block both the initiation of SSSE and SSSE-induced hippocampal damage and terminate established anticonvulsant-resistant SSSE. SSSE results in a rapid and dramatic increase in the expression of preprotachykinin A (a precursor of SP) mRNA and SP in principal neurons in CA3, CA1, and the dentate gyrus as well as in hippocampal mossy fibers. SP also increases glutamate release from hippocampal slices. Enhanced expression of SP during SSSE may modulate hippocampal excitability and contribute to the maintenance of SSSE. Thus, SPR antagonists may constitute a novel category of drugs in antiepileptic therapy.

Analgesics↗
PubMed1999

Periventricular nodular heterotopia and childhood absence epilepsy.

A young female presented with an epileptic syndrome resembling childhood absence epilepsy, a normal neurologic examination, generalized 3-Hz spike-and-wave discharges, and clinical absences. Her seizures responded to treatment with valproic acid. Other abnormalities in her electroencephalogram prompted neuroimaging studies, which demonstrated periventricular nodular heterotopia. Review of published reports confirmed this presentation to be atypical of this developmental lesion. The authors describe their patient and discuss this unexpected association and the relevant reports briefly.

Cerebral Ventricles↗
PubMed1999

Metabolic and endocrine aspects of the ketogenic diet.

The ketogenic diet (KD) is designed to simulate the biochemical effects of fasting by maintaining a state of ketosis. The complex interplay of endocrine and metabolic factors requires that a continuous ingestion of a diet high in lipid calories is necessary to achieve such a state and yet maintain body weight. The resulting condition provides for much of the cerebral energy requirements in the form of ketone bodies. We review energy metabolism with special emphasis on fatty acid oxidation to provide the readers with a foundation that facilitates identification of patients who will especially benefit from this diet, as well as to assist clinicians in screening candidates who may experience a catastrophic outcome if fasted and placed on this diet. The review includes a discussion of the role of carnitine in mitochondrial fatty acid metabolism, and the criteria for carnitine supplementation. Only limited information is available regarding the interaction of the diet with the commonly used antiepileptic drugs.

3-Hydroxybutyric Acid↗
PubMed1999

The pharmacologic basis of antiepileptic drug action.

The development of medications used in the treatment of epilepsy has accelerated over the past decade, and has benefited from a parallel growth in our knowledge of the basic mechanisms underlying neuronal excitability and synchronization. This understanding of the pharmacologic basis of antiepileptic drug (AED) action has, in large part, arisen from recent advances in cellular and molecular biology, coupled with avenues of drug discovery that have departed somewhat from the largely empiric approaches of the past. Physicians now have available to them an ever-growing armentarium of AEDs, necessitating a firmer appreciation of their mechanisms of action if more rational approaches toward both clinical application and research are to be adopted. An important example in this regard is the concept of rational polypharmacy for patients with epilepsy who are refractory to monotherapy. This review summarizes our current understanding of the molecular targets of clinically significant AEDs, comparing and contrasting their differing mechanisms of action.

Animals↗
PubMed1999

Ontogeny of self-sustaining status epilepticus.

Rat pups of ages of 20, 25, 30 and 35 postnatal days were subjected to the perforant-path stimulation model of status epilepticus (SE). This treatment resulted in age- and stimulus-frequency-dependent loss of inhibition in the dentate granule cell layer. Only 35% of the 20-day-old animals, but 88% of the 35-day-olds, progressed to self-sustaining status epilepticus (SSSE). Loss of inhibition as measured by 0.1-Hz paired-pulse testing and histologic damage that extended to the contralateral side, including both the hilus and some extrahippocampal limbic structures, were associated with SSSE. This model of SE differs from in vitro models of SE, in which immature animals show an increased susceptibility to epileptogenic stimuli, and provides us with a novel method to study epileptogenicity in the developing brain.

Animals↗
PubMed1999

Status epilepticus during pregnancy. A case report.

BACKGROUND: Status epilepticus is a rare but potentially life threatening complication that women with epilepsy may experience during pregnancy. Poor compliance may contribute to the occurrence of status epilepticus, resulting in the need for substantial increases in anticonvulsant dosing to suppress seizures. CASE: A 39-year-old woman, gravida 2, para 0, abortion 1, with a history of epilepsy since childhood, delivered twins following an episode of myoclonic status epilepticus. The infants tolerated the maternal seizures and the aggressive anticonvulsant therapy without residual problems. CONCLUSION: Status epilepticus seems more likely to occur in women with epilepsy during the third trimester. Fourteen of 19, or 74%, of cases reviewed, including the case we report on here, experienced status epilepticus in the third trimester or during labor.

Anticonvulsants↗
PubMed1998

Time-dependent decrease in the effectiveness of antiepileptic drugs during the course of self-sustaining status epilepticus.

An animal model of self-sustaining status epilepticus (SSSE) induced in rats by brief intermittent perforant path stimulation (PPS) was examined with regard to the effects of two conventional antiepileptic drugs, diazepam and phenytoin. Thirty or sixty minutes PPS induced SSSE characterized by continuous behavioral and electrographic seizures lasting for hours. Both diazepam (10 mg/kg i. v.) and phenytoin (50 mg/kg i.v.) prevented the establishment of SSSE when administered 10 min prior to PPS. The injection of diazepam to seizing animals, 10 min after the end of 30 min PPS, was significantly less effective than pretreatment in attenuating SSSE. Administration of diazepam after 60 min PPS was characterized by a further decrease of its efficacy. Phenytoin was effective in aborting SSSE when injected 10 min after 30 min PPS. However, its efficacy was vastly decreased if injected 40 min after 30 min PPS, or 10 min after 60 min PPS. It is concluded that antiepileptic drugs, while highly effective in blocking the induction of SSSE, failed to affect its maintenance. SSSE induced by PPS is an advantageous animal model of refractory status epilepticus, which may be used in preclinical studies of novel antiepileptic drugs.

Animals↗
PubMed1998

Galanin modulation of seizures and seizure modulation of hippocampal galanin in animal models of status epilepticus.

We examined the role of hippocampal galanin in an animal model of status epilepticus (SE). Control rats showed abundant galanin-immunoreactive (Gal-IR) fibers in the dentate hilus, whereas no Gal-IR neurons were observed. Three hours after the onset of self-sustaining SE (SSSE), induced either by intermittent stimulation of the perforant path for 30 min (PPS) or by injection of lithium and pilocarpine, Gal-IR fibers disappeared in the hilus and remained absent for up to 1 week afterward. Twelve hours after the induction of SE by PPS or 3 hr after pilocarpine administration, Gal-IR neurons appeared in the hilus; these neurons increased in number after 1 d and gradually declined 3 and 7 d later. Galanin concentration in the hippocampus, measured by ELISA, significantly decreased on the plateau of SSSE and increased 24 hr after PPS. Galanin (0.05 nmol) injected into the hilus prevented the induction of SSSE, and 0.5 nmol of galanin stopped established SSSE. These effects were attenuated by galanin receptor antagonists (M35 > M40 >/= M15). 2-Ala-galanin (5 nmol), a putative agonist of galanin type 2 receptors, prevented but was unable to stop SSSE. M35 facilitated the development of SSSE when given before PPS. We suggest that hippocampal galanin acts as an endogenous anticonvulsant via galanin receptors. SE-induced galanin depletion in the hippocampus may contribute to the maintenance of seizure activity, whereas the increase of galanin concentration and the appearance of galanin-immunoreactive neurons may favor the cessation of SSSE. The seizure-protecting action of galanin SSSE opens new perspectives in the treatment of SE.

Animals↗
PubMed1998

Patterns of status epilepticus-induced neuronal injury during development and long-term consequences.

The lithium-pilocarpine model of status epilepticus (SE) was used to study the type and distribution of seizure-induced neuronal injury in the rat and its consequences during development. Cell death was evaluated in hematoxylin- and eosin-stained sections and by electron microscopy. Damage to the CA1 neurons was maximal in the 2- and 3-week-old pups and decreased as a function of age. On the other hand, damage to the hilar and CA3 neurons was minimal in the 2-week-old rat pups but reached an adult-like pattern in the 3-week-old animals, and damage to amygdalar neurons increased progressively with age. The 3-week-old animals also demonstrated vulnerability of the dentate granule cells. To evaluate neuronal apoptosis, we used terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) stain, confocal fluorescence microscopy of ethidium bromide-stained sections, electron microscopy, and DNA electrophoresis. Neurons displaying all of those features of apoptotic death in response to SE were seen in the CA1 region of the 2-week-old pups and in the hilar border of the dentate granule cells of the 3-week-old animals. Some (3/11) of the animals that underwent SE at 2 weeks of age and most of the animals that underwent SE at 3 or 4 weeks of age (8/11 and 6/8, respectively) developed spontaneous seizures later in life; the latter showed SE-induced synaptic reorganization as demonstrated by Timm methodology. These results provide strong evidence for the vulnerability of the immature brain to seizure-induced damage, which bears features of both necrotic and apoptotic death and contributes to synaptic reorganization and the development of chronic epilepsy.

Age Factors↗
PubMed1998

Self-sustaining status epilepticus after brief electrical stimulation of the perforant path.

We examined the duration of intermittent perforant path stimulation (PPS) needed to induce self-sustaining status epilepticus (SSSE) in rats. Seven-minute PPS did not induce SSSE. Some rats receiving 15 min and all animals after 30 min PPS developed SSSE that continued for hours. The animals killed 3 days after SSSE showed extensive neuronal damage. Those which were allowed to survive for 6 weeks after SSSE displayed spontaneous seizures.

Animals↗
PubMed1998

Frontal lobe proton magnetic-resonance spectroscopy in Graves' disease: a pilot study.

Patients with hyperthyroidism may show impaired performance on several neuropsychological tests that require complex visual discrimination, conceptualization, mental flexibility or organization. These neurocognitive impairments appear to be consistent with prefrontal lobe dysfunction. This pilot study was undertaken to characterize the metabolite profile in the right prefrontal cortex in six patients with untreated Graves' disease by using in vivo proton magnetic-resonance spectroscopy (1H-MRS). For comparison, 1H-MRS was also carried out in seven healthy controls. The choline/creatine (Cho/Cr) and N-acetyl aspartate/creatine (Naa/Cr) ratios were determined. Cho/Cr ratios of the hyperthyroid patients were significantly lower than that of controls (means +/- SD = 0.61 +/- 0.09 vs. 0.90 +/- 0.18, p = .05). The two groups did not differ in their Naa/Cr ratios. Follow-up data after antithyroid treatment were available in three patients: Cho/Cr ratios were higher after treatment (euthyroidism) than before treatment (1.06 vs. 0.55; 0.82 vs. 0.54; 1.15 vs. 0.76). Tentatively, these preliminary data are most consistent with reversible reductions in the concentrations of choline-containing compounds (especially glycerophosphocholine and phosphocholine) in the prefrontal area during hyperthyroidism. However, these findings await confirmation by a definitive study with a larger sample size. A possible explanation of the findings is an altered brain cholinergic-adrenergic balance in hyperthyroidism.

Adolescent↗
PubMed1998

Pathogenesis of the developmental epilepsies.

The developmental epilepsies are distinctive in that they occur in a dynamic and plastic substrate. A variety of acquired insults may present with remarkably similar seizure syndromes that are age-specific and evolve with time. This evolution may be a consequence of the brain injury itself or an alteration of normal brain maturation due to an unfavorable electrical environment. Idiopathic epilepsies are now being correlated with specific gene defects, particularly those involving ion channels and/or neurotransmitter receptors. Despite this specificity, idiopathic seizure syndromes may be caused by mutations in different genes or different mutations in the same gene, and particular syndromes may manifest heterogeneous clinical seizure types. Not all localization-dependent epilepsies are symptomatic, as a growing number of genes have been identified with partial seizure syndromes. Febrile seizures probably do not represent a homogeneous entity, but multiple disorders that may be associated with developmental abnormalities and various coexisting seizure types.

Age Factors↗
PubMed1998

Clinical, biochemical and cytomorphological observations in juvenile chronic lymphocytic thyroiditis.

OBJECTIVE: To determine the clinical, biochemical, ultrasonological and cytomorphological features in goitrous juvenile chronic lymphocytic thyroiditis(CLT). SETTING: Tertiary referral center for thyroid disorders. SUBJECTS: A total of 455 children were evaluated for goiter. Of these 122 children had features of CLT in FNAC and were further studied. METHODS: All subjects were subjected to detailed clinical examination. The thyroid functional status was assessed by estimation of serum concentration of thyroid hormones (thyroxine and triiodothyronine) and thyrotropin (TSH). In addition the antithyroid antibody titers were measured. Ultrasonological and cytomorphological characteristics in these patients were also evaluated. RESULTS: The mean age at presentation was 12.5 years (SD 3.93). The male: female ratio was 1:7.7. Thyroid functional status as assessed by serum thyroxine and thyrotropin levels revealed, euthyroidism in 67 (54.9%), hypothyroidism in 30 (24.6%), subclinical hypothyroidism in 22 (18%) and hyperthyroidism in 3 (2.5%). Thyroid antimicrosomal antibodies were detected in significant titers in 90 (73.8%) and antithyroglobulin was positive in 71 (58.2%). The positivity of the antimicrosomal and antithyroglobulin antibodies were much higher in subjects with hypothyroidism and was detected in 86.5% and 69.2%, respectively. The mean urinary iodine excretion was 74.1 micrograms/g of creatinine (SD 31.4) indicating mild iodine deficiency. Fine needle aspiration cytoloty (FNAC) revealed features of chronic lymphocytic thyroiditis. Hurthle cell changes was seen in only 12% of the cases. The epithelium was more often hyperplastic and vacuolation of the cytoplasm and peripheral vacuolations were seen frequently. Giant cells and epithelioid cells were seen in many cases. CONCLUSIONS: In any child presenting with firm goiter, a diagnosis of CLT should be excluded. Many subjects with juvenile CLT have biochemical evidence of hypothyroidism but only few symptoms or clinical features.

Adolescent↗
PubMed1997

GABA metabolism during status epilepticus in the developing rat brain.

The rate of synthesis of GABA, the major inhibitory neurotransmitter, was determined in parietal cortex and hippocampus during SE induced by systemic administration of lithium (3 mEq/kg) followed 20 h later by pilocarpine (100 mg/kg) in 1-4-week-old rats. Our results show that the immature hippocampus is better capable of maintaining GABA synthesis in the face of SE at the earliest stages of development studied (74.1% of basal in 1-week-old) and that development results in a progressive decline in the ability to maintain GABA synthesis in the face of SE (44.1% of basal by 4 weeks) that may parallel the ontogeny of self-sustaining seizures. Our data describe an aspect of developmental GABA neurochemistry which may in part explain the relative resistance of the immature hippocampus to seizure spread and of certain types of seizure-induced damage.

Age Factors↗
PubMed1997

Induction of brain derived neurotrophic factor mRNA by seizures in neonatal and juvenile rat brain.

Seizures have been shown to regulate neurotrophin expression in adult mammalian brain. However, there has been some controversy as to whether seizures affect neurotrophin expression in very immature brain. In the present study, we have examined the effects of seizures induced by pilocarpine following lithium pretreatment or by kainic acid on the expression of brain derived neurotrophic factor (BDNF) mRNA in developing rat brain by in situ hybridization. In adult brain, lithium/pilocarpine treatment resulted in dramatic elevations of hybridization to BDNF cRNA in neocortical and limbic brain structures. In developing brain, lithium/pilocarpine induced elevations of BDNF mRNA in the hippocampus, piriform and entorhinal cortex as early as postnatal day 7 (P7). By P12, the pattern of enhanced expression was similar to that of the adult. Maximal elevations of hybridization were present 2 to 4 h following pilocarpine injection. Electrophysiological recording demonstrated that lithium/pilocarpine treatment resulted in electrographic seizures. Pretreatment with diazepam blocked the seizures as well as the elevation of BDNF mRNA. Kainic acid induced elevations of BDNF mRNA in the CA3 subfield of the hippocampal pyramidal cell layer, but not in other brain areas in pups as young as P7. These data indicate that seizures during the neonatal and early juvenile period of brain development induce elevated BDNF mRNA expression, and that different methods of seizure induction yield different patterns of elevations in hybridization. Furthermore, BDNF may be capable of playing a role in the development of seizure susceptibility in the immature brain.

Animals↗
PubMed1997

Serum neuron-specific enolase is a marker for neuronal damage following status epilepticus in the rat.

We determined the serum concentrations of neuron-specific enolase (s-NSE) in rat pups of 1, 2, 3, and 4 weeks of age and in adult rats that were subjected to lithium-pilocarpine status epilepticus (SE). Damage to brain regions was rated on a scale of 0 (no damage) to 5 (> 50% cell loss). Rat pups of 1-2 weeks of age had a higher baseline s-NSE than the adults. Following SE, 1 week old rat pups had no elevation of s-NSE and no histologic evidence of damage. At older ages the increases in NSE ranged from 18.9 +/- 0.8 ng/ml in the 2 week old (vs. 11.5 +/- 0.5 control) to 35.8 +/- 2.1 ng/ml in the 3 week old (vs. 12.1 +/- 0.8 control). In the adult rats s-NSE increased from 5.4 +/- 0.4 in the control animals to 30.4 +/- 1.3 after SE. The different brain regions examined had distinctive ontogenic profiles for SE-induced damage. Elevation of s-NSE after SE correlated with overall histologic evidence for damage.

Animals↗