Biomedical subjects

T Z Baram

Publications and source records attributed to T Z Baram.

At least 73 records · Page 4Linked to original sources

PubMed1995

Peptide-induced infant status epilepticus causes neuronal death and synaptic reorganization.

Status epilepticus (SE) produced by excitatory amino acids is a well established model in adult rodents. Limbic neuronal degeneration and synaptic reorganization observed after, for example, kainic acid-induced SE are considered relevant to human epilepsy. Kainic acid also produces severe seizures in infant rats, but neuronal injury and sprouting have not been demonstrated. The results of the present study show that corticotropin releasing hormone (CRH)-induced SE causes limbic neuronal death and reorganization in infant rats. In adults, CRH produced seizures at much higher doses, and no neuronal degeneration. As a modulator of the CNS stress response, CRH is activated in various 'stressful' circumstances. Its age-dependent ability to kill neurons represents a unique form of cell death potentially important in human medicine.

Animals↗

PubMed1995

Cerebrospinal fluid corticotropin and cortisol are reduced in infantile spasms.

Infantile spasms respond to ACTH, and levels of the hormone in cerebrospinal fluid of untreated infants with this disorder were found to be lower than in age-matched controls. In this study we analyzed cerebrospinal fluid cortisol and ACTH using improved immunoassays in a larger cohort of infants with infantile spasms. Analysis of 20 patients and 15 age-matched controls revealed significantly lower levels of both ACTH and cortisol in the cerebrospinal fluid. These data, combined with the efficacy of ACTH and glucocorticoids for infantile spasms, support an involvement of the brain-adrenal-axis in this disorder.

Adrenocorticotropic Hormone↗

PubMed1995

ACTH does not control neonatal seizures induced by administration of exogenous corticotropin-releasing hormone.

ACTH has been used extensively for treatment of massive infantile spasms (MIS) and other intractable seizures. The mechanisms by which ACTH exerts anticonvulsant effects are unknown. ACTH is a neuropeptide with both endocrine and neuromodulatory properties; its efficacy against MIS could derive from intrinsic anticonvulsant properties or from hormonal effects, either directly or through glucocorticoids. We tested ACTH activity against exogenous corticotropin-releasing hormone (CRH)-induced seizures in the infant rat model. CRH was administered into the cerebral ventricles of 85 infant rats aged 5-13 days. ACTH was used either 20-60 min before CRH administration or "chronically" (pretreatment with four doses of ACTH every 6 h, before CRH administration). In a separate group of rat pups, we measured plasma corticosterone to ascertain ACTH availability. Administration of CRH, an age-specific endogenous convulsant, resulted in a prolonged series of seizures after 2- to 55-min latency. There was no difference in latency between controls (9.5 +/- 1.2 min) and ACTH-treated rats (12.4 +/- 2.8 min for combined acute and chronic groups). CRH-induced seizure duration (88.2 +/- 9 vs. 74.7 +/- 9.4 min) and severity of seizures was also unchanged by ACTH treatment. ACTH reached the circulation and caused significant increase in plasma glucocorticoids. ACTH does not block the convulsant action of exogenous CRH in infant rats. An alternative mechanism for the anticonvulsant effect of ACTH may be suppression of synthesis and secretion of an endogenous convulsant, i.e., CRH.

Adrenocorticotropic Hormone↗

PubMed1995

Regional localization and developmental expression of the BCR gene in rodent brain.

The BCR gene is implicated in the development of Ph-positive leukemia through its fusion with the nonreceptor tyrosine kinase gene ABL. The normal 160 kDa Bcr protein has several functional domains, and recently one specific role for Bcr was established in the regulation of respiratory burst activity in white blood cells. Bcr expression levels are relatively constant throughout mouse development until adulthood in brain and in hematopoietic tissues, a pattern that is distinctly different from that of the functionally related n-chimerin gene. In the present study, RNA in situ hybridization was used to explore the normal cellular function of Bcr in rodent brain and hematopoietic organs. The data pinpoint the high bcr expression in the brain to the hippocampal pyramidal cell layer and the dentate gyrus, and to the piriform cortex and the olfactory nuclei, reflecting a potentially interesting function for Bcr in these highly specialized brain regions.

Animals↗

PubMed1994

Status epilepticus results in reversible neuronal injury in infant rat hippocampus: novel use of a marker.

Despite ready induction of severe limbic status epilepticus by systemic kainic acid (KA) in infant rats, excitotoxic neuronal injury has not been observed. The mechanisms of this resistance of the immature hippocampus to excitotoxicity are unknown. Acid fuchsin stain has been used as a marker of irreversibly injured neurons in the adult brain. We speculated that the dye might map reversibly injured neurons in the infant. Subsequent to KA-induced status epilepticus in 11-day-old rats, acid fuchsin stain was evident in the hippocampal CA3, CA1, dentate gyrus and hilus by 24 h, peaked at 48 h and disappeared by 6 days, without evidence for neuronal loss. Acid fuchsin may be a useful tool for delineating the distribution of reversibly injured immature neurons in experimental seizure paradigms.

Animals↗

PubMed1994

Subacute sclerosing panencephalitis in an infant: diagnostic role of viral genome analysis.

Subacute sclerosing panencephalitis (SSPE) is related to "defective" measles virus or vaccination, though an association with parainfluenza viruses has been reported. SSPE is characterized by a slow, erratic course and elevated cerebrospinal fluid measles titers. An immunocompetent, vaccinated infant, with onset of symptoms in parainfluenza virus season and a catastrophic course is described. Cerebrospinal fluid titers were negative, but postmortem brain had typical SSPE lesions. Patient brain-derived RNA, subjected to reverse transcription followed by polymerase chain reaction yielded polymerase chain reaction products with measles virus but not parainfluenza virus genes. The sequenced fragment revealed multiple mutations, typical for SSPE. SSPE can thus present in infants, with short latency and no cerebrospinal fluid antibodies. Viral genomic analysis may be diagnostic, permitting early therapy.

Antigens, Viral↗

PubMed1994

Glucocorticoid receptor mRNA ontogeny in the fetal and postnatal rat forebrain.

Glucocorticoid receptor (GR) ontogeny and distribution in postnatal rat brain have been demonstrated, but onset and distribution of GR gene expression during fetal life has not been reported. This study focuses on the distribution of GR-mRNA in the fetal and postnatal rat forebrain, with emphasis on hypothalamic and limbic structures. Time pregnant rats were decapitated at 8:30-9:30 AM on Gestational Days 14 (F14), F16, F17, F18, and F19. Postnatally, rats were sacrificed on Days 1, 4, 6, 10, and 16. Cryostat sections were subjected to in situ hybridization, using a cRNA probe directed to the GR-mRNA. GR-mRNA was detectible in the hippocamposeptal formation as early as F14. By F16, GR gene expression was evident in the hypothalamic paraventricular nucleus (PVN) as well. During late gestation (F17-F19), GR-mRNA was localized also in the thalamus, hippocampus, amygdala, and discrete cortical regions. Postnatally, GR-mRNA abundance was high in the PVN, CA1/CA2 hippocampal field, piriform cortex and dorsal endopiriform nucleus, specific amygdaloid nuclei, and the suprachiasmatic nucleus. In PVN, GR-mRNA was present prior to the onset of CRH gene expression (F17), which may suggest a role for GR in neuronal differentiation.

Aging↗

PubMed1994

Necrosis in pontine gliomas: radiation induced or natural history?

PURPOSE: To determine whether the central necrotic lesions that develop in a large number of patients with pontine gliomas are secondary to radiation therapy, specifically high-dose (7,200-7,800 cGy) hyperfractionation radiation therapy, or are part of the biologic progression of this tumor. MATERIALS AND METHODS: The authors analyzed neuroimaging studies of 31 consecutive patients with pontine-centered gliomas and assessed the time of onset of necrosis, the type and dose of radiation therapy administered, and the length of survival. RESULTS: Necrosis was present at diagnosis in eight of the 31 patients (26%). Time to appearance and total prevalence of central necrosis did not differ in the standard versus hyperfractionated therapy groups. The time between diagnosis and the appearance of necrosis correlated with length of survival (P = .005, Kendall correlation). CONCLUSION: In a substantial number of patients, central necrosis in pontine gliomas is not caused by radiation therapy but is an indication of an advanced tumor stage. Children with central necrosis at diagnosis have a significantly shorter median survival than do those without, regardless of the type of therapy administered.

Brain Neoplasms↗

PubMed1994

Corticotropin-releasing hormone mediates the response to cold stress in the neonatal rat without compensatory enhancement of the peptide's gene expression.

A variety of stressors activate the hypothalamic-pituitary-adrenal axis, with secretion and compensatory enhanced synthesis of hypothalamic corticotropin-releasing hormone (CRH). Whether CRH is a major effector in the stress response of the neonatal rat and whether the peptide's gene expression is subsequently up-regulated are not fully understood. We studied the effect of cold-separation stress on plasma corticosterone (CORT) levels and CRH messenger RNA (CRH-mRNA) abundance in the paraventricular nucleus. Rats (4-16 days old) were subjected to maximal tolerated cold-separation. CORT and CRH-mRNA abundance were measured before and at several time points after stress. Cold-separation stress resulted in a significant plasma CORT increase in all age groups studied. This was abolished by the administration of an antiserum to CRH on both postnatal days 6 and 9. CRH-mRNA increased in rats aged 9 days or older, but not in 6-day-old rats, by 4 h after stress. These results suggest the presence of robust CRH-mediated adrenal responses to cold-separation stress in neonatal rats. Before postnatal day 9, however, the compensatory increase in CRH-mRNA abundance is minimal.

Adaptation, Physiological↗

PubMed1993

Effects of a specific glucocorticoid receptor antagonist on corticotropin releasing hormone gene expression in the paraventricular nucleus of the neonatal rat.

Mechanisms controlling the synthesis of corticotropin releasing hormone (CRH) in neonatal rats, and the ontogeny of glucocorticoid (GC) feedback control of hypothalamic CRH remain unknown. Specific issues are whether stress induces up-regulation of CRH gene expression during the first postnatal week, and the role of GC feedback, at the hypothalamic level, in the stress-hyporesponsive period. We studied the ontogeny of the negative feedback regulation of CRH gene expression by GC in the paraventricular nucleus (PVN). We implanted chronic cannulae containing a GC-receptor antagonist, RU 38486, in rats on postnatal days 3 to 13. Three days later, animals were sacrificed, and brains were analyzed for CRH-messenger RNA (CRH-mRNA), using semi-quantitative in situ hybridization. Animals implanted with cholesterol-containing cannulae served to evaluate the stressful effect of implantation on CRH-mRNA abundance. The presence of GC receptor messenger RNA (GR-mRNA) in the PVN of neonatal rats was also determined. RU 38486 did not increase CRH-mRNA abundance during the first postnatal week, despite the presence of GR-mRNA in the PVN. Chronic-implantation stress also failed to increase CRH synthesis. CRH gene expression in the PVN was enhanced in infant rats implanted with RU-38486 on postnatal day 9 or later. Cholesterol implantation on days 9, 10 (but not later), resulted in increased PVN-CRH-mRNA. Thus, CRH-mRNA is up-regulated by chronic blockade of GC receptors only subsequent to the eighth postnatal day. Furthermore, such blockade does not affect the response of CRH-mRNA to chronic stress in the neonatal rat.

Animals↗

PubMed1993

Short-interval amygdala kindling in neonatal rats.

The kindling paradigm provides a powerful tool for studying the generation, propagation and generalization of seizures. Such reproducible quantitative paradigms are a prerequisite for the experimental study of epilepsy in the developing brain. Kindling has been extensively utilized as a model of limbic seizures in the adult rat; amygdala short-interval kindling has been studied in > or = 15-day-old rats. We applied the short-interval kindling method, i.e., stimulation at every 15 min, to 7-12-day-old rats. Stage-5 behavioral seizures were achieved even in 7-day-old rats; however, the progression of behavioral kindling differed somewhat from that of older rats. Correlation of electrographic discharges and behavioral phenomena was inversely related to age. Reliable progressive amygdala discharges were difficult to assess in most < or = 10-day-old rats. Spontaneous seizures occurred relatively frequently in younger age groups. The amygdala short-interval kindling paradigm is reproducibly and reliably applicable to rats during the 2nd postnatal week. The presence of progressive focal to bilateral-generalized seizures suggests a significant functional maturity of the amygdala-limbic circuitry at this age.

Aging↗

PubMed1993

Pathophysiology of massive infantile spasms: perspective on the putative role of the brain adrenal axis.

Massive infantile spasms are an age-specific seizure syndrome of infancy. Uniquely, the spasms respond to hormonal manipulation using adrenocorticotropic hormone (ACTH) or glucocorticoids. A hypothesis explaining the efficacy of hormonal therapy, age-specificity, multiple causative factors, and spontaneous resolution of infantile spasms is presented. Corticotropin-releasing hormone (CRH), an excitant neuropeptide suppressed by ACTH/steroids, is implicated. Evidence for the age-specific convulsant properties of CRH is presented, and a putative scenario in which a stress-induced enhancement of endogenous CRH-mediated seizures is discussed. Clinical testing of the CRH-excess theory and its therapeutic implications are suggested.

Adrenocorticotropic Hormone↗

PubMed1993

Methods for implanting steroid-containing cannulae into the paraventricular nucleus of neonatal rats.

Implantation of cannulae into brains of neonatal rats presents methodological difficulties. We discuss such issues as avoiding tissue injury, and describe successful techniques. Cannulae size, methods of preparation, insertion, and securing are evaluated. We present a modified cannula holder applicable to the soft neonatal brain. Application of these methods to the study of glucocorticoid receptors in the neonatal rat hypothalamus is illustrated.

Animals↗

PubMed1992

CRH gene expression in the fetal rat is not increased after pharmacological adrenalectomy.

A regimen of twice daily metyrapone injections (100 mg/kg), resulted in pharmacological adrenalectomy of pregnant rats and fetuses in utero, i.e. depression of plasma corticosterone and elevation of plasma adrenocorticotropic hormone (ACTH). Toxicity was minimal on days 14-17 of pregnancy, and increased with higher maternal weight and pregnancy progression. Corticotropin releasing hormone (CRH) messenger RNA abundance in the pregnant adults increased significantly within 48 h of metyrapone initiation. No change in CRH gene expression in the paraventricular nucleus of fetuses (days 17-18) was seen, even after 72 h of the regimen. This is compatible with the independence of CRH gene expression of glucocorticoid feedback in the fetal rat.

Adrenalectomy↗

PubMed1992

Ontogenic study of lithium-pilocarpine-induced status epilepticus in rats.

Lithium is known to potentiate the ability of pilocarpine to induce status epilepticus in rats. The goal of this study was to determine whether lithium could potentiate pilocarpine-induced seizures in developing animals. Behavioral, electroencephalographic (EEG), and histopathological changes induced by systemic administration of lithium (3 meq/kg) followed 20 h later by pilocarpine (3, 10, 30, 60 mg/kg) were studied in 3-30-day-old rats. Lithium followed by pilocarpine (30 and 60 mg/kg) induced hyperactivity, tremor, loss of postural control and scratching but no electrographic seizures in 3-8-day-old rats. In the 7-10-day-old animals pretreatment with lithium and pilocarpine 60 mg/kg induced status epilepticus with sustained myoclonus and continuous bilateral synchronous spike and sharp wave, but doses of pilocarpine lower than 60 mg/kg had no effect. The susceptibility to lithium-pilocarpine-induced status epilepticus increased markedly during the third postnatal week of life. During this time period, rats treated with lithium (3 meq/kg) plus pilocarpine 10 mg/kg exhibited behavioral and EEG manifestations of status epilepticus. The same combination of lithium and pilocarpine failed to induce status epilepticus either before or after the third week of life. Histopathological analysis of the brains of the animals used in these studies failed to demonstrate the widespread damage reported in adult rats that have undergone lithium-pilocarpine-induced status epilepticus.

Aging↗

PubMed1992

Corticotropin-releasing hormone-induced seizures in infant rats originate in the amygdala.

The neuroanatomical substrate of seizures induced by picomolar amounts of corticotropin-releasing hormone in infant rats was investigated. Electrographic and behavioral phenomena were monitored in 42 rat pups aged 5 to 22 days. Rat pups carried bipolar electrodes implanted in subcortical limbic structures, as well as cortical electrodes and intracerebroventricular cannulae. The administration of corticotropin-releasing hormone produced age-specific seizures within minutes, which correlated with rhythmic amygdala discharges. Paroxysmal hippocampal and cortical discharges developed subsequently in some rats. Corticotropin-releasing hormone-induced electrographic and behavioral seizures originate in the amygdala.

Aging↗

PubMed1992

Section of the corpus callosum in kainic acid induced seizures in rats: behavioral, electroencephalographic and neuropathological study.

Clinical and experimental data suggest that the role of corpus callosum in epilepsy includes synchronization, spread, excitation and inhibition. Section of the corpus callosum (SCC) is known to be a useful therapy in selected types of generalized epilepsy, i.e., tonic, atonic and generalized convulsive seizures, but not partial seizures which may be exacerbated by this procedure. The goal of this study was to determine the effect of SCC in the kainic acid (KA) model of limbic seizures in rats. Using several doses of KA (2.5, 5 and 10 mg/kg) injected systemically, we found a potentiation of the behavioral, electrographic and histological effects of KA in the SCC group of animals compared to the sham-operated control rats. A low dose of kainic acid (2.5 and 5 mg/kg) induced status epilepticus in the SCC animals, but not in the sham-operated control rats. These data demonstrate that in the KA model of temporal lobe seizures, SCC not only fails to protect, but actually intensifies seizures. This finding is compatible with the hypothesis that there is an inhibitory influence, via the corpus callosum, of the non epileptic neocortex on its contralateral homologue in the kainic acid model.

Animals↗

PubMed1992

Brain-adrenal axis hormones are altered in the CSF of infants with massive infantile spasms.

Massive infantile spasms (MIS), a seizure disorder unique to infants, is considered an age-dependent response of the immature brain to various insults and stressors. The seizures improve with ACTH and glucocorticoids, both major components of the brain-adrenal axis. We hypothesized that CNS levels of these hormones are abnormal in infants with MIS and studied CSF from 14 infants with MIS and 13 age-matched controls by analysis for corticotropin-releasing hormone (CRH), ACTH, cortisol, and interleukin-1-beta. ACTH levels in CSF of patients were significantly lower than those of controls, but differences in cortisol levels between patients and controls were not statistically significant. CRH levels in both groups were similar and fluctuated diurnally. These results indicate an alteration of specific CNS components of the brain-adrenal axis in MIS.

Adrenocorticotropic Hormone↗