What are the reasons for the strikingly different approaches to the use of ACTH in infants with West syndrome?

A large body of experience has been compiled in different countries, documenting the efficacy of adenocorticotropic hormone (ACTH) for infantile spasms. This is important, because it may serve as a key for understanding this disorder, as well as for designing better medicines. However, significant discrepancies exist among studies originating in different countries regarding the relative efficacy of small or large ACTH doses. These differences may be caused by a number of factors, including potential genetic or environmental-related differences in the biology of the disorder or associated genetic components that determine responsiveness to ACTH. In addition, striking differences in the preparations used around the world may be responsible. These include bio-availability and extent of blood brain barrier penetration, efficacy in activating the efficacy-mediating 'ACTH receptors', the presence in certain preparations of competing analogs, and others. These issues should not detract from the overall agreement that ACTH might be the most useful medication currently available to treat WS

Stress-induced transcriptional regulation in the developing rat brain involves increased cyclic adenosine 3',5'-monophosphate regulatory element binding activity

The cAMP-regulatory element (CRE) binding protein (CREB) functions as a trans-acting regulator of genes containing the CRE sequence in their promoter. These include a number of critical genes, such as CRF, involved in the hypothalamic response to stressful stimuli in the adult. The ability of the developing rat (during the first 2 postnatal weeks) to mount the full complement of this stress response has been questioned. We have previously demonstrated the stress-induced up-regulation of the transcription of hypothalamic CRF during the second postnatal week in the rat. The focus of the current study was to explore the mechanism of transcriptional regulation in response to stress through the physiological induction of transcriptional trans-activators that bind to the CRE in the developing rat brain. CRE-binding activity was detected via gel shift analysis in extracts from both the hypothalamus and the cerebral cortex of the developing rat. CREB was identified in these extracts by Western blot analysis and was shown to be the major contributor to the CRE-binding activity by gel shift analysis with two specific antibodies directed against CREB. After acute hypothermic stress, the abundance of CRE-binding activity (but not of total immunoreactive CREB), increased in hypothalamic extracts. This enhanced CRE-binding activity was blocked by an antiserum directed against CREB and was accompanied by an apparent increase in CREB phosphorylation. These results indicate that posttranslational enhancement of CRE-binding activity is likely to constitute an important mechanism for up-regulation of genes possessing the CRE sequence in the developing rat hypothalamus by adverse external signals

Developmental seizures induced by common early-life insults: short- and long-term effects on seizure susceptibility.

The immature brain is highly susceptible to seizures induced by a variety of insults, including hypoxia, fever, and trauma. Unlike early life epilepsy associated with congenital dysplasias or genetic abnormalities, insults induce a hyperexcitable state in a previously normal brain. Here we evaluate the epileptogenic effects of seizure-inducing stimuli on the developing brain, and the age and regional specificity of these effects

Ontogeny of somatostatin gene expression in rat diencephalon.

Somatostatin gene expression is first detectable, using in situ hybridization, on the 14th fetal day in rat diencephalon. Other structures expressing somatostatin messenger RNA include the anterior basal periventricular nucleus, amygdalo-hippocampal complex, dorsolateral thalamus and distinct areas in the parieto-frontal cortex. Semiquantitative analysis reveals that somatostatin synthesis increases progressively throughout the last third of fetal life and onto postnatal life

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