Higher levels of estradiol replacement correlate with better spatial memory in surgically menopausal young and middle-aged rats.

The current study investigated whether, for spatial reference memory, age impacts (1) sensitivity to surgical ovarian hormone loss (Ovx), (2) response to estradiol therapy (ET), and (3) the relation between circulating estradiol levels and memory scores in ovary-intact sham and Ovx plus ET rats. Young, middle-aged and aged Fischer-344 rats received sham, Ovx or Ovx plus ET treatments, and were then tested on the Morris maze. After the last test trial, a probe trial was given whereby the platform was removed. Circulating estradiol levels were then determined and correlated with performance. In Study 1, Ovx facilitated learning on day one, but impaired performance after day one, in young rats. Ovx did not influence performance in middle-aged rats. In young and middle-aged Ovx rats, ET enhanced performance with higher exogenous estradiol levels correlating with better performance during testing and the probe trial. There was no relationship between endogenous estradiol levels and performance in sham young or middle-aged rats. Study 2 showed that, like middle-aged rats, aged rats were not impacted by Ovx. Further, for aged Ovx rats, the ET regimen that was beneficial at earlier ages was no longer effective during test trials, and had only minor benefits for platform localization as assessed by the probe trial. Collectively, the findings suggest that the effects of Ovx as well as responsivity to the currently utilized ET regimen changes with age. Further, there appears to be a distinction between sensitivity to Ovx and responsiveness to ET after Ovx for spatial reference memory performance.

Increased intracranial pressure in a case of pediatric multiple sclerosis.

A 15-year-old girl presented to our emergency department with dizziness, anorexia, nausea, and malaise. Clinical examination and magnetic resonance imaging studies showed characteristic features of multiple sclerosis. Surprisingly, a diagnostic lumbar puncture showed significant intracranial hypertension in addition to numerous oligoclonal bands, elevated immunoglobulin G index and immunoglobulin G/albumin ratio in the cerebrospinal fluid. It is proposed that a large burden of active demyelinating disease may cause increased intracranial pressure, thus providing an additional sound rationale for prompt therapeutic administration of intravenous high-dose steroids.

Nerve growth factor in treatment and pathogenesis of Alzheimer's disease.

The etiology of Alzheimer's disease (AD) is still unknown. In addition, this terrible neurodegenerative disease will increase exponentially over the next two decades due to longer lifespan and an aging "baby-boomer" generation. All treatments currently approved for AD have moderate efficacy in slowing the rate of cognitive decline in patients, and no efficacy in halting progression of the disease. Hence, there is an urgent need for new drug targets and delivery methods to slow or reverse the progression of AD. One molecule that has received much attention in its potential therapeutic role in AD is nerve growth factor (NGF). This review will demonstrate data from humans and animals which promote NGF as a potential therapeutic target by (1) outlining the hypothesis behind using NGF for the treatment of AD, (2) reviewing both the normal and AD altered signaling pathways and effects of NGF in the central nervous system (CNS), and (3) examining the results of NGF treatment obtained from animal models of AD and AD patients.

Interleukin-6 increases the expression of key proteins associated with steroidogenesis in human NCI-H295R adrenocortical cells.

Mechanisms of interleukin-6 (IL-6)-induced cortisol release (CR) were investigated by exposing H295R cells to IL-6 and determining mRNA/protein expression (PCR/western blots) for steroidogenic enzymes (SE), steroidogenic acute regulatory protein (StAR), steroidogenic factor-1 (SF-1) (enhances SE/StAR expression), activator protein 1 (AP-1) (regulates SE/StAR expression) and adrenal hypoplasia congenita-like protein (DAX-1) (inhibits SE/StAR expression). Promoter activity of StAR (SPA) was measured by a luciferase-coupled promoter. Cortisol release was increased by 10ng/mL IL-6 (24h P<0.01). Proteins/mRNAs (StAR, cholesterol side chain cleavage enzyme, SF-1, AP-1) and SPA were increased by IL-6 (60min 1-50ng/mL IL-6; 5ng/mL IL-6 30-120min P<0.05). Four other SE proteins/mRNAs were also increased by 10ng/mL IL-6 (60min P<0.01). Protein/mRNA for DAX-1 was decreased by IL-6 (60min 1-50ng/mL IL-6; 5ng/mL IL-6 30-120min P<0.01). Phosphorylation of Janus kinase (JAK) and signal transducer and activator of transcription (STAT) was increased by IL-6 (JAK2 60min 1-50ng/mL IL-6; 10ng/mL IL-6 5-60min P<0.05; STAT1 and STAT3 60min 10ng/mL IL-6 P<0.01). Inhibition of JAK/STAT with AG490 (10µM) or piceatannol (50µM) blocked (P<0.01 10ng/mL IL-6vs. IL-6 plus AG490 or piceatannol) IL-6-induced increases in SPA and StAR mRNA. In summary, IL-6-induced CR may be facilitated by increased StAR and SE mediated by increased SF-1 and AP-1, decreased DAX-1, and increased phosphorylation of JAK/STAT.

ERK-mediated NGF signaling in the rat septo-hippocampal pathway diminishes with age.

RATIONALE: Degeneration of basal forebrain cholinergic neurons (BFCNs) plays an important role in aging and Alzheimer's disease (AD) pathology. This degeneration may be a result of disrupted nerve growth factor (NGF) signaling. Aged rats have memory deficits, BFCN degeneration, and disrupted NGF signaling. OBJECTIVE: In this study we identify a rapid NGF signaling pathway in BFCNs and the second messenger system associated with that signaling. We also identify age-dependent alterations in this signaling pathway. MATERIALS AND METHODS: After cognitive assessment using the Morris water maze, rats were given an intra-hippocampal NGF injection. Basal forebrain immunohistochemical analysis, confocal microscopy, and inhibitor studies were performed. RESULTS: An increase in immunoreactivity for the NGF receptor TrkA was found in cell bodies of BFCNs 15 min and 1 h post-NGF injection. Immunohistochemistry studies with phospho-ERK and phospho-AKT antibodies showed that this rapid signaling occurred through MAP kinase, but not PI-3 kinase pathways. MAPK inhibitor studies attenuated the NGF-induced effects. Both TrkA and phospho-ERK (extracellular signal-regulated kinase) immunoreactivities were diminished in aged rats and phospho-ERK immunoreactivity-correlated with aged rat performance in the Morris water maze. CONCLUSIONS: Rapid NGF signaling likely occurs in the rat CNS through the MAPK signaling pathway. This rapid signaling pathway is diminished in aged rats compared to young ones and may contribute to memory deficits observed in aged rats. As cholinergic degeneration coupled with altered levels of NGF and TrkA receptors are also seen in human aging and AD, ERK-related dysfunction may be relevant in human conditions as well.

Pediatric superior vena cava syndrome: assessment at low radiation dose 64-slice CT angiography.

We report a case of an 8-year-old boy with a history of aortopexy for aortic compression and multiple venous thrombosis. A 64-slice multidetector-row computed tomography examination was performed to evaluate the cause of esophageal varices and the extent of previously reported thrombi. Despite extremely low radiation dose settings, the 64-slice computed tomography angiography was fully diagnostic and showed discontinuity of the superior vena cava and brachiocephalic veins. In addition, the azygous system and large collateral vessels across the anterior, medial, and posterior mediastinum and chest wall were observed. This case shows that in pediatric patients complicated vascular pathology can reliably be assessed and radiation exposure can be safely minimized.

Ovarian hormones and cognition in the aged female rat: II. progesterone supplementation reverses the cognitive enhancing effects of ovariectomy.

The authors hypothesized that the progesterone component of some hormone replacement therapies in women is detrimental to cognition. A previous study showed that ovariectomy (ovx) in aged rats enhanced spatial working memory and decreased elevated progesterone levels. The current study evaluated whether progesterone administration counteracts these cognitive enhancing effects of ovx. Aged sham and aged ovx rats given progesterone exhibited compromised learning of the working and reference memory components of the task, and made more working memory errors on the latter testing days compared with aged ovx rats not given progesterone. Results suggest that whereas ovx of the aged female rat enhances learning and the ability to handle numerous items of spatial working memory information, progesterone is detrimental to these aspects of performance. These findings may speak to studies in menopausal women which suggest that combination hormone therapies have a negative impact on cognition.