The role of the chorda tympani nerve in the activation of the rat hypothalamic histaminergic system by leptin.

A possible pathway through which leptin activates the histaminergic system was studied using in vivo microdialysis in rats. Intraperitoneal injection of leptin (1.3 mg/kg) caused a significant increase in hypothalamic histamine release, however, its intracerebroventricular injection (10 microg/rat) did not cause any significant changes in the release. Furthermore, leptin (1.3 mg/kg) had no effect on histamine release in rats whose chorda tympani nerves, a branch of the facial nerve which mediates taste information, were transected bilaterally. These findings indicate that leptin activates the histaminergic system by the peripheral signal inputs via the chorda tympani resulting in the suppression of food intake.

The role of atypical and conventional PKC in dehydroepiandrosterone-induced glucose uptake and dexamethasone-induced insulin resistance.

We have reported that both dehydroepiandrosterone (DHEA) and dexamethasone (Dexa) directly activate PKC. In this study, we investigated the effects of these hormones on conventional PKC (cPKC) and atypical PKC (aPKC). DHEA and Dexa directly activated PKCbeta and PKCzeta to the same degree. In rat adipocytes, DHEA and Dexa activated endogenous immunoprecitable PKCzeta to 246 and 164%, respectively, from basal level (100%). In adipocytes, 5 min treatment with DHEA increased phosphatidylinositol 3-kinase (PI 3-kinase) activity in immunoprecipitate with anti-phosphotyrotyrosine antibody to 235%. Preincubation with wortmannin, myristoylated PKCzeta pseudosubstrate, but not with Go6976, abolished DHEA-induced 2-deoxyglucose (DOG) uptake. cPKC inhibitors prevented Dexa-induced insulin resistance. Moreover, DHEA and Dexa increased DOG uptake to 330 and 220%, respectively, in adipocytes overexpressed with wild-type PKCzeta, but not in those overexpressed with dominant negative. These results indicate that DHEA and Dexa activate both cPKC and aPKC, and Dexa-induced cPKC activation may lead to insulin resistance. In contrast, DHEA may mimic or enhance insulin action via PI 3-kinase and aPKC.

Stem cell factor augments Fc epsilon RI-mediated TNF-alpha production and stimulates MAP kinases via a different pathway in MC/9 mast cells.

Mast cells express the receptor tyrosine kinase kit/stem cell factor receptor (SCFR) which is encoded by the proto-oncogene c-kit. Ligation of SCFR induces its dimerization and activation of its intrinsic tyrosine kinase activity leading to activation of Raf-1, phospholipases, phosphatidylinositol 3-kinase, and extracellular signal-regulated kinases. However, little is known about the downstream signals initiated by SCFR ligation except for activation of extracellular signal-regulated kinases. The murine mast cell line, MC/9, synthesizes and secretes TNF-alpha following the aggregation of high affinity Fc receptors for IgE (Fc epsilonRI). Ligation of SCFR or Fc epsilonRI on MC/9 cells resulted in the activation of all three MAP kinase family members, extracellular signal-regulated kinases, c-Jun amino-terminal kinase (JNK), and p38. Stem cell factor (SCF)-induced activation of JNK and p38 was insensitive to wortmannin, cyclosporin A, and FK506 whereas activation of these kinases through Fc epsilonRI was sensitive to these drugs. Coligation of SCFR augmented Fc epsilonRI-mediated activation of MAP kinases, especially JNK activation, and SCF augmented Fc epsilonRI-mediated TNF-alpha production in MC/9 cells, although SCF alone did not induce TNF-alpha production. This augmentation by SCF was regulated at the level of transcription, at least in part, since the promoter activity of TNF-alpha was enhanced following addition of SCF. These results demonstrate that SCF can augment Fc epsilonRI-mediated JNK activation and cytokine gene transcription but via pathways that are regulated differently than the ones activated through Fc epsilonRI.

Single-trial analysis of P3 in patients with generalized epilepsy.

The latencies and amplitudes of averaged P3, and the latencies, amplitudes and frequency components of single EEG responses to target tones were analyzed in 9 control subjects (CS group), 6 epileptics whose mean IQ was 100 (EP group) and 6 epileptics whose mean IQ was 52 (RE group), using an auditory oddball task. All of the subjects responded to the target tones correctly and there were no differences in the incidence of error in response to the target tones, or in the latencies and amplitudes of the averaged P3 among the three groups. However, the reaction times (RTs) in the RE group were significantly longer than those in the other groups (P < 0.05). Single EEG responses to target tone (single-trial ERPs) were classified into 2 types, those with and those without the P3 component. Type 1 had the P3 component and was observed in 42% of all of the responses in the RE group, significantly less than those in the CS (64%) and EP (61%) groups. The peak latencies of P3 in type 1 were similar among the three groups, but the amplitudes of P3 in type 1 in the RE group were significantly greater than those in the CS and EP groups. RTs in the RE group were significantly longer than those in the other groups, and had no correlation with the P3 latencies of type 1. There was little difference in the results of the frequency analysis among the three groups. These results suggest that all subjects in three groups recognized the target tones correctly, but they did not evaluate every target tone, since the incidence of P3 was almost 60% in the CS and EP groups, and 40% in the RE group. The characteristics of cognition and evaluation in three groups were the same, but the decrease in incidence of evaluation and the dissociation between the cognition and the response execution might be caused by impairment of the subject-environment contact mechanism, which resulted in the decrement of IQ in the RE group.

Increased hypothalamic somatostatin mRNA following dexamethasone administration in rats.

There is increasing evidence to suggest that supraphysiological doses of glucocorticoids suppress growth hormone secretion in vivo by augmenting somatostatin release from the hypothalamus; previously, we reported an increase in hypothalamic somatostatin content in dexamethasone-treated rats. To further examine whether the production of somatostatin really is augmented, hypothalamic somatostatin mRNA levels were determined by the Northern blot technique in female rats receiving 330 micrograms of dexamethasone daily for three days. In two series of experiments, hypothalamic somatostatin mRNA levels in dexamethasone-treated rats were significantly (p < 0.05) increased to 133 +/- 19 (mean +/- SD)% and 153 +/- 38% of the controls. In the dexamethasone-treated rats, plasma growth hormone levels were markedly suppressed compared with those of the controls. These results further support the hypothesis that pharmacological doses of glucocorticoids increase the production and release of somatostatin from the hypothalamus and thus inhibit growth hormone secretion, overriding the direct stimulatory effect of glucocorticoids on growth hormone production at the pituitary level.

The effect of nifedipine and dipyridamole on the Doppler blood flow waveforms of umbilical and uterine arteries in hypertensive pregnant women.

In a study of 45 hypertensive pregnant women, the systolic velocity/diastolic velocity ratio and pulsatility index of the umbilical and uterine arteries showed good correlation with the maternal blood pressure, and they appeared to provide a good parameter for the fetoplacental condition. Using the pulse Doppler method, we studied the effects of the antihypertensive agent nifedipine and of dipyridamole (an agent used to treat proteinuria) on the blood flow of the umbilical and uterine arteries in 16 hypertensive pregnant women. The results proved that both drugs caused a decrease in the vascular resistance of the umbilical artery and suggested that they increased the blood flow volume of this artery and were useful in the treatment of hypertension during pregnancy.

Antisense DNA downregulates protein kinase C isozymes (beta and alpha) and insulin-stimulated 2-deoxyglucose uptake in rat adipocytes.

Rat adipocytes were treated with antisense dimethoxytrityl pentadecadeoxynucleotides, complementary to mRNA initiation codon regions for alpha and beta isozymes of protein kinase C (PKC). This antisense treatment provoked 50-70% decreases in PKC and insulin-stimulated 2-deoxyglucose uptake, but did not inhibit insulin-stimulated diacylglycerol synthesis. Sense or nonsense oligodeoxynucleotides were without effect on PKC and 2-deoxyglucose uptake. These results suggest that: (i) PKC-alpha and PKC-beta isozymes can be specifically downregulated in rat adipocytes by antisense oligodeoxynucleotides, and (ii) insulin-stimulated glucose transport requires PKC.