Dexamethasone downregulates chemokine receptor CXCR4 and exerts neuroprotection against hypoxia/ischemia-induced brain injury in neonatal rats

OBJECTIVE: Hypoxia/ischemia (H/I) induces rapid and massive brain damage in neonatal rat brain, resulting in long-term consequences on structural and functional maturation of the central nervous system. Inflammatory mediators contribute to these permanent pathological changes, which are sensitive to corticoid treatments. Since the chemokine receptor CXCR4, specific for the SDF-1 alpha/CXCL12 ligand, regulates both apoptotic and neuroregeneration processes, this receptor was quantified 2 days following H/I in neonatal rat brain in relation with dexamethasone (DEX) treatment. METHODS: Seven-day-old male rats were exposed to a 90-min hypoxia following unilateral carotid ligation (H/I) and were sacrificed 48 h later. Glucocorticoid-pretreated animals were injected subcutaneously 5 h prior to hypoxia with 0.5 microg/g DEX. Glial fibrillary acidic protein and cresyl violet staining were used for assessing the extent of brain lesion subdivided into necrotic and penumbra-like areas. The density of CXCR4 receptors was determined by quantitative autoradiography using [(125)I]SDF-1 alpha as a ligand. RESULTS: The H/I resulted in a massive lesion ipsilateral to the carotid ligation, which was extended to cortical, striatal, hippocampal and thalamic areas, while the contralateral hemisphere remained apparently unaffected. DEX decreased the lesion size by reducing mainly the necrotic area. H/I induced a marked increase in CXCR4 receptor binding in the penumbra-like areas. DEX pretreatment decreased CXCR4 receptor density in the penumbra and attenuated astrocytosis. Furthermore, DEX strongly lowered mortality rate and reduced functional recovery time right after hypoxia. CONCLUSION: The rapid enhancement in CXCR4 chemokine receptor binding in the affected brain areas suggests that SDF-1 alpha/CXCR4 may play a role in the hypoxia-induced inflammatory reaction in the neonatal brain. Attenuation of CXCR4 expression and astrogliosis could contribute to the neuroprotective effect of DEX pretreatment via influencing the inflammatory cascade induced by H/I in the neonatal brain.     

Median raphe mediates estrogenic effects to the hippocampus in female rats

Subcortical regions such as the medial septum-diagonal band of Broca and supramammillary area have been shown to mediate indirect oestrogenic effects on hippocampal morphology and function. Here, the role of the median raphe (MR), a serotonergic subcortical structure, is studied. To this end, 17beta-estradiol-filled 30-gauge cannulae were implanted into the MR of female ovariectomized rats; cholesterol-filled cannulae served as controls. After seven days, using unbiased electron microscopic stereological calculations and semiquantitative analysis, the spine synapse density and surface density of glial fibrillary acidic protein-positive astrocyte processes, respectively, were determined in the stratum radiatum of the CA1 region of the hippocampus. Changes in the serotonergic innervation of the hippocampal CA1 region were determined by immunohistochemistry and subsequent morphometric analysis. In the stratum radiatum of the CA1 region, local estradiol application into the MR resulted in a 47% increase in spine synapse density. Simultaneously, the density of glial fibrillary acidic protein-positive fibers decreased by 16%. The density of serotonin (5-HT) innervation of the strata lacunosum moleculare and radiatum of the CA1 region of the hippocampus was reduced in response to estradiol, as shown by a decrease in the length of fibers (27.6 and 48.3% decrease, respectively) and the number of large varicosities (32.5 and 38.8% decrease, respectively). These observations suggest a major role of the MR in mediating oestrogenic effects on the hippocampus and an involvement of the serotonergic system.     

Olanzapine versus clozapine in treatment-resistant or treatment-intolerant schizophrenia

Clozapine has been the gold standard for treatment of patients with refractory schizophrenia but is associated with serious safety liabilities. This has prompted the search for therapeutic alternatives for treatment-resistant schizophrenia. The objective of this study was to compare the efficacy and safety of olanzapine versus clozapine in schizophrenic patients who failed to respond adequately to antipsychotic medication or who experienced intolerable adverse effects associated with the medication. This 18-week, randomized, double-blind, parallel study compared treatment with either olanzapine (5-25 mg/day, n=75) or clozapine (100-500 mg/day, n=72) in patients with schizophrenia who were nonresponsive to, or intolerant of, standard acceptable antipsychotic therapy. At the 18-week endpoint, no statistically significant differences were found between olanzapine and clozapine in any efficacy measure used: Positive and Negative Syndrome Scale (PANSS) total, positive, negative, or general psychopathology or Clinical Global Impression severity (CGI-S). Response rates based on the criteria of Kane et al. [Arch. Gen. Psychiatry 45 (1988) 789] were also not significantly different between olanzapine-treated (57.9%) and clozapine-treated patients (60.8%). There were no significant differences in measurements of extrapyramidal symptoms or electrocardiography, and no clinically and statistically significant changes were seen in vital signs or laboratory measures in either group. Both treatments were well tolerated. Olanzapine demonstrated similar efficacy to clozapine in patients who had failed previous treatment because of lack of efficacy (treatment resistance) or intolerable side effects (treatment intolerance). Olanzapine therefore presents a safe alternative in the treatment of refractory schizophrenia.     

Alpha-methyl-l-tryptophan positron emission tomography in epilepsy with cortical developmental malformations

Preliminary studies suggest that alpha[(11)C]methyl-l-tryptophan positron emission tomography can detect the epileptic focus within malformations of cortical development. We determined the sensitivity and specificity of alpha-[(11)C]methyl-l-tryptophan positron emission tomography in identifying epileptic focus in children with intractable, neocortical epilepsy with and without malformations of cortical development. Seventy-three epileptic children were classified into lesional and nonlesional groups, and compared regarding focal increased alpha-[(11)C]methyl-l-tryptophan uptake. The sensitivity and specificity of focal increased alpha-[(11)C]methyl-l-tryptophan uptake, using intracranial electroencephalogram localization of seizure onset as the standard, were compared between lesional and nonlesional groups. The specificity of alpha-[(11)C]methyl-l-tryptophan positron emission tomography for detecting seizure onset lobe was equally high in lesional (97%) and nonlesional groups (100%), whereas sensitivity was higher in the lesional than the nonlesional group (47% versus 29%; P = 0.047). The incidence of alpha-[(11)C]methyl-l-tryptophan uptake abnormality was higher in the lesional than the nonlesional group (P < 0.01). Alpha-[(11)C]methyl-l-tryptophan positron emission tomography localized and visualized epileptogenic regions in 25% of patients with nonlocalizing magnetic resonance imaging. Although overall sensitivity of alpha-[(11)C]methyl-l-tryptophan positron emission tomography in identifying neocortical epileptic focus is modest, specificity is extremely high. When an alpha-[(11)C]methyl-l-tryptophan focus is detected, it likely represents the epileptogenic region to be resected.     

Elucidation of the anatomy of a satiety network: Focus on connectivity of the parabrachial nucleus in the adult rat

We hypothesized that brain regions showing neuronal activation after refeeding comprise major nodes in a satiety network, and tested this hypothesis with two sets of experiments. Detailed c‐Fos mapping comparing fasted and refed rats was performed to identify candidate nodes of the satiety network. In addition to well‐known feeding‐related brain regions such as the arcuate, dorsomedial, and paraventricular hypothalamic nuclei, lateral hypothalamic area, parabrachial nucleus (PB), nucleus of the solitary tract and central amygdalar nucleus, other refeeding activated regions were also identified, such as the parastrial and parasubthalamic nuclei. To begin to understand the connectivity of the satiety network, the interconnectivity of PB with other refeeding‐activated neuronal groups was studied following administration of anterograde or retrograde tracers into the PB. After allowing for tracer transport time, the animals were fasted and then refed before sacrifice. Refeeding‐activated neurons that project to the PB were found in the agranular insular area; bed nuclei of terminal stria; anterior hypothalamic area; arcuate, paraventricular, and dorsomedial hypothalamic nuclei; lateral hypothalamic area; parasubthalamic nucleus; central amygdalar nucleus; area postrema; and nucleus of the solitary tract. Axons originating from the PB were observed to closely associate with refeeding‐activated neurons in the agranular insular area; bed nuclei of terminal stria; anterior hypothalamus; paraventricular, arcuate, and dorsomedial hypothalamic nuclei; lateral hypothalamic area; central amygdalar nucleus; parasubthalamic nucleus; ventral posterior thalamic nucleus; area postrema; and nucleus of the solitary tract. These data indicate that the PB has bidirectional connections with most refeeding‐activated neuronal groups, suggesting that short‐loop feedback circuits exist in this satiety network. J. Comp. Neurol. 524:2803–2827, 2016. © 2016 Wiley Periodicals, Inc.     

Effect of perinatal stress on the biogenic amine neurotransmitter level of the adult rat's brain

The amount of biogenic amines (dopamine and serotonin) and their metabolites (DOPAC, HVA, 5-HIAA, and 5-HTOL) in five regions of the brain (frontal cortex, hypothalamus, hippocampus, striatum, and brainstem) was studied in the male and female offspring of control and perinatally (48 h before birth or 48 h after birth) food and water deprived dams, when they were three months old, by using HPLC-EC determination. The increase of amine or metabolite level was dominant (19 values increased and 10 decreased related to control). Before-birth stress caused increase in 9 case and only 2 decreased, while in the case of after-birth stress 10 increased and 8 decreased. However, though there is no possibility to decide an exact tendency of direction, the after-birth stress (transmitted by milk) has more expressed effect. Striatum and brainstem were the most touched regions. There was a gender dependence with the dominance of males, except striatum. Blood plasma nociceptin level was also studied and there was a significant elevation in males after pre- and postnatal deprivation, while in females only after postnatal deprivation. The importance of the results in correlation with other stress effects is discussed.     

Beta lactoglobulin homologue placental protein 14 (PP14) in serum of patients with trophoblastic disease and non-trophoblastic gynecologic malignancy

Summary Serum levels of beta lactoglobulin homologue placental protein 14 (PP14) were measured by a sensitive radioimmunoassay in various trophoblastic diseases and non-trophoblastic gynecologic malignancies. While trace amounts of protein were detected in sera of non-pregnant subjects (22.3±13.7 g/l), during first half of normal pregnancy a dramatic rise of serum-PP14 levels was demonstrable with a peak-value at 7th–10th week of gestation, followed by a decline thereafter. Serial determinations of PP14 have been performed in 31 patients with trophoblastic tumour (20 hydatidiform moles, 4 invasive moles and 7 choriocarcinomas). In patients with hydatidiform moles and invasive moles (273.5±106.5g/l and 162.2±109.6g/l) respective values before therapy were much exceeding the nonpregnant controls. After therapy there was a rapid decline of the serum-PP14 levels within two weeks. In patients with choriocarcinoma the PP14 values were moderately elevated (66.4±25.7g/l), and declined following the remission of disease. In 32 gynecological tumours (21 carcinomas of the cervix, 4 endometrial carcinomas, 5 ovarian carcinomas, 2 carcinomas of the vulva) the pretreatment levels were not different to normal controls.     

Serum levels of placenta-specific tissue protein 12 (PP12) in pregnancies complicated by pre-eclampsia, diabetes or twins

PP12 is one of the recently discovered soluble tissue antigens of the placenta. During normal pregnancy maternal serum PP12 levels rise during the first 18 weeks reaching a mean peak value of 139.9 +/- 40.26 micrograms/l; after that there is a fall to a mean value of 111.9 +/- 42.39 micrograms/l between 28 and 40 weeks. Significantly higher mean serum PP12 levels were found in the third trimester in two high risk pregnancy groups (281.09 +/- 117.08 micrograms/l in pre-eclamptic toxaemia and 203.71 +/- 73.77 micrograms/l in diabetes) while serum PP12 levels remained normal (114.94 +/- 58.06 micrograms/l) in twin pregnancy. The increase of serum PP12 concentration in toxaemia and in diabetes may be of considerable diagnostic significance.