The neurotoxic 3-nitropropionic acid (3-NP), a freckled milk vetch-derived inhibitor of mitochondrial enzymatic processes that is capable of mimicking the typical pathological features of neurodegenerative disorders, behaved in a differentiated manner in a hibernating rodent (hamster) with respect to a nonhibernating rodent (rat). Treatment of the two rodents with both an acute and chronic 3-NP dose supplied deleterious neuronal effects due to distinct histamine receptor (H n R) transcriptional activities, especially in the case of the rat. In hamsters, these treatment modalities accounted for overall reduced global activity in a freely moving environment and overt motor symptoms such as hindlimb dystonia and clasping with respect to the greater abnormal motor behaviors in rats. This behavioral difference appeared to be strongly related to qualitative fewer neuronal alterations and, namely, lesser crenated cell membranes, swollen mitochondria, and darkened nuclei in hamster brain areas. Moreover, a mixed H 1,3 R mRNA expression pattern was reported for both rodents treated with a chronic 3-NP dose as demonstrated by predominantly low H 1 R mRNA levels (Ͼ50%) in rat striatum and cortex, whereas extremely high H 3 R levels (Ͼ80%) characterized the lateral and central amygdala nuclei plus the striatum of hamsters. Interestingly, the H 3 R antagonist (thioperamide) blocked 3-NP-dependent behaviors plus induced an up-regulation of H 1 R levels in mainly the above-reported hamster amygdalar nuclei. Overall, these results show, for the first time, that a major protective role against neurodegenerative events appears to be strongly related to the expression activity of H 1,3 R subtypes of amygdalar neurons in this hibernating model.

Recently, considerable interest has been aroused by the specific actions of bisphenol A (BPA). The present investigation represents a first study dealing with the interaction of BPA with the biologically more active somatostatin receptor subtype (sst 2 ) in the rat limbic circuit. After treating pregnant female Sprague-Dawley rats with two doses (400 µg/kg/day; 40 µg/kg/day) of BPA, the binding activity of the above receptor subtype was evaluated in some limbic regions of the offspring. The higher dose proved to be the more effective one, as demonstrated by the elevated affinity of sst 2 with its specific radioligand, [ 125 I]-Tyr 0 somatostatin-14. The most dramatic effects of BPA on sst 2 levels occurred at the low-affinity states of such a subtype in some telencephalic limbic areas of postnatal rats (10 days of age; postnatal day [PND] 10). These included lower (p < 0.05) sst 2 levels in the gyrus dentate of the hippocampus and basomedial nucleus of the amygdala; significantly higher (p < 0.01) levels were observed only for the high-affinity states of the periventricular nucleus of the hypothalamus. A similar trend was maintained in PND 23 rats with the exception of much lower levels of the high-affinity sst 2 receptor subtype in the amygdala nucleus and ventromedial hypothalamic nucleus. However, greater changes produced by this environmental estrogen were reported when the binding activity of sst 2 was checked in the presence of the two more important selective agonists (zolpidem and Ro 15-4513) specific for the α-containing γ-aminobutyric acid (GABA) type A receptor complex. In this case, an even greater potentiating effect (p < 0.001) was mainly obtained for the low-affinity sst 2 receptor subtype in PND 10 animals, with the exception of the high-affinity type in the ventromedial hypothalamic nucleus and gyrus dentate. These results support the contention that an sst 2 subtype α-containing GABA type A receptor system might represent an important neuromediating station capable of promoting estrogenlike mechanisms of BPA, especially during the early developmental phases. Materials and Methods AnimalsSexually mature Sprague-Dawley female rats (200-250 g) were purchased from Charles River (Como, Italy), caged individually, housed in the Cellular Biology Department (University of Calabria, Cosenza, Italy) stabularium, and maintained on a 12-hr dark/12-hr light schedule (lights on 14:00-2:00 hr). Animal maintenance and experimental procedures were in accordance with the Guide for Care and Use of Laboratory Animals (20). Efforts were made to minimize animal suffering and reduce the number of specimens used. Bisphenol A AdministrationThirty-two 60-day-old female rats were subdivided into three experimental groups in which four females were housed per cage with stainless steel wire lids for 3 days for acclimation purposes. Afterward these rats received either 40 µg/kg/day BPA (lBPA; Sigma Chemical, Milan, Italy) po or 400 µg/kg/day BPA (hBPA) po dissolved in arachis oil and were compared with controls that consi...

Common environmental contaminants such as heavy metals and pesticides pose serious risks to behavioral and neuroendocrine functions of many aquatic organisms. In the present study, we show that the heavy metal cadmium and the pesticide endosulfan produce such effects through an interaction of specific cerebral histamine receptor subtypes in the teleost ornate wrasse (Thalassoma pavo). Treatment of this teleost with toxic cadmium levels for 1 week was sufficient to induce abnormal swimming movements, whereas reduced feeding behaviors were provoked predominantly by elevated endosulfan concentrations. In the brain, these environmental contaminants caused neuronal degeneration in cerebral targets such as the mesencephalon and hypothalamus, damage that appeared to correlate with altered binding levels of the three major histamine receptors (subtypes 1, 2, and 3). Although cadmium accounted for reduced binding activity of all three subtypes in most brain regions, it was subtype 2 that seemed to be its main target, as shown by a very great (p < 0.001) down-regulation in mesencephalic areas such as the stratum griseum central layer. Conversely, endosulfan provided very great and great (p < 0.01) up-regulating effects of subtype 3 and 1 levels, respectively, in preoptic-hypothalamic areas such as the medial part of the lateral tuberal nucleus, and in the suprachiasmatic nucleus. These results suggest that the neurotoxicant-dependent abnormal motor and feeding behaviors may well be tightly linked to binding activities of distinct histamine subtypes in localized brain regions of the Thalassoma pavo.

Considerable attention has been focused on environmental disruptors such as the xenoestrogen bisphenol A, which influences reproductive, developmental, and cognitive activities through its interaction with specific neuromediating systems in an estrogen-like fashion. In the present study, the effects of this xenoestrogen proved to be preferentially directed toward hypothalamic and extrahypothalamic somatostatin receptor subtype 3, which displayed a higher binding affinity of its specific nonpeptide agonist L-796-778 than that of L-779-976 (subtype 2). One type of action, with respect to animals treated with vehicle alone, consisted of a very strong (p < 0.001) decrease of somatostatin receptor subtype 3 mRNA levels in layer V of the frontoparietal cortex of adult rats (Sprague-Dawley) after transplacental and lactational exposure to bisphenol A (400 microg/kg/day). Similarly, such treatment in 7-day-old rats was responsible for a very strong reduction of the subtype 3 mRNA levels in the hypothalamic periventricular nuclei and a strong (p < 0.01) increase of the subtype 3 mRNA levels in the ventromedial nuclei. Moreover, even greater upregulated and downregulated activities were reported when subtype 3 mRNA levels were determined in the presence of receptor agonists specific for distinct alpha GABA(A) receptor subunits (alpha(1,5)). The predominant effects of bisphenol A on somatostatin receptor subtype 3 mRNA levels occurring in an alpha GABA(A) subunit-dependent manner tend to suggest the early modulatory importance of this environmental disruptor on cross-talking mechanisms that are implicated in the plasticity of neural circuits, with consequential influence on neuroendocrine/sociosexual behaviors.

Background: The biology of malignant peritoneal mesothelioma (MPM) is largely unknown. In the present study, we assessed the expression of survivin and other members of the inhibitors of apoptosis proteins (IAP) family (IAP-1, IAP-2 and X-IAP) in a series of 32 MPM surgical specimens and investigated the effects of survivin knockdown in an established MPM cell line. Methods: Expression of different IAPs was measured by immunohistochemistry. MPM cells were transfected with a small-interfering RNA (siRNA) targeting survivin mRNA and analyzed for survivin expression, growth rate, and ability to undergo spontaneous and drug (cisplatin, doxorubicin)-induced apoptosis. Results: Survivin expression was observed in 29 (91%) surgical MPM specimens, whereas the positivity rate for the other IAPs ranged from 69% to 100%. Transfection of MPM cells with the survivin siRNA induced a marked inhibition of survivin protein expression, a time-dependent decline in cell growth and an enhanced rate of spontaneous and drug-induced apoptosis, with a concomitant increase in the catalytic activity of caspase-9. Conclusion: Our results show for the first time that survivin, as well as other IAPs, is largely expressed in clinical MPMs and suggest that strategies aimed at down-regulating survivin may provide a novel approach for the treatment of the malignancy.