Participation of brainstem monoaminergic nuclei in behavioral depression

Several lines of research have now suggested the controversial hypothesis that the central noradrenergic system acts to exacerbate depression as opposed to having an antidepressant function. If correct, lesions of this system should increase resistance to depression, which has been partially but weakly supported by previous studies. The present study reexamined this question using two more recent methods to lesion noradrenergic neurons in mice: intraventricular (ivt) administration of either the noradrenergic neurotoxin, DSP4, or of a dopamine-β-hydroxylase-saporin immunotoxin (DBH-SAP ITX) prepared for mice. Both agents given 2 weeks prior were found to significantly increase resistance to depressive behavior in several tests including acute and repeated forced swims, tail suspension and endotoxin-induced anhedonia. Both agents also increased locomotor activity in the open field. Cell counts of brainstem monoaminergic neurons, however, showed that both methods produced only partial lesions of the locus coeruleus and also affected the dorsal raphe or ventral tegmental area. Both the cell damage and the antidepressant and hyperactive effects of ivt DSP4 were prevented by a prior i.p. injection of the NE uptake blocker, reboxetine. The results are seen to be consistent with recent pharmacological experiments showing that noradrenergic and serotonergic systems function to inhibit active behavior. Comparison with previous studies utilizing more complete and selective LC lesions suggest that mouse strain, lesion size or involvement of multiple neuronal systems are critical variables in the behavioral and affective effects of monoaminergic lesions and that antidepressant effects and hyperactivity may be more likely to occur if lesions are partial and/or involve multiple monoaminergic systems.     

Reduced nitric oxide synthase in the brainstem contributes to enhanced sympathetic drive in rats with heart failure

Recent studies have suggested that central nervous mechanisms are involved in the enhanced sympathetic drive observed in heart failure (HF). Nitric oxide (NO) in the brainstem has been shown to reduce sympathetic nerve activity. The aim of this study was to determine whether the expression of neuronal nitric oxide synthase (nNOS) in the brainstem is reduced in rats with HF. Heart failure was produced by myocardial infarction in Wistar-Kyoto rats (HF group). Hemodynamic and echocardiographic examinations were performed. Western blot analysis for nNOS in the nucleus tractus solitarii (NTS) and the rostral ventrolateral medulla (RVLM) in the brainstem were performed to determine the expression of the nNOS gene in the HF group or sham-operated (control) group. We also performed in situ hybridization for nNOS mRNA and distribution in the brainstem. The expression of nNOS protein in the NTS and the RVLM were reduced in the HF group compared to the control group. The expression of nNOS mRNA in the brainstem was also reduced in the HF group, particularly in the NTS, compared to the control group. Intracisternal injection of NG-monomethyl-L-arginine elicited a smaller pressor response in the HF group than in the control group. These results suggest that reduced nNOS expression in the NTS and the RVLM, and the resulting reduced NO production of these sites, contribute to the enhanced sympathetic drive in HF.     

Signal transduction involving Ras-GTPase contributes to development of hypertension and end-organ damage in spontaneously hypertensive rats-treated with L-NAME.

The purpose of this study was to examine the effect of inhibition of Ras-GTPase mediated signalling on the development of hypertension and end-organ damage in spontaneously hypertensive rats chronically treated with nitric oxide synthesis inhibitor L-NAME (SHR-L-NAME). Administration of L-NAME in drinking water (80 mg/L) for 3 weeks significantly elevated mean arterial blood pressure (MABP) (223+/-4 mmHg) as compared to that of SHR controls (165+/-3 mmHg). The administration of Ras-GTPase inhibitor FPTIII (232 ng/min) to SHR-L-NAME during the last 6 days significantly attenuated high blood pressure (192+/-4 mmHg). Morphological studies of the kidneys and hearts showed that treatment with FPTIII minimized the extensive arterial fibrinoid necrosis, arterial thrombosis, narrowing of arterial lumen with marked arterial hyperplastic arterial changes that were observed in vehicle treated SHR-L-NAME. L-NAME-induced increase in urine volume and protein was also significantly lower in FPTIII-treated animals. The impaired vascular responsiveness to isoprenaline in the perfused mesenteric vascular bed of SHR-L-NAME-treated animals was significantly attenuated by FPTIII treatment. In isolated perfused hearts, recovery of left ventricular function from a 40 min of global ischemia was significantly better in FPTIII-treated SHR-L-NAME. Treatment with FPTIII also significantly reduced expression of cardiac sodium-hydrogen exchanger-1 (NHE-1) which was elevated in SHR-L-NAME. These data indicate that inhibition of Ras-GTPase-mediated signalling can attenuate end-organ damage during severe hypertension and endothelial dysfunction.     

Vascular xanthine oxidoreductase contributes to the antihypertensive effects of sodium nitrite in l-NAME hypertension

Nitrate and nitrite have emerged as an important novel source of nitric oxide (NO). We have previously demonstrated that sodium nitrite is an antihypertensive compound that exerts antioxidant effects in experimental hypertension. These unpredicted antioxidant effects of nitrite raised the question whether the beneficial effects found were caused by its conversion to NO or simply due to reversal of endothelial dysfunction as a consequence of its antioxidant effects. Here, we evaluated the antihypertensive effects of a daily dose of sodium nitrite for 4 weeks in l-NAME-induced hypertension in rats. We studied the effects of nitrite on markers of NO bioavailability, vascular oxidative stress, and expression of xanthine oxidoreductase. Moreover, we tested if xanthine oxidoreductase inhibition could attenuate the acute hypotensive effects of sodium nitrite in l-NAME hypertensive rats. We found that a single pharmacological dose of sodium nitrite exerts antihypertensive effects in l-NAME-induced hypertension. While the beneficial antihypertensive properties of nitrite were associated with increased levels of NO metabolites, hypertension increased vascular xanthine oxidoreductase expression by approximately 40 %, with minor increases in vascular superoxide production. The inhibition of xanthine oxidoreductase by oxypurinol attenuated the acute hypotensive effects of nitrite. Taken together, our results show that nitrite exerts antihypertensive effects in l-NAME hypertensive rats and provide evidence that xanthine oxidoreductase plays an important role in this antihypertensive effect.     

Role of brainstem and spinal noradrenergic and adrenergic neurons in the development and maintenance of hypertension in spontaneously hypertensive rats

Summary In young and adult spontaneously hypertensive rats (SHR), dopamine -hydroxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT) activities in discrete areas of the brainstem and spinal cord were measured as indices of noradrenergic and adrenergic neuronal activities. In young SHR, the DBH activities were elevated in the locus coeruleus (LC), A2 cell area and thoracic intermediolateral cell area (IML). The elevation disappeared at adult SHR. In young SHR, no significant change of PNMT activity was observed in the A1, A2, nucleus tractus solitarii (NTS), LC and IML areas, while, in adult SHR, the PNMT activity in the A1 cell area and DBH activity in the NTS were elevated. Lowering of blood pressure by hydralazine decreased the PNMT activity elevated in the A1 cell area and elevated it in the NTS.Plasma levels of norepinephrine and epinephrine, as measured in blood samples collected via aortic cannula at resting state, were much lower than many reported values in blood collected from the decapitated trunk. In young SHR, a significant elevation of plasma norepinephrine and DBH levels was confirmed as signs of peripheral sympathetic nervous activation. The elevation disappeared at adult SHR. Plasma epinephrine levels raised under restraint stress were much higher in SHR at all ages than in normotensive controls.In young SHR, the selective activation of noradrenergic neurons of the IML, A2 and LC areas, accompanied by activation of the peripheral sympathetic nervous system, initiates the hypertension. In adult SHR, the activation of adrenergic neurons in the A1 cell area including the nucleus reticularis lateralis may not be involved in the maintenance of hypertension but may be the results of hypertension.     

Lesions in the septal nuclei of the rat raise mean systemic arterial pressure and prevent the development of sound-withdrawal hypertension

Midline lesions in the hippocampal commisure involving the bed nucleus (I) in the forebrains of rats, and lesions which destroyed the medial septal nuclei (III), caused mean systemic arterial pressure to rise by 30–40 mm Hg in female rats of an inbred hypertensive Wistar strain. Lesions involving the anteromedial portions of both lateral septal nuclei (II) raised mean arterial pressure by 10–20 mm Hg. After pentolinium, mean arterial pressure remained raised, by approximately 20 mm Hg, in the 7th postoperative week after lesions I, II and III. The mean systemic arterial pressures of intact and shamlesioned rats rose by 30–40 mm Hg when exposed to reduction of sound level from 65–85 to 35–45 db for 5–6 weeks: this treatment did not influence the mean arterial pressures of rats with lesions I, II or III. The pressor effects of (-)-noradrenaline (0m?25 μg), tyramine (25 μg), angiotensin (10 ng) and vasopressin (0m?2 mU) did not differ in ganglion blocked sham-lesioned and lesioned animals. Organ/body weight ratios did not increase in the lesioned animals; overall, both the pituitary and adrenal weights were just significantly (P > 0m?05) reduced. Lesions II and III caused a significant reduction in kidney weight and lesion II a significant rise in the index of thyroid activity.     

House-dust mite allergen and ozone exposure decreases histamine H3 receptors in the brainstem respiratory nuclei

Allergic airway diseases in children are a common and a growing health problem. Changes in the central nervous system (CNS) have been implicated in contributing to some of the symptoms. We hypothesized that airway allergic diseases are associated with altered histamine H3 receptor expression in the nucleus tractus solitarius (NTS) and caudal spinal trigeminal nucleus, where lung/airway and nasal sensory afferents terminate, respectively. Immunohistochemistry for histamine H3 receptors was performed on brainstem sections containing the NTS and the caudal spinal trigeminal nucleus from 6- and 12-month-old rhesus monkeys who had been exposed for 5 months to house dust mite allergen (HDMA) + O₃ or to filtered air (FA). While histamine H3 receptors were found exclusively in astrocytes in the caudal spinal trigeminal nucleus, they were localized to both neuronal terminals and processes in the NTS. HDMA + O₃ exposure significantly decreased histamine H3 receptor immunoreactivity in the NTS at 6 months and in the caudal spinal trigeminal nucleus at 12 months of age. In conclusion, exposing young primates to HDMA + O₃ changed histamine H3 receptor expression in CNS pathways involving lung and nasal afferent nerves in an age-related manner. Histamine H3 receptors may be a therapeutic target for allergic asthma and rhinitis in children.     

The Implication of the First Agonist Bound Activated GPCR X-ray Structure on GPCR in Silico Modeling

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脂联素基因5'端调控区核苷酸多态性与2型糖尿病肾病相关性研究

研究了272名(86名非糖尿病者和186名2型糖尿病病人)深圳地区人群脂联素基因-11377C/G和-11391G/A单核苷酸多态性基因型分布及其与2型糖尿病肾病发病的相关性。结果发现-11377C/G多态性与糖尿病发病无关,-11391G/A多态性与2型糖尿病发病相关(χ2=7.662,P<0.005)。-11391基因变异和/或-11377变异可能与糖尿病早期肾病发病相关。     

Structure-based design in the GPCR target space

The G protein-coupled receptors (GPCRs) are membrane proteins that transmit signals via G-protein coupling. They have long been the target of small molecule therapeutics accounting for 30% of the launched drug targets. They are subdivided into several classes, with rhodopsins corresponding to the largest class. Furthermore, a high number of new rhodopsin-like GPCR proteins are included in the druggable genome, thus they are projected to continue being of value to the pharmaceutical and biotechnology sectors. We present a comprehensive review of the structural information pertaining to GPCRs, in light of the most recently deposited crystal structures, along with comparisons of the available to-date structures at different activation states. Finally, computational approaches to GPCR modeling are discussed in conjunction with critical perspectives regarding feasibility and limitations.     

Exercise training contributes to H2O2/VEGF signaling in the lung of rats with monocrotaline-induced pulmonary hypertension

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling and right ventricle overload. Given that angiogenesis is a key factor involved in the reduction of vascular resistance to blood flow, we tested the hypothesis that aerobic exercise exerts a positive impact on hydrogen peroxide (H₂O₂) and protein kinase B (Akt) levels in the lung parenchyma. To study the effects of aerobic exercise on lung angiogenesis signaling, Wistar rats were administered monocrotaline (MCT) (60 mg/kg i.p.) or the same volume of saline (0.9% NaCl i.p.). There was an increase in H₂O₂ (43%) in PAH-trained animals (TM) compared to control animals (SM). H₂O₂ showed a positive correlation (r = 0.77) with vascular endothelial growth factor (VEGF). VEGF was higher (4.7 fold) in TM animals compared to SM. VEGF and angiopoietin-1 (Ang-1) showed positive staining in the lung parenchyma of TM and SM. Glutathione peroxidase showed higher activity in the TM group (49%) compared to trained control (TC). Aerobic exercise increased the activity of peroxiredoxin (P < 0.05). The increase in VEGF was positively correlated with Akt phosphorylation (r = 0.73). p-Akt was shown to be increased in TM animals when compared to SM animals (2.5 fold). The change in fractional area, fractional shortening and systolic tricuspid annular plane excursion showed improvement after exercise training. Therefore, aerobic exercise promotes H₂O₂/VEGF/p-Akt signaling for pulmonary physiological angiogenesis. It is associated with an improvement in RV function, as evaluated by echocardiography.     

Macrophage migration inhibitory factor contributes to development of nonsteroidal anti-inflammatory drugs-induced gastric injury in mice

Macrophage migration inhibitory factor (MIF) plays an important role in the development of inflammation. In this study, we evaluated the role of MIF in gastric injury induced by non-steroidal anti-inflammatory drugs (NSAIDs) in mice. To induce gastric injury, mice were intraperitnoneally injected with 35 mg/kg of indomethacin. The level of MIF protein was up-regulated and severe gastric injury with inflammatory infiltrate was observed in the stomach of wild-type (WT) mice treated with indomethacin. The severity of gastric injury in MIF-deficient mice was less than that in WT mice. Increase in TNF-α in gastric tissue of mice treated with indomethacin was suppressed in MIF-deficient mice. The expression of HSP70, which has a cytoprotective role, was remarkably up-regulated in the stomach of MIF-deficient mice compared with WT mice after indomethacin treatment. Our results suggest that MIF is essential for the development of gastric injury-induced by NSAIDs.     

Effects of morphine and morphine withdrawal on brainstem neurons innervating hypothalamic nuclei that control the pituitary-adrenocortical axis in rats

Different data support a role for brainstem noradrenergic inputs to the hypothalamic paraventricular nucleus (PVN) in the control of hypothalamus - pituitary - adrenocortical (HPA) axis. However, little is known regarding the functional adaptive changes of noradrenergic afferent innervating the PVN and supraoptic nucleus (SON) during chronic opioid exposure and upon morphine withdrawal. Here we have studied the expression of Fos after administration of morphine and during morphine withdrawal in the rat hypothalamic PVN and SON. Fos production was also studied in brainstem regions that innervate hypothalamic nuclei: the nucleus of solitary tract (NTS - A2) and the ventrolateral medulla (VLM - A1) and combined with immunostaining for tyrosine hydroxylase (TH) for immunohistochemical identification of active neurons during morphine withdrawal. Male rats were implanted with s.c. placebo or morphine (tolerant/dependent) pellets for 7 days. On day 8 rats received an injection of saline i.p., morphine i.p., saline s.c. or naloxone s.c. Acute morphine administration produced an increase in Fos expression at hypothalamic nuclei and in the brainstem regions, and tolerance developed towards this effect. Precipitated morphine withdrawal induced marked Fos immunoreactivity within the PVN and SON. Concomitantly, numerous neurons in the brainstem were stimulated by morphine withdrawal. Moreover, catecholaminergic-positive neurons in the brainstem showed a significant increase in Fos expression in response to morphine withdrawal. These findings demonstrate that chronic activation of opioid receptors results in altered patterns of immediate-early genes (IEG) expression in the PVN and SON, which occurs concurrently with an increased activity of their inputs from the brainstem.     

From plants to man: the GPCR "tree of life"

This Perspective focuses on the article by Fredriksson and Schi?th in the May [corrected] 2005 issue of Molecular Pharmacology. Their article describes the expansion and evolution of G protein-coupled receptors during the nematode-to-chordate split.