Beta amyloid peptides (Aβ) are found to be associated with dysfunction of hypothalamic-pituitary-adrenal axis (HPA axis) that leads to memory and cognitive deficits in patients with Alzheimer's disease (AD). Phosphodiesterase 4 (PDE4) inhibitors increase the intracellular cAMP activities, which may ameliorate cognitive deficits associated with AD. However, it remains unclear whether PDE4-mediated reversal of cognitive impairment in mouse model of AD is related to HPA axis and downstream cAMP-dependent pathway. The present study investigated the effects of PDE4 inhibitor rolipram on Aβ1-42-induced cognitive dysfunction and its underlying mechanisms. The step-down passive avoidance (PA) and Morris water-maze (MWM) tests were conducted 1 week (1 W), 2 months (2 M), and 6 months (6 M) after intracerebroventricular microjection (i.c.v.) of Aβ1-42. The results suggested that memory impairment emerged as early as 1 W, peaked at 2 M, and lasted until 6 M after injection. Chronic treatment with rolipram (0.1, 0.5, 1.0 mg/kg/d, i.p.) for 2 weeks (i.e., treatment started at 1.5 months after Aβ1-42 microinjection) dose-dependently improved memory performance in both MWM and PA tests. Moreover, rolipram reversed the Aβ-induced increases in serum corticosterone (CORT), corticotropin-releasing factor, and glucocorticoid receptors (CRF-R and GR) levels, whereas it decreases in brain-derived neurotropic factor (BDNF) and the ratio of pCREB to CREB expression. These effects of rolipram were prevented by pre-treatment with PKA inhibitor H89. The findings indicated that the protective effects of rolipram against Aβ1-42-induced memory deficits might involve HPA axis and cAMP-CREB-BDNF signaling.
Stress can act as a precipitation factor in the onset of emotional disorders, particularly depression. Trans-resveratrol is a polyphenolic compound enriched in polygonum cuspidatum and has been found to exert antidepressant-like effects in our previous studies. In present study, we assessed the effects of trans-resveratrol used in combination with piperine, commonly known as a bioavailability enhancer, on chronic unpredictable mild stress-induced depressive-like behaviors and relevant molecular targets. Trans-resveratrol used alone reduced the immobility time of rats in the forced swimming test, with the maximal effects of trans-resveratrol around 60 % inhibition at the highest dose tested, 40 mg/kg. However, when a subthreshold dose of piperine, 2.5 mg/kg was used in combination with trans-resveratrol, the minimum effective dose of trans-resveratrol in reducing the immobility time was reduced to 20 mg/kg. Further evidence from neurochemical (monoamines in the frontal cortex and the hippocampus), biochemical (monoamine oxidase, MAO activities) and molecular biological (cAMP, PKA, CREB and BDNF) assays supported the findings in the behavioral studies. These results suggest that the co-treatment strategy with trans-resveratrol and piperine might be an alternative therapy that provides efficacious protection against chronic stress.
Introduction: Studies have shown that primary aldosteronism (PA) has a higher risk of cardiovascular events than essential hypertension (EH). Endothelial dysfunction is an independent predictor of cardiovascular events. Whether PA and EH differ in the endothelial dysfunction is uncertain. Our study was designed to investigate the levels of biomarkers of endothelial dysfunction (Asymmetric dimethylarginine, ADMA; E-selectin, and Plasminogen activator inhibitor-1, PAI-1) and assess the microvascular endothelial function in patients with PA and EH, respectively. Methods: The biomarkers of endothelial dysfunction were measured by enzyme-linked immunosorbent assay (ELISA). Microvascular endothelial function was evaluated by Pulse amplitude tonometry (PAT). Results: Thirty-one subjects with EH and 36 subjects with PA including 22 with aldosterone-producing adenoma (APA) and 14 with idiopathic hyperaldosteronism (IHA) were enrolled in our study. The ADMA levels among the three groups were different (APA 47.83 (27.50, 87.74) ng/ml vs EH 25.08 (22.44, 39.79) ng/ml vs IHA 26.00 (22.23, 33.75) ng/ml; p = 0.04), however, when the APA group was compared with EH and IHA group, there was no statistical significance (47.83 (27.50, 87.74) ng/ml vs 25.08 (22.44, 39.79) ng/ml for EH, p = 0.11; 47.83 (27.50, 87.74) ng/ml vs IHA 26.00 (33.75) ng/ml, p = 0.07). The results of ADMA levels are presented as Median (p25, p75). Whereas, levels of PAI-1 and E-selectin, microvascular endothelial function were not significantly different between PA and EH subjects. Conclusions: Our study shows no significant differences between PA and EH in terms of biomarkers of endothelial dysfunction and microvascular endothelial function. The microvascular endothelial function of PA and EH patients is comparable.
Primary hyperaldosteronism accounts for less than 0.5% of cases of hypertension' and accelerated hypertension was a rare but recognised feature of the syndrome in early series. We report a case of untreated Conn's syndrome with accelerated hypertension leading to hypertensive cardiac failure and renal impairment.A 30-year-old Samoan man presented with a one year history of poorly controlled hypertension. Treatment with bendrofluazide, enalapril, and diltiazem had been unsuccessful; additionally he admitted to non-compliance. Blood pressure (BP) was 180/120 mmHg; fundoscopy showed arterio-venous nipping and silver wiring. Serum potassium was 3.0 mmol/L, and creatinine 0.10 mmol/L. Electrocardiogram showed left ventricular ( L v hypertrophy and chest X-ray showed cardiothoracic ratio of 0.49. Echocardiogram demonstrated increased LV size (end diastolic diameter 6.0 cm) and mass (262 gm), with normal LV function (fractional shortening 38%).Investigations excluded hypercortisolism, phaeochromocytoma, and renovascular disease. A random aldosterone: renin ratio was elevated at 223, with ambulant aldosterone 969 pmol/L (reference range[RR] 111-860 pmol/L) and renin 9 mU/L (RR 5-75 mUL) consistent with primary aldosteronism. A saline suppression test confirmed autonomous aldosterone secretion with basal recumbent level of 21 13 pmolL (RR 44-444 p m o l ) falling to only 899 pmol/L (RR <200 pmolL) after 2 litre of normal saline. Abdominal C T scan showed a 1.5X 1.5X2 cm low attenuation lesion in the left adrenal.Spironolactone 200 mg/day and verapamil 240 mg/ day were started and surgery recommended. However, the patient discharged himself from hospital and, despite repeated efforts, did not attend follow up.Twenty-one months later he presented, still untreated, with a two week history of dyspnoea and leg swelling. On examination BP was 260/140 mmHg and the jugular venous pressure was elevated to 15 cm with prominent V waves. The apex beat was displaced laterally and a summation gallop was audible. Marked peripheral oedema was present. Bi-basal chest dullness, inspiratory crackles and pulsatile hepatomegaly were present. Fundoscopy revealed arteriolar narrowing and hard exudates. Serum potassium was 2.9 mmol/L and creatinine 0.17 mmol/L. Electrocardiogram showed marked LV hypertrophy with a strain pattern. Chest Xray showed marked cardiomegaly (CTR 0.61) and pulmonary oedema. Initial management included nitrate infusion, spironolactone, felodipine, and frusemide. Echocardiography showed 4-chamber enlargement with severe concentric LV hypertrophy and dilatation, and a fractional shortening of 10%.Over the next six days he diuresed 13 kg. Serum potassium normalised with oral potassium chloride replacement and serum creatinine improved to 0.14 mmoVL. LV function had improved with fractional shortening of 17%. A computerised tomography scan confirmed the left adrenal lesion, unchanged in size. The patient agreed to surgery, and an uncomplicated laparoscopic left adrenalectomy was performed 15 days after admission; histology o...
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