Improved Learning and Memory in Aged Mice Deficient in Amyloid β-Degrading Neutral Endopeptidase

BACKGROUND: Neutral endopeptidase, also known as neprilysin and abbreviated NEP, is considered to be one of the key enzymes in initial human amyloid-beta (Abeta) degradation. The aim of our study was to explore the impact of NEP deficiency on the initial development of dementia-like symptoms in mice. METHODOLOGY/PRINCIPAL FINDINGS: We found that while endogenous Abeta concentrations were elevated in the brains of NEP-knockout mice at all investigated age groups, immunohistochemical analysis using monoclonal antibodies did not detect any Abeta deposits even in old NEP knockout mice. Surprisingly, tests of learning and memory revealed that the ability to learn was not reduced in old NEP-deficient mice but instead had significantly improved, and sustained learning and memory in the aged mice was congruent with improved long-term potentiation (LTP) in brain slices of the hippocampus and lateral amygdala. Our data suggests a beneficial effect of pharmacological inhibition of cerebral NEP on learning and memory in mice due to the accumulation of peptides other than Abeta degradable by NEP. By conducting degradation studies and peptide measurements in the brain of both genotypes, we identified two neuropeptide candidates, glucagon-like peptide 1 and galanin, as first potential candidates to be involved in the improved learning in aged NEP-deficient mice. CONCLUSIONS/SIGNIFICANCE: Thus, the existence of peptides targeted by NEP that improve learning and memory in older individuals may represent a promising avenue for the treatment of neurodegenerative diseases

Capsaicin-Induced Changes in LTP in the Lateral Amygdala Are Mediated by TRPV1

The transient receptor potential vanilloid type 1 (TRPV1) channel is a well recognized polymodal signal detector that is activated by painful stimuli such as capsaicin. Here, we show that TRPV1 is expressed in the lateral nucleus of the amygdala (LA). Despite the fact that the central amygdala displays the highest neuronal density, the highest density of TRPV1 labeled neurons was found within the nuclei of the basolateral complex of the amygdala. Capsaicin specifically changed the magnitude of long-term potentiation (LTP) in the LA in brain slices of mice depending on the anesthetic (ether, isoflurane) used before euthanasia. After ether anesthesia, capsaicin had a suppressive effect on LA-LTP both in patch clamp and in extracellular recordings. The capsaicin-induced reduction of LTP was completely blocked by the nitric oxide synthase (NOS) inhibitor L-NAME and was absent in neuronal NOS as well as in TRPV1 deficient mice. The specific antagonist of cannabinoid receptor type 1 (CB1), AM 251, was also able to reduce the inhibitory effect of capsaicin on LA-LTP, suggesting that stimulation of TRPV1 provokes the generation of anandamide in the brain which seems to inhibit NO synthesis. After isoflurane anesthesia before euthanasia capsaicin caused a TRPV1-mediated increase in the magnitude of LA-LTP. Therefore, our results also indicate that the appropriate choice of the anesthetics used is an important consideration when brain plasticity and the action of endovanilloids will be evaluated. In summary, our results demonstrate that TRPV1 may be involved in the amygdala control of learning mechanisms

Safety of cryoballoon ablation for the treatment of atrial fibrillation: first European results from the Cryo AF Global Registry

Abstract Funding Acknowledgements Type of funding sources: Other. Main funding source(s): Medtronic, Inc. OnBehalf Cryo AF Global Registry Investigators Background Since introduced in Europe over 15 years ago, cryoballoon ablation for the treatment of patients with atrial fibrillation (AF) has proven to be safe and effective. Purpose Report on patient and procedural characteristics, ablation techniques, and outcomes. Also, determine the independent predictors of a procedural adverse event in real-world usage. Methods Patients with AF were enrolled in the prospective, multicenter Cryo AF Global Registry (NCT02752737) and treated with cryoballoon ablation at 38 European centers according to standard-of-care. The primary efficacy endpoint was freedom from a ≥30 sec episode of AF/atrial flutter (AFL)/atrial tachycardia (AT) at 12-months. The primary safety endpoint was the rate of serious adverse events related to the device and/or procedure. Univariate and multivariable models identified baseline patient and procedural characteristics that predicted a serious procedure-related complication. Results: Of 1,418 subjects who completed an index procedure, the cohort was 62 ± 11 years of age, 37.7% female, and 72.2% paroxysmal AF (PAF). In total, 32.2% of patients were treated with cryoablation as a first-line therapy. Non-general anesthesia was used in 76.0% of procedures. Ablation adjunctive to the cryoballoon pulmonary vein isolation was applied in few cases: 2.0% of patients were treated with a cavotricuspid isthmus (CTI) line with focal radiofrequency ablation and 0.8% of patients received other non-PVI ablation. The mean procedure, left atrial dwell, and fluoroscopy times were 81 ± 34, 54 ± 25, and 14 ± 13 minutes, respectively. Among the 766 patients with 12-month follow-up, freedom from AF/AFL/AT recurrence ≥30 sec was 83.3% (95% CI: 79.8-86.3%) and 71.6% (95% CI: 64.6-77.4%) in patients with PAF and persistent AF, respectively. The serious procedure- and device-related adverse event rates were 4.7% and 2.0%, respectively. Female sex was significantly associated with the occurrence of an adverse event in univariate analysis (P &amp;lt; 0.05), but (after accounting for patient age and NYHA status) no baseline patient characteristic independently predicted a procedure-related adverse event. However, prolonged procedure duration (OR = 1.01 (95% CI: 1.00-1.01)), use of general anesthesia (OR = 1.71 (95% CI: 1.01 – 2.92)), and delivery of a CTI line (OR = 3.04 (95% CI: 1.01-9.20) were each independently associated with the occurrence of a serious procedural safety event (all P &amp;lt; 0.05). Conclusion: Cryoablation treated patients across the AF disease spectrum with one-third of patients treated prior to antiarrhythmic drug usage and another third treated for persistent AF. The results indicate extra diligence is warranted in patients under general anesthesia and for those who receive adjunctive CTI ablation. Cryoballoon ablation is consistently safe for patients independent of baseline patient characteristics and comorbidities in real-world use. </jats:sec

Priming of LTP in amygdala and hippocampus by prior paired pulse facilitation paradigm in mice lacking brain serotonin

This study focuses on analyzing long term potentiation (LTP) changes in the lateral nucleus of the amygdala (LA) and in the CA1 region of the hippocampus in slices derived from mice deficient in tryptophan hydroxylase 2 (TPH2(-/-)), the rate-limiting enzyme for 5-HT synthesis in the brain. We found a reduced LTP in both brain structures in TPH2(-/-) mice. However, we found no changes in the magnitude of LTP in TPH2(-/-) mice compared to wildtype mice when it was preceded by a paired pulse protocol. Whereas the magnitude of long term depression (LTD) did not differ between wildtype and TPH2(-/-) mice, priming synapses by LTD-induction facilitated subsequent CA1-LTP in wildtype mice to a greater extent than in TPH2(-/-) mice. In the LA we found no differences between the genotypes in this protocol of metaplasticity. These data show that, unlike exogenous 5-HT application, lack of 5-HT in the brain impairs cellular mechanisms responsible for induction of LTP. It is supposed that suppression of LTP observed in TPH2(-/-) mice might be compensated by mechanisms of metaplasticity induced by paired pulse stimulation or low frequency stimulation before the induction of LTP

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of −18%. There were no significant betweengroup differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo.</p