Role of phosphodiesterase 5 in synaptic plasticity and memory

Phosphodiesterases (PDEs) are enzymes that break down the phosphodiesteric bond of the cyclic nucleotides, cAMP and cGMP, second messengers that regulate many biological processes. PDEs participate in the regulation of signal transduction by means of a fine regulation of cyclic nucleotides so that the response to cell stimuli is both specific and activates the correct third messengers. Several PDE inhibitors have been developed and used as therapeutic agents because they increase cyclic nucleotide levels by blocking the PDE function. In particular, sildenafil, an inhibitor of PDE5, has been mainly used in the treatment of erectile dysfunction but is now also utilized against pulmonary hypertension. This review examines the physiological role of PDE5 in synaptic plasticity and memory and the use of PDE5 inhibitors as possible therapeutic agents against disorders of the central nervous system (CNS)

CL316,243, a β3-adrenergic receptor agonist, induces muscle hypertrophy and increased strength.

Studies in vitro have demonstrated that β3-adrenergic receptors (β3-ARs) regulate protein metabolism in skeletal muscle by promoting protein synthesis and inhibiting protein degradation. In this study, we evaluated whether activation of β3-ARs by the selective agonist CL316,243 modifies the functional and structural properties of skeletal muscles of healthy mice. Daily injections of CL316,243 for 15 days resulted in a significant improvement in muscle force production, assessed by grip strength and weight tests, and an increased myofiber cross-sectional area, indicative of muscle hypertrophy. In addition, atomic force microscopy revealed a significant effect of CL316,243 on the transversal stiffness of isolated muscle fibers. Interestingly, the expression level of mammalian target of rapamycin (mTOR) downstream targets and neuronal nitric oxide synthase (NOS) was also found to be enhanced in tibialis anterior and soleus muscles of CL316,243 treated mice, in accordance with previous data linking β3-ARs to mTOR and NOS signaling pathways. In conclusion, our data suggest that CL316,243 systemic administration might be a novel therapeutic strategy worthy of further investigations in conditions of muscle wasting and weakness associated with aging and muscular diseases

Antagonizing α7 nicotinic receptors with methyllycaconitine (MLA) potentiates receptor activity and memory acquisition

Abstract α7 nicotinic acetylcholine receptors (α7nAChRs) have been targeted to improve cognition in different neurological and psychiatric disorders. Nevertheless, no α7nAChR activating ligand has been clinically approved. Here, we investigated the effects of antagonizing α7nAChRs using the selective antagonist methyllycaconitine (MLA) on receptor activity in vitro and cognitive functioning in vivo. Picomolar concentrations of MLA significantly potentiated receptor responses in electrophysiological experiments mimicking the in vivo situation. Furthermore, microdialysis studies showed that MLA administration substantially increased hippocampal glutamate efflux which is related to memory processes. Accordingly, pre-tetanus administration of low MLA concentrations produced longer lasting potentiation (long-term potentiation, LTP) in studies examining hippocampal plasticity. Moreover, low doses of MLA improved acquisition, but not consolidation memory processes in rats. While the focus to enhance cognition by modulating α7nAChRs lies on agonists and positive modulators, antagonists at low doses should provide a novel approach to improve cognition in neurological and psychiatric disorders

LTP and memory impairment caused by extracellular A\u3b2 and Tau oligomers is APP-dependent

The concurrent application of subtoxic doses of soluble oligomeric forms of human amyloid-beta (oA\u3b2) and Tau (oTau) proteins impairs memory and its electrophysiological surrogate long-term potentiation (LTP), effects that may be mediated by intra-neuronal oligomers uptake. Intrigued by these findings, we investigated whether oA\u3b2 and oTau share a common mechanism when they impair memory and LTP in mice. We found that as already shown for oA\u3b2, also oTau can bind to amyloid precursor protein (APP). Moreover, efficient intra-neuronal uptake of oA\u3b2 and oTau requires expression of APP. Finally, the toxic effect of both extracellular oA\u3b2 and oTau on memory and LTP is dependent upon APP since APP-KO mice were resistant to oA\u3b2- and oTau-induced defects in spatial/associative memory and LTP. Thus, APP might serve as a common therapeutic target against Alzheimer's Disease (AD) and a host of other neurodegenerative diseases characterized by abnormal levels of A\u3b2 and/or Tau

Time-dependent reversal of synaptic plasticity induced by physiological concentrations of oligomeric Aβ42: an early index of Alzheimer’s disease

The oligomeric amyloid-β (Aβ) peptide is thought to contribute to the subtle amnesic changes in Alzheimer’s disease (AD) by causing synaptic dysfunction. Here, we examined the time course of synaptic changes in mouse hippocampal neurons following exposure to Aβ42 at picomolar concentrations, mimicking its physiological levels in the brain. We found opposite effects of the peptide with short exposures in the range of minutes enhancing synaptic plasticity, and longer exposures lasting several hours reducing it. The plasticity reduction was concomitant with an increase in the basal frequency of spontaneous neurotransmitter release, a higher basal number of functional presynaptic release sites, and a redistribution of synaptic proteins including the vesicle-associated proteins synapsin I, synaptophysin, and the post-synaptic glutamate receptor I. These synaptic alterations were mediated by cytoskeletal changes involving actin polymerization and p38 mitogen-activated protein kinase. These in vitro findings were confirmed in vivo with short hippocampal infusions of picomolar Aβ enhancing contextual memory and prolonged infusions impairing it. Our findings provide a model for initiation of synaptic dysfunction whereby exposure to physiologic levels of Aβ for a prolonged period of time causes microstructural changes at the synapse which result in increased transmitter release, failure of synaptic plasticity, and memory loss

Extracellular Tau Oligomers Produce An Immediate Impairment of LTP and Memory

Non-fibrillar soluble oligomeric forms of amyloid-\u3b2 peptide (oA\u3b2) and tau proteins are likely to play a major role in Alzheimer's disease (AD). The prevailing hypothesis on the disease etiopathogenesis is that oA\u3b2 initiates tau pathology that slowly spreads throughout the medial temporal cortex and neocortices independently of A\u3b2, eventually leading to memory loss. Here we show that a brief exposure to extracellular recombinant human tau oligomers (oTau), but not monomers, produces an impairment of long-term potentiation (LTP) and memory, independent of the presence of high oA\u3b2 levels. The impairment is immediate as it raises as soon as 20\u2009min after exposure to the oligomers. These effects are reproduced either by oTau extracted from AD human specimens, or naturally produced in mice overexpressing human tau. Finally, we found that oTau could also act in combination with oA\u3b2 to produce these effects, as sub-toxic doses of the two peptides combined lead to LTP and memory impairment. These findings provide a novel view of the effects of tau and A\u3b2 on memory loss, offering new therapeutic opportunities in the therapy of AD and other neurodegenerative diseases associated with A\u3b2 and tau pathology

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Outcomes from elective colorectal cancer surgery during the SARS-CoV-2 pandemic

This study aimed to describe the change in surgical practice and the impact of SARS-CoV-2 on mortality after surgical resection of colorectal cancer during the initial phases of the SARS-CoV-2 pandemic

Fisiologia

Il volume di Linda Costanzo si rivolge principalmente alle lauree triennali. L'impostazione non è di fisiologia medica ma di fisiologia di base. Il testo descrive i principali concetti di fisiologia sia a livello cellulare (capp. 1 e 2) sia a livello di organo (capp. da 3 a 10). L'autrice ha voluto sempre enfatizzare le relazioni tra i diversi sistemi per sottolineare i meccanismi integrativi per l'omeostasi. Infatti anche le poche correlazioni cliniche relegate all'interno di box sono presentate sempre enfatizzando l’aspetto fisiologico di correlazione tra i diversi sistemi. Ad esempio il diabete mellito di Tipo I ha implicazioni non solo sul sistema endocrino, ma anche cardiovascolare, respiratorio, renale e dell’equilibrio acido-base. Il testo è sintetico e schematico e prevede una relazione molto stretta con l'iconografia. Al termine di ogni capitolo sono riassunti i punti chiave e sono presenti domande di autovalutazione. In realtà la fisiologia è anche una materia “di calcolo” e il vero modo di verificare di aver realmente compreso i principi che la regolano è affrontare problemi/esercizi pratici. Per questo all'interno del testo, viene data una definizione di tutti gli elementi delle equazioni presentate e, più volte all'interno del singolo capitolo, vengono presentati esercizi svolti

Abiotic and Herbivory Combined Stress in Tomato: Additive, Synergic and Antagonistic Effects and Within-Plant Phenotypic Plasticity

Background: Drought, N deficiency and herbivory are considered the most important stressors caused by climate change in the agro- and eco-systems and varied in space and time shaping highly dynamic and heterogeneous stressful environments. This study aims to evaluate the tomato morpho-physiological and metabolic responses to combined abiotic and herbivory at different within-plant spatial levels and temporal scales. Methods: Leaf-level morphological, gas exchange traits and volatile organic compounds (VOCs) profiles were measured in tomato plants exposed to N deficiency and drought, Tuta absoluta larvae and their combination. Additive, synergistic or antagonistic effects of the single stress when combined were also evaluated. Morpho-physiological traits and VOCs profile were also measured on leaves located at three different positions along the shoot axes. Results: The combination of the abiotic and biotic stress has been more harmful than single stress with antagonistic and synergistic but non-additive effects for the morpho-physiological and VOCs tomato responses, respectively. Combined stress also determined a high within-plant phenotypic plasticity of the morpho-physiological responses. Conclusions: These results suggested that the combined stress in tomato determined a “new stress state” and a higher within-plant phenotypic plasticity which could permit an efficient use of the growth and defense resources in the heterogeneous and multiple stressful environmental conditions