Memory-rescuing effects of cannabidiol in an animal model of cognitive impairment relevant to neurodegenerative disorders

Rationale Cannabidiol, the main nonpsychotropic constituent of Cannabis sativa, possesses a large number of pharmacological effects including anticonvulsive, sedative, hypnotic, anxiolytic, antipsychotic, anti-inflammatory, and neuroprotective, as demonstrated in clinical and preclinical studies. Many neurodegenerative disorders involve cognitive deficits, and this has led to interest in whether cannabidiol could be useful in the treatment of memory impairment associated to these diseases. Objectives We used an animal model of cognitive impairment induced by iron overload in order to test the effects of cannabidiol in memory-impaired rats. Methods Rats received vehicle or iron at postnatal days 12-14. At the age of 2 months, they received an acute intraperitoneal injection of vehicle or cannabidiol (5.0 or 10.0 mg/kg) immediately after the training session of the novel object recognition task. In order to investigate the effects of chronic cannabidiol, iron-treated rats received daily intraperitoneal injections of cannabidiol for 14 days. Twenty-four hours after the last injection, they were submitted to object recognition training. Retention tests were performed 24 h after training. Results A single acute injection of cannabidiol at the highest dose was able to recover memory in iron-treated rats. Chronic cannabidiol improved recognition memory in iron-treated rats. Acute or chronic cannabidiol does not affect memory in control rats. Conclusions The present findings provide evidence suggesting the potential use of cannabidiol for the treatment of cognitive decline associated with neurodegenerative disorders. Further studies, including clinical trials, are warranted to determine the usefulness of cannabidiol in humans suffering from neurodegenerative disorders.

Cognitive Training and Educational Intervention for Individuals with Hypertension: Effects on Cognition

Objectives: To evaluate the possibility of combining cognitive training to an educational intervention composed by eight sessions about hypertension for a better management of the disease among the elderly. Methods: 64 older adults who reported having hypertension, divided into experimental group (EG, n=35) and control group (CG, n=29) participated in the study. Control participants received training after the post-test. The protocol contained socio-demographic and clinical data, Mini-Mental State Examination (MMSE), Geriatric Depression Scale (GDS), Rivermead Behavioral Memory Test (RBMT), Verbal Fluency Animal Category (VF) and Short Cognitive Test (SKT). Results: The EG showed better cognitive performance when compared with the CG, at post-test. Conclusion: Cognitive gains may occur after psychoeducational interventions for older adults with hypertension.

Combined effect of AMPK/PPAR agonists and exercise training in mdx mice functional performance

The present investigation was undertaken to test whether exercise training (ET) associated with AMPK/PPAR agonists (EM) would improve skeletal muscle function in mdx mice. These drugs have the potential to improve oxidative metabolism. This is of particular interest because oxidative muscle fibers are less affected in the course of the disease than glycolitic counterparts. Therefore, a cohort of 34 male congenic C57Bl/10J mdx mice included in this study was randomly assigned into four groups: vehicle solution (V), EM [AICAR (AMPK agonist, 50 mg/Kg-1.day-1, ip) and GW 1516 (PPAR delta agonist, 2.5 mg/Kg-1.day-1, gavage)], ET (voluntary running on activity wheel) and EM+ET. Functional performance (grip meter and rotarod), aerobic capacity (running test), muscle histopathology, serum creatine kinase (CK), levels of ubiquitined proteins, oxidative metabolism protein expression (AMPK, PPAR, myoglobin and SCD) and intracellular calcium handling (DHPR, SERCA and NCX) protein expression were analyzed. Treatments started when the animals were two months old and were maintained for one month. A significant functional improvement (p<0.05) was observed in animals submitted to the combination of ET and EM. CK levels were decreased and the expression of proteins related to oxidative metabolism was increased in this group. There were no differences among the groups in the intracellular calcium handling protein expression. To our knowledge, this is the first study that tested the association of ET with EM in an experimental model of muscular dystrophy. Our results suggest that the association of ET and EM should be further tested as a potential therapeutic approach in muscular dystrophies.

Exercise Training Restores Cardiac Protein Quality Control in Heart Failure

Exercise training is a well-known coadjuvant in heart failure treatment; however, the molecular mechanisms underlying its beneficial effects remain elusive. Despite the primary cause, heart failure is often preceded by two distinct phenomena: mitochondria dysfunction and cytosolic protein quality control disruption. The objective of the study was to determine the contribution of exercise training in regulating cardiac mitochondria metabolism and cytosolic protein quality control in a post-myocardial infarction-induced heart failure (MI-HF) animal model. Our data demonstrated that isolated cardiac mitochondria from MI-HF rats displayed decreased oxygen consumption, reduced maximum calcium uptake and elevated H2O2 release. These changes were accompanied by exacerbated cardiac oxidative stress and proteasomal insufficiency. Declined proteasomal activity contributes to cardiac protein quality control disruption in our MI-HF model. Using cultured neonatal cardiomyocytes, we showed that either antimycin A or H2O2 resulted in inactivation of proteasomal peptidase activity, accumulation of oxidized proteins and cell death, recapitulating our in vivo model. Of interest, eight weeks of exercise training improved cardiac function, peak oxygen uptake and exercise tolerance in MI-HF rats. Moreover, exercise training restored mitochondrial oxygen consumption, increased Ca2+-induced permeability transition and reduced H2O2 release in MI-HF rats. These changes were followed by reduced oxidative stress and better cardiac protein quality control. Taken together, our findings uncover the potential contribution of mitochondrial dysfunction and cytosolic protein quality control disruption to heart failure and highlight the positive effects of exercise training in re-establishing cardiac mitochondrial physiology and protein quality control, reinforcing the importance of this intervention as a nonpharmacological tool for heart failure therapy.

Physical training prevents body weight gain but does not modify adipose tissue gene expression

The relationship of body weight (BW) with white adipose tissue (WAT) mass and WAT gene expression pattern was investigated in mice submitted to physical training (PT). Adult male C57BL/6 mice were submitted to two 1.5-h daily swimming sessions (T, N = 18), 5 days/week for 4 weeks or maintained sedentary (S, N = 15). Citrate synthase activity increased significantly in the T group (P < 0.05). S mice had a substantial weight gain compared to T mice (4.06 ± 0.43 vs 0.38 ± 0.28 g, P < 0.01). WAT mass, adipocyte size, and the weights of gastrocnemius and soleus muscles, lung, kidney, and adrenal gland were not different. Liver and heart were larger and the spleen was smaller in T compared to S mice (P < 0.05). Food intake was higher in T than S mice (4.7 ± 0.2 vs 4.0 ± 0.3 g/animal, P < 0.05) but oxygen consumption at rest did not differ between groups. T animals showed higher serum leptin concentration compared to S animals (6.37 ± 0.5 vs 3.11 ± 0.12 ng/mL). WAT gene expression pattern obtained by transcription factor adipocyte determination and differentiation-dependent factor 1, fatty acid synthase, malic enzyme, hormone-sensitive lipase, adipocyte lipid binding protein, leptin, and adiponectin did not differ significantly between groups. Collectively, our results showed that PT prevents BW gain and maintains WAT mass due to an increase in food intake and unchanged resting metabolic rate. These responses are closely related to unchanged WAT gene expression patterns.

Adaptations of the aging animal to exercise: role of daily supplementation with melatonin

The pineal gland, through melatonin, seems to be of fundamental importance in determining the metabolic adaptations of adipose and muscle tissues to physical training. Evidence shows that pinealectomized animals fail to develop adaptive metabolic changes in response to aerobic exercise and therefore do not exhibit the same performance as control-trained animals. The known prominent reduction in melatonin synthesis in aging animals led us to investigate the metabolic adaptations to physical training in aged animals with and without daily melatonin replacement. Male Wistar rats were assigned to four groups: sedentary control (SC), trained control (TC), sedentary treated with melatonin (SM), and trained treated with melatonin (TM). Melatonin supplementation lasted 16 wk, and the animals were subjected to exercise during the last 8 wk of the experiment. After euthanasia, samples of liver, muscle, and adipose tissues were collected for analysis. Trained animals treated with melatonin presented better results in the following parameters: glucose tolerance, physical capacity, citrate synthase activity, hepatic and muscular glycogen content, body weight, protein expression of phosphatidylinositol 3-kinase (PI3K), mitogen-activated protein kinase (MAPK), and protein kinase activated by adenosine monophosphate (AMPK) in the liver, as well as the protein expression of the glucose transporter type 4 (GLUT4) and AMPK in the muscle. In conclusion, these results demonstrate that melatonin supplementation in aging animals is of great importance for the required metabolic adaptations induced by aerobic exercise. Adequate levels of circulating melatonin are, therefore, necessary to improve energetic metabolism efficiency, reducing body weight and increasing insulin sensitivity.

Musical Training Induces Functional Plasticity in Human Hippocampus

Training can change the functional and structural organization of the brain, and animal models demonstrate that the hippocampus formation is particularly susceptible to training-related neuroplasticity. In humans, however, direct evidence for functional plasticity of the adult hippocampus induced by training is still missing. Here, we used musicians' brains as a model to test for plastic capabilities of the adult human hippocampus. By using functional magnetic resonance imaging optimized for the investigation of auditory processing, we examined brain responses induced by temporal novelty in otherwise isochronous sound patterns in musicians and musical laypersons, since the hippocampus has been suggested previously to be crucially involved in various forms of novelty detection. In the first cross-sectional experiment, we identified enhanced neural responses to temporal novelty in the anterior left hippocampus of professional musicians, pointing to expertise-related differences in hippocampal processing. In the second experiment, we evaluated neural responses to acoustic temporal novelty in a longitudinal approach to disentangle training-related changes from predispositional factors. For this purpose, we examined an independent sample of music academy students before and after two semesters of intensive aural skills training. After this training period, hippocampal responses to temporal novelty in sounds were enhanced in musical students, and statistical interaction analysis of brain activity changes over time suggests training rather than predisposition effects. Thus, our results provide direct evidence for functional changes of the adult hippocampus in humans related to musical training.

Data quality of animal health records on Swiss dairy farms

High-quality data are essential for veterinary surveillance systems, and their quality can be affected by the source and the method of collection. Data recorded on farms could provide detailed information about the health of a population of animals, but the accuracy of the data recorded by farmers is uncertain. The aims of this study were to evaluate the quality of the data on animal health recorded on 97 Swiss dairy farms, to compare the quality of the data obtained by different recording systems, and to obtain baseline data on the health of the animals on the 97 farms. Data on animal health were collected from the farms for a year. Their quality was evaluated by assessing the completeness and accuracy of the recorded information, and by comparing farmers' and veterinarians' records. The quality of the data provided by the farmers was satisfactory, although electronic recording systems made it easier to trace the animals treated. The farmers tended to record more health-related events than the veterinarians, although this varied with the event considered, and some events were recorded only by the veterinarians. The farmers' attitude towards data collection was positive. Factors such as motivation, feedback, training, and simplicity and standardisation of data collection were important because they influenced the quality of the data.

Is there good simulation basic training for end-to-side vascular microanastomoses?

BACKGROUND Microvascular anastomosis is the cornerstone of free tissue transfers. Irrespective of the microsurgical technique that one seeks to integrate or improve, the time commitment in the laboratory is significant. After extensive previous training on several animal models, we sought to identify an animal model that circumvents the following issues: ethical rules, cost, time-consuming and expensive anesthesia, and surgical preparation of tissues required to access vessels before performing the microsurgical training, not to mention that laboratories are closed on weekends. METHODS Between January 2012 and April 2012, a total of 91 earthworms were used for 150 microsurgical training exercises to simulate vascular end-to-side microanastomosis. The training sessions were divided into ten periods of 7 days. Each training session included 15 simulations of end-to-side vascular microanastomoses: larger than 1.5 mm (n=5), between 1.0 and 1.5 mm (n=5), and smaller than 1.0 mm (n=5). A linear model with the main variables being the number of weeks (as a numerical covariate) and the size of the animal (as a factor) was used to determine the trend in time of anastomosis over subsequent weeks as well as the differences between the different size groups. RESULTS The linear model shows a significant trend (p<0.001) in time of anastomosis in the course of the training, as well as significant differences (p<0.001) between the groups of animals of different sizes. For microanastomoses larger than 1.5 mm, the mean anastomosis time decreased from 19.3±1.0 to 11.1±0.4 min between the first and last week of training (decrease of 42.5%). For training with smaller diameters, the results showed a decrease in execution time of 43.2% (diameter between 1.0 and 1.5 mm) and 40.9% (diameter<1.0 mm) between the first and last periods. The study demonstrates an improvement in the dexterity and speed of nodes execution. CONCLUSION The earthworm appears to be a reliable experimental model for microsurgical training of end-to-side microanastomoses. Its numerous advantages are discussed here and we predict training on earthworms will significantly grow and develop in the near future. LEVEL OF EVIDENCE III This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Assessment of anastomotic leakage: A Novel System for the Training of Surgeons to Perform a Tubular Anastomosis and Objectively Evaluate Anastomotic Leak

Introduction: Dehiscence of the suture line of an anastomosis can lead to reoperation, temporary or permanent stoma, and even sepsis or death. Few techniques for the laboratory training of tubular anastomosis use ex-vivo animal tissues. We describe a novel model that can be used in the laboratory for the training of anastomosis in tubular tissues and objectively assess any anastomotic leak. [See PDF for complete abstract]

Mechanisms of protein regulation in rat skeletal muscle during resistance exercise and training

The cellular mechanisms through which adult rat skeletal muscle protein is regulated during resistance exercise and training was investigated. A model of non-voluntary resistance exercise was described which involves the electrically-stimulated contraction of the lower leg muscles of anesthetized rats against a weighted pulley-bar. Muscle protein synthesis rates were measured by in vivo constant infusion of $\sp3$H-leucine following a single bout of resistance exercise. Specific messenger RNA levels were determined by dot-blot hybridization analysis using $\sp{32}$P-labelled DNA probes after a single bout and multiple bouts of phasic training. The effects of phasic training on increasing skeletal muscle mass was assessed. Between 12 and 36 hours following a single resistance exercise bout (24-192 contractions), total mixed and myofibril protein synthesis rates were significantly increase (32%-65%) after concentric (gastrocnemius m.) and eccentric (tibialis anterior m.) contractions. Eccentric contractions had greater effects on myofibril synthesis with more prolonged increases in synthesis rates. Lower numbers of eccentric than concentric contractions were required to increase synthesis. Cellular RNA was increased after exercise but the relative levels of skeletal $\alpha$-actin and cytochrome c mRNAs were unchanged. Since increases in synthesis rates exceeded increases in RNA, post-transcriptional mechanisms may be primarily responsible for increased protein synthesis after a resistance exercise bout. After 10-22 weeks of phasic eccentric resistance training, muscle enlargement (16%-30%) was produced in the tibialis anterior m. after all training paradigms examined. In contrast, gastrocnemius m. enlargement after phasic concentric training occurred after moderate (24/bout) but not after high (192/bout) repetition training. The absence of muscle growth in the gastrocnemius m. after high repetition training despite increased synthesis rates after the initial bout and RNA and possibly mRNA accumulation during training suggests a role for post-translational mechanisms (protein degradation) in the control of muscle growth in the gastrocnemius m. It is concluded that muscle protein during resistance exercise and training is regulated at several cellular levels. The particular response may be influenced by the exercise intensity and duration, the training frequency and the type of contractile work (eccentric vs. concentric) performed. ^

Un modèle animal simple pour l'apprentissage des techniques de microanastomoses vasculaires de congruences diefférentes

BACKGROUND Since the pioneering work of Jacobson and Suarez, microsurgery has steadily progressed and is now used in all surgical specialities, particularly in plastic surgery. Before performing clinical procedures it is necessary to learn the basic techniques in the laboratory. OBJECTIVE To assess an animal model, thereby circumventing the following issues: ethical rules, cost, anesthesia and training time. METHODS Between July 2012 and September 2012, 182 earthworms were used for 150 microsurgical trainings to simulate discrepancy microanastomoses. Training was undertaken over 10 weekly periods. Each training session included 15 simulations of microanastomoses performed using the Harashina technique (earthworm diameters >1.5 mm [n=5], between 1.0 mm and 1.5 mm [n=5], and <1.0 mm [n=5]). The technique is presented and documented. A linear model with main variable as the number of the week (as a numeric covariate) and the size of the animal (as a factor) was used to determine the trend in time of anastomosis over subsequent weeks as well as differences between the different size groups. RESULTS The linear model showed a significant trend (P<0.001) in time of anastomosis in the course of the training, as well as significant differences (P<0.001) between the groups of animal of different sizes. For diameter >1.5 mm, mean anastomosis time decreased from 19.6±1.9 min to 12.6±0.7 min between the first and last week of training. For training involving smaller diameters, the results showed a reduction in execution time of 36.1% (P<0.01) (diameter between 1.0 mm and 1.5 mm) and 40.6% (P<0.01) (diameter <1.0 mm) between the first and last weeks. The study demonstrates an improvement in the dexterity and speed of nodes' execution. CONCLUSION The earthworm appears to be a reliable experimental model for microsurgical training of discrepancy microanastomoses. Its numerous advantages, as discussed in the present report, show that this model of training will significantly grow and develop in the near future.

Lab animal allergy surveillance at a private medical school in three dissimilar animal research facilities

Very few studies have described MUP-1 concentrations and measured prevalence of Laboratory Animal Allergy (LAA) at such a diverse institution as the private medical school (MS) that is the focus of this study. Air sampling was performed in three dissimilar animal research facilities at MS and quantitated using a commercially available ELISA. Descriptive data was obtained from an anonymous laboratory animal allergy survey given to both animal facility employees and the researchers who utilize these facilities alike. Logistic regression analysis was then implemented to investigate specific factors that may be predictive of developing LAA as well as factors influencing the reporting of LAA symptoms to the occupational health program. Concentrations of MUP-1 detected ranged from below detectable levels (BDL) to a peak of 22.64 ng/m3 . Overall, 68 employees with symptoms claimed they improved while away from work and only 25 employees reported their symptoms to occupational health. Being Vietnamese, a smoker, not wearing a mask, and working in any facility longer than one year were all significant predictors of having LAA symptoms. This study suggests a LAA monitoring system that relies on self-reporting can be inadequate in estimating LAA problems. In addition, efforts need to be made to target training and educational materials for non-native English speaking employees to overcome language and cultural barriers and address their specific needs. ^

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Coronary flow responses to exercise training: further evidence of the benefit of an underutilized therapeutic modality

Inactivity is associated with endothelial dysfunction and the development of cardiovascular disease. Exercise training has a favourable effect in the management of hypertension, heart failure and ischaemic heart disease. These beneficial effects are probably mediated through improvements of vascular function and, in this issue of Clinical Science, Hagg and co-authors propose a coronary artery effect. The use of a Doppler technique for non-invasive assessment of coronary flow reserve in a small animal model is an exciting aspect of this study. If feasible in the hands of other investigators, the availability of sequential coronary flow measurements in animal models may help improve our understanding of the mechanisms of disorders of the coronary circulation.