Pre- and post-natal development of the diaphragm

Animal models were used to examine properies of the diaphragm (the main respiratory muscle) before and after birth. The study revealed an insufficient blood supply to the fetus can result in structural and functional damage to the diaphragm. Damage was prevented when the mother was supplemented with creatine during pregnancy.

The role of oxytocin in mother-infant relations : a systematic review of human studies

Background: Oxytocin is associated with the establishment and quality of maternal behavior in animal models. Parallel investigations in humans are now under way. This article reviews the current research examining the role of oxytocin in mother-infant relations, attachment, and bonding in humans. Methods: A systematic search was made of three electronic databases and other bibliographic sources for published research studies that examined oxytocin and mother-infant relations in humans, including attachment, maternal behavior, parenting, and mother-infant relations. Results: Eight studies were identified, all of which were unique in their methodologies, populations studied, and measures used. Seven studies found significant and strong associations between levels or patterns of oxytocin and aspects of mother-infant relations or attachment. Conclusions: Oxytocin appears to be of crucial importance for understanding mother-infant relationships. The findings of this review suggest that the pioneering, but preliminary, research undertaken to date is promising and that replication with larger samples is needed. Research that draws on more robust measures of attachment and bonding, as well as improved measures of oxytocin that include both central and peripheral levels, will elucidate the role of oxytocin in human mother-infant relationships. As the production of oxytocin is by no means restricted to mothers, the extension of the oxytocin studies to fathering, as well as to alloparental caregiving, would be an intriguing next step.

Marsupial milk : identifying signals for regulating mammary function and development of the young

The role of milk in providing nutrition for the young is well established. However, it is becoming apparent that milk has a more comprehensive role in programming and regulating growth and development of the suckled young, and an autocrine impact on the mammary gland so that it functions appropriately during the lactation cycle. This central role of milk is best studied in animal models, such as marsupials that have evolved a different lactation strategy to eutherians and allow researchers to more easily identify regulatory mechanisms that are not as readily apparent in eutherian species. For example, the tammar wallaby (Macropus eugenii) has evolved with a unique reproductive strategy of a short gestation, birth of an altricial young and a relatively long lactation during which the mother progressively changes the composition of the major, and many of the minor components of milk. Thus, in contrast to eutherians, there is a far greater investment in development of the young during lactation and it is likely that many of the signals that regulate development of eutherian embryos in utero are delivered by the milk. This requires the co-ordinated development and function of the mammary gland. Inappropriate timing of these signalling events in mammals may result in either limited or abnormal development of the young, and potentially a higher incidence of mature onset disease. The tammar is emerging as an attractive model to better understand the role of milk factors in these processes.

Randomized placebo controlled trials of n-acetyl cysteine as adjunct therapy for schizophrenia and bipolar disorder

Glutathione is the principal antioxidant of the brain. There is evidence of oxidative stress, lowered brain glutathione and genetic linkage involve glutathione metabolic genes in schizophrenia and bipolar disorder. N-acetyl cysteine (NAC) is a safe, orally bioavailable, precursor of glutathione. NAC has been shown to reverse animal models of oxidative stress, and raises brain glutathione levels.

Oxidative stress in psychiatric disorders : evidence base and therapeutic implications

Oxidative stress has been implicated in the pathogenesis of diverse disease states, and may be a common pathogenic mechanism underlying many major psychiatric disorders, as the brain has comparatively greater vulnerability to oxidative damage. This review aims to examine the current evidence for the role of oxidative stress in psychiatric disorders, and its academic and clinical implications. A literature search was conducted using the Medline, Pubmed, PsycINFO, CINAHL PLUS, BIOSIS Previews, and Cochrane databases, with a time-frame extending to September 2007. The broadest data for oxidative stress mechanisms have been derived from studies conducted in schizophrenia, where evidence is available from different areas of oxidative research, including oxidative marker assays, psychopharmacology studies, and clinical trials of antioxidants. For bipolar disorder and depression, a solid foundation for oxidative stress hypotheses has been provided by biochemical, genetic, pharmacological, preclinical therapeutic studies and one clinical trial. Oxidative pathophysiology in anxiety disorders is strongly supported by animal models, and also by human biochemical data. Pilot studies have suggested efficacy of N-acetylcysteine in cocaine dependence, while early evidence is accumulating for oxidative mechanisms in autism and attention deficit hyperactivity disorder. In conclusion, multi-dimensional data support the role of oxidative stress in diverse psychiatric disorders. These data not only suggest that oxidative mechanisms may form unifying common pathogenic pathways in psychiatric disorders, but also introduce new targets for the development of therapeutic interventions.

Alzheimer's, angiotensin IV and an aminopeptidase

The angiotensin AT₄ receptor was originally defined as the specific, high affinity binding site for the hexapeptide angiotensin IV (Ang IV). Subsequently, the peptide LVV-hemorphin 7 was also demonstrated to be a bioactive ligand of the AT₄ receptor. Central administration of Ang IV or LVV-hemorphin 7 (LVV-H7) markedly enhances learning and memory in normal rodents and reverse memory deficits observed in animal models of amnesia. The high affinity binding site has a broad distribution in the brain including areas such as the hippocmapus that are involved in memory processing. The high affinity Ang IV binding site (AT₄ receptor) has been identified as the transmembrane enzyme, insulin-regulated membrane aminopeptidase (IRAP). Insulin-regulated aminopeptidase is a type II integral membrane spanning protein belonging to the M1 family of aminopeptidases and in insulin-responsive cells colocalizes with GLUT4 in specific intra-cellular vesicles. Both Ang IV and LVV-H7 are competitive inhibitors of IRAP catalytic activity and are not substrates of the enzyme.

The angiotensin IV/AT4 receptor

The angiotensin AT4 receptor was originally defined as the specific, high-affinity binding site for the hexapeptide angiotensin IV (Ang IV). Subsequently, the peptide LVV-hemorphin 7 was also demonstrated to be a bioactive ligand of the AT4 receptor. Central administration of Ang IV, its analogues or LVV-hemorphin 7 markedly enhance learning and memory in normal rodents and reverse memory deficits observed in animal models of amnesia. The AT4 receptor has a broad distribution and is found in a range of tissues, including the adrenal gland, kidney, lung and heart. In the kidney Ang IV increases renal cortical blood flow and decreases Na+ transport in isolated renal proximal tubules. The AT4 receptor has recently been identified as the transmembrane enzyme, insulin-regulated membrane aminopeptidase (IRAP). IRAP is a type II integral membrane spanning protein belonging to the M1 family of aminopeptidases and is predominantly found in GLUT4 vesicles in insulin-responsive cells. Three hypotheses for the memory-potentiating effects of the AT4 receptor/IRAP ligands, Ang IV and LVV-hemorphin 7, are proposed: (i) acting as potent inhibitors of IRAP, they may prolong the action of endogenous promnestic peptides; (ii) they may modulate glucose uptake by modulating trafficking of GLUT4; (iii) IRAP may act as a receptor, transducing the signal initiated by ligand binding to its C-terminal domain to the intracellular domain that interacts with several cytoplasmic proteins.

Ability of predator odour exposure to elicit conditioned versus sensitised post traumatic stress disorder-like behaviours, and forebrain ΔFosB expression, in rats

At present, exposure of a rodent to the odour of a predator is one of the most common animal models of post traumatic stress disorder (PTSD). Despite this, the model remains incompletely characterized, particularly in regard to within subject assessment of major PTSD-like behaviours. In an attempt to redress this situation, we have extensively characterized the two broad categories of behaviour that are considered to characterize PTSD, that is sensitized behaviours such as social withdrawal and hypervigilance and conditioned behaviours such as avoidance of trauma linked cues. Specifically, we determined the presence and duration of both conditioned and sensitized behaviours, in the same cohort of animals, after three exposures to predator odour. Conditioned fear was assessed on the basis of inhibition of locomotor activity upon return to context 2, 7, 14, 21, and 28 days after the last odour exposure session. To assess the impact on sensitization behaviours, we monitored acoustic startle responses and social interaction behaviour 4, 9, 16, 23, and 30 days after the last exposure session. In addition to examining the behavioural consequences associated with odour exposure, we also determined the key brain regions that were activated using ΔFosB immunohistochemistry. Our results show that the two groups of behaviours thought to characterize PTSD (conditioned and sensitized) do not travel together in the predator odour model, with clear evidence of enduring changes in conditioned fear but little evidence of changes in social interaction or acoustic startle. With regard to associated patterns of activity in the brain, we observed that odour-exposed animals exhibited significantly higher numbers of FosB-positive nuclei in only the medial prefrontal cortex (mPFC), a finding that can be viewed as being consistent with the observed behavioural changes.

Voluntary exercise does not affect stress-induced tachycardia, but improves resistance to cardiac arrhythmias in rats

1. It is currently unknown whether long-term voluntary exercise has enduring cardioprotective effects in animal models.

2. The present study was conducted in three groups of rats: (i) sedentary controls (n = 6); (ii) 24 h runners (n = 8; unlimited access to running wheels); and (iii) 2 h runners (n = 8; access to running wheels limited to 2 h daily). After termination of the 6 week exercise protocol, all rats were implanted with the telemetric electrocardiogram transmitters and were studied 1 week later.

3. Resting heart rate (HR) values in the control rats, 24 h runners and 2 h runners were 372 ± 7, 361 ± 9 and 298 ± 5 b.p.m., respectively (P < 0.05 for 2 h runners vs controls). The high-frequency spectral power in the control rats, 24 h runners and 2 h runners was 3.9 ± 0.2, 4.3 ± 0.3 and 5.3 ± 0.3 s2, respectively (P < 0.05 for 2 h runners vs controls), whereas intrinsic HR was 383 ± 3, 377 ± 2 and 346 ± 3 b.p.m., respectively (P < 0.001 for 2 h runners vs controls). Restraint stress provoked tachycardia of similar magnitude in all groups.

4. After completion of telemetric studies, haemodynamic indices and susceptibility to cardiac arrhythmias were assessed in anaesthetized animals, there were no major between-group differences in HR, arterial pressure, contractility indices or sensitivity to β-adrenoceptor stimulation (dobutamine) or blockade (atenolol). The effective refractory period in the control rats, 24 h runners and 2 h runners was 49 ± 2, 55 ± 2 and 60 ± 4 ms, respectively (P = 0.054 for 2 h runners vs controls). A significantly higher dose of aconitine was required to provoke ventricular arrhythmias in the 24 h and 2 h running groups compared with controls (489 ± 76, 505 ± 88 and 173 ± 33 μg, respectively; P < 0.05).

5. We conclude that, in rats, long-term voluntary exercise has enduring cardioprotective effects mediated at the level of both the central nervous system and the heart.

New drug targets in depression : inflammatory, cell-mediated immune, oxidative and nitrosative stress, mitochondrial, antioxidant, and neuroprogressive pathways. And new drug candidates—Nrf2 activators and GSK-3 inhibitors

This paper reviews new drug targets in the treatment of depression and new drug candidates to treat depression. Depression is characterized by aberrations in six intertwined pathways: (1) inflammatory pathways as indicated by increased levels of proinflammatory cytokines, e.g. interleukin-1 (IL-1), IL-6, and tumour necrosis factor α. (2) Activation of cell-mediated immune pathways as indicated by an increased production of interferon γ and neopterin. (3) Increased reactive oxygen and nitrogen species and damage by oxidative and nitrosative stress (O&NS), including lipid peroxidation, damage to DNA, proteins and mitochondria. (4) Lowered levels of key antioxidants, such as coenzyme Q10, zinc, vitamin E, glutathione, and glutathione peroxidase. (5) Damage to mitochondria and mitochondrial DNA and reduced activity of respiratory chain enzymes and adenosine triphosphate production. (6) Neuroprogression, which is the progressive process of neurodegeneration, apoptosis, and reduced neurogenesis and neuronal plasticity, phenomena that are probably caused by inflammation and O&NS. Antidepressants tend to normalize the above six pathways. Targeting these pathways has the potential to yield antidepressant effects, e.g. using cytokine antagonists, minocycline, Cox-2 inhibitors, statins, acetylsalicylic acid, ketamine, ω3 poly-unsaturated fatty acids, antioxidants, and neurotrophic factors. These six pathways offer new, pathophysiologically guided drug targets suggesting that novel therapies could be developed that target these six pathways simultaneously. Both nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activators and glycogen synthase kinase-3 (GSK-3) inhibitors target the six above-mentioned pathways. GSK-3 inhibitors have antidepressant effects in animal models of depression. Nrf2 activators and GSK-3 inhibitors have the potential to be advanced to phase-2 clinical trials to examine whether they augment the efficacy of antidepressants or are useful as monotherapy.

Leptin and the development of obesity and diabetes in Psammomys obesus

The recently discovered ob gene and its circulating product, leptin, may be critical factors in the control of energy balance. Recent studies in ob/ob mice, which lack circulating leptin, have shown dramatic reductions in food intake and bodyweight after leptin treatment. In addition, studies in both humans with obesity and animal models of obesity have demonstrated hyperleptinemia. Here, we report a longitudinal study examining changes in circulating leptin during the development of obesity and diabetes in Psammomys obesus. Over the 8 weeks of the study, lean animals increased their bodyweight by 154% and leptin levels remained essentially unchanged. In contrast, animals that developed obesity (223 % increase in bodyweight), hyperglycemia, and hyperinsulinemia also developed hyperleptinemia between 4 weeks and 8 weeks of age. These results demonstrate that the development of hyperleptinemia is associated with the development of obesity and subsequent metabolic abnormalities.

Maternal dietary intake during pregnancy has longstanding consequences for the health of her offspring

Over the past 100 years, advances in pharmaceutical and medical technology have reduced the burden of communicable disease, and our appreciation of the mechanisms underlying the development of noncommunicable disease has broadened. During this time, a number of studies, both in humans and animal models, have highlighted the importance of maintaining an optimal diet during pregnancy. In particular, a number of studies support the hypothesis that suboptimal maternal protein and fat intake during pregnancy can have long-term effects on the growing fetus, and increase the likelihood of these offspring developing cardiovascular, renal, or metabolic diseases in adulthood. More recently, it has been shown that dietary intake of a number of micronutrients may offset or reverse the deleterious effects of macronutrient imbalance. Furthermore, maternal fat intake has also been identified as a major contributor to a healthy fetal environment, with a beneficial role for unsaturated fats during development as well as a beneficial impact on cell membrane physiology. Together these studies indicate that attempts to optimise maternal nutrition may prove to be an efficient and cost-effective strategy for preventing the development of cardiovascular, renal, or metabolic diseases.

Δ-6 desaturase substrate competition : dietary linoleic acid (18∶2n-6) has only trivial effects on α-linolenic acid (18∶3n-3) bioconversion in the teleost rainbow trout

It is generally accepted that, in vertebrates, omega-3 (n-3) and omega-6 (n-6) poly-unsaturated fatty acids (PUFA) compete for ?-6 desaturase enzyme in order to be bioconverted into long-chain PUFA (LC-PUFA). However, recent studies into teleost fatty acid metabolism suggest that these metabolic processes may not conform entirely to what has been previously observed in mammals and other animal models. Recent work on rainbow trout has led us to question specifically if linoleic acid (LA, 18:2n-6) and ?-linolenic acid (ALA, 18:3n-3) (?-6 desaturase substrates) are in direct competition for access to ?-6 desaturase. Two experimental diets were formulated with fixed levels of ALA, while LA levels were varied (high and low) to examine if increased availability of LA would result in decreased bioconversion of ALA to its LC-PUFA products through substrate competition. No significant difference in ALA metabolism towards n-3 LC-PUFA was exhibited between diets while significant differences were observed in LA metabolism towards n-6 LC-PUFA. These results are evidence for minor if any competition between substrates for ?-6 desaturase, suggesting that, paradoxically, the activity of ?-6 desaturase on n-3 and n-6 substrates is independent. These results call for a paradigm shift in the way we approach teleost fatty acid metabolism. The findings are also important with regard to diet formulation in the aquaculture industry as they indicate that there should be no concern for possible substrate competition between 18:3n-3 and 18:2n-6, when aiming at increased n-3 LC-PUFA bioconversion in vivo.

Rapid development of non-alcoholic steatohepatitis in Psammomys obesus (Israeli Sand Rat)

Background and AimsA major impediment to establishing new treatments for non-alcoholic steatohepatitis is the lack of suitable animal models that accurately mimic the biochemical and metabolic characteristics of the disease. The aim of this study was to explore a unique polygenic animal model of metabolic disease as a model of non-alcoholic steatohepatitis by determining the effects of 2% dietary cholesterol supplementation on metabolic and liver endpoints in Psammomys obesus (Israeli sand rat).MethodsP. obesus were provided ad libitum access to either a standard rodent diet (20% kcal/fat) or a standard rodent diet supplemented with 2% cholesterol (w/w) for 4 weeks. Histological sections of liver from animals on both diets were examined for key features of non-alcoholic steatohepatitis. The expression levels of key genes involved in hepatic lipid metabolism were measured by real-time PCR.ResultsP. obesus fed a cholesterol-supplemented diet exhibited profound hepatomegaly and steatosis, and higher plasma transaminase levels. Histological analysis identified extensive steatosis, inflammation, hepatocyte injury and fibrosis. Hepatic gene expression profiling revealed decreased expression of genes involved in delivery and uptake of lipids, and fatty acid and triglyceride synthesis, and increased expression of genes involved in very low density lipoprotein cholesterol synthesis, triglyceride and cholesterol export.ConclusionsP. obesus rapidly develop non-alcoholic steatohepatitis when fed a cholesterol-supplemented diet that appears to be histologically and mechanistically similar to patients.