Review Of Animal Studies Research Articles

The fetal origins of hypertension

Numerous experiments in animals have been performed to investigate the effect of prenatal undernutrition on the development of hypertension in later life, with inconclusive results. We systematically reviewed animal studies examining the effects of maternal undernutrition on SBP, DBP, and mean arterial blood pressure (BP) in offspring. A search was performed in Medline and Embase to identify articles that reported on maternal undernutrition and hypertension in experimental animal studies. Summary estimates of the effect of undernutrition on SBP, DBP, and mean arterial BP were obtained through meta-analysis. Of the 6151 articles identified, 194 were considered eligible after screening titles and abstracts. After detailed evaluation, 101 met the inclusion criteria and were included in the review. Both maternal general and protein undernutrition increased SBP [general undernutrition: 14.5 mmHg, 95% confidence interval (CI) 10.8-18.3; protein undernutrition: 18.9 mmHg, 95% CI 16.1-21.8] and mean arterial BP (general undernutrition: 5.0 mmHg, 95% CI 1.4-8.6; protein undernutrition: 10.5 mmHg, 95% CI 6.7-14.2). There was substantial heterogeneity in the results. DBP was increased by protein undernutrition (9.5 mmHg, 95% CI 2.6-16.3), whereas general undernutrition had no significant effect. The results of this meta-analysis generally support the view that in animals, maternal undernutrition--both general and protein--results in increased SBP and mean arterial BP. DBP was only increased after protein undernutrition. The results depended strongly on the applied measurement technique and animal model.

Erythropoietin: a candidate treatment for mood symptoms and memory dysfunction in depression

Current pharmacological treatments for depression have a significant treatment-onset-response delay, an insufficient efficacy for many patients and fail to reverse cognitive dysfunction. Erythropoietin (EPO) has neuroprotective and neurotrophic actions and improves cognitive function in animal models of acute and chronic neurodegenerative conditions and in patients with cognitive decline. We systematically reviewed the published findings from animal and human studies exploring the potential of EPO to treat depression-related cognitive dysfunction and depression. We identified five animal studies (two in male rats, two in male mice and one in male rats and mice) and seven human proof-of-concept studies (five in healthy volunteers and two in depressed patients) that investigated the above. All of the reviewed animal studies but one and all human studies demonstrated beneficial effects of EPO on hippocampus-dependent memory and antidepressant-like effects. These effects appear to be mediated through direct neurobiological actions of EPO rather than upregulation of red cell mass. The reviewed studies demonstrate beneficial effects of EPO on hippocampus-dependent memory function and on depression-relevant behavior, thus highlighting EPO as a candidate agent for future management of cognitive dysfunction and mood symptoms in depression. Larger-scale clinical trials of EPO as a treatment for mood and neurocognitive symptoms in patients with mood disorder are therefore warranted.

Effects of stress on alcohol drinking: a review of animal studies.

While stress is often proposed to play a significant role in influencing alcohol consumption, the relationship between stress and alcohol is complex and poorly understood. Over several decades, stress effects on alcohol drinking have been studied using a variety of animal models and experimental procedures, yet this large body of literature has generally produced equivocal results. This paper reviews results from animal studies in which alcohol consumption is evaluated under conditions of acute/sub-chronic stress exposure or models of chronic stress exposure. Evidence also is presented indicating that chronic intermittent alcohol exposure serves as a stressor that consequently influences drinking. The effects of various acute/sub-chronic stress procedures on alcohol consumption have generally been mixed, but most study outcomes suggest either no effect or decreased alcohol consumption. In contrast, most studies indicate that chronic stress, especially when administered early in development, results in elevated drinking later in adulthood. Chronic alcohol exposure constitutes a potent stressor itself, and models of chronic intermittent alcohol exposure reliably produce escalation of voluntary alcohol consumption. A complex and dynamic interplay among a wide array of genetic, biological, and environmental factors govern stress responses, regulation of alcohol drinking, and the circumstances in which stress modulates alcohol consumption. Suggestions for future directions and new approaches are presented that may aid in developing more sensitive and valid animal models that not only better mimic the clinical situation, but also provide greater understanding of mechanisms that underlie the complexity of stress effects on alcohol drinking.

Translational research in transcranial direct current stimulation (tDCS): a systematic review of studies in animals

Recent therapeutic human studies testing transcranial direct current stimulation (tDCS) has shown promising results, although many questions remain unanswered. Translational research with experimental animals is an appropriate framework for investigating its mechanisms of action that are still undetermined. Nevertheless, animal and human studies are often discordant. Our aim was to review tDCS animal studies, examining and comparing their main findings with human studies. We performed a systematic review in Medline and other databases, screening for animal studies in vivo that delivered tDCS. Studies in vitro and using other neuromodulatory techniques were excluded. We extracted data according to Animal Research: Reporting In Vivo Experiments (ARRIVE) guidelines for reporting in vivo animal research. Thus, we collected data on sample characteristics (size, gender, weight and specimen) and methodology (experimental procedures, experimental animals, housing and husbandry, as well as analysis). We also collected data on methods for delivering tDCS (location, size, current and current density of electrodes and electrode montage), experimental effects (polarity-, intensity- and after-effects) and safety. Only 12 of 48 potentially eligible studies met our inclusion criteria and were reviewed. Quality assessment reporting was only moderate and studies were heterogeneous regarding tDCS montage methodology, position of active and reference electrodes, and current density used. Nonetheless, almost all studies demonstrated that tDCS had positive immediate and long-lasting effects. Vis-à-vis human trials, animal studies applied higher current densities (34.2 vs. 0.4 A/m(2), respectively), preferred extra-cephalic positions for reference electrodes (60% vs. 10%, respectively) and used electrodes with different sizes more often. Potential implications for translational tDCS research are discussed.

The role of serotonin receptor subtypes in treating depression: a review of animal studies

Serotonin reuptake inhibitors (SSRIs) are effective in treating depression. Given the existence of different families and subtypes of 5-HT receptors, multiple 5-HT receptors may be involved in the antidepressant-like behavioral effects of SSRIs. Behavioral pharmacology studies investigating the role of 5-HT receptor subtypes in producing or blocking the effects of SSRIs were reviewed. Few animal behavior tests were available to support the original development of SSRIs. Since their development, a number of behavioral tests and models of depression have been developed that are sensitive to the effects of SSRIs, as well as to other types of antidepressant treatments. The rationale for the development and use of these tests is reviewed. Behavioral effects similar to those of SSRIs (antidepressant-like) have been produced by agonists at 5-HT(1A), 5-HT(1B), 5-HT(2C), 5-HT(4), and 5-HT(6) receptors. Also, antagonists at 5-HT(2A), 5-HT(2C), 5-HT(3), 5-HT(6), and 5-HT(7) receptors have been reported to produce antidepressant-like responses. Although it seems paradoxical that both agonists and antagonists at particular 5-HT receptors can produce antidepressant-like effects, they probably involve diverse neurochemical mechanisms. The behavioral effects of SSRIs and other antidepressants may also be augmented when 5-HT receptor agonists or antagonists are given in combination. The involvement of 5-HT receptors in the antidepressant-like effects of SSRIs is complex and involves the orchestration of stimulation and blockade at different 5-HT receptor subtypes. Individual 5-HT receptors provide opportunities for the development of a newer generation of antidepressants that may be more beneficial and effective than SSRIs.

Duration of Untreated Chlamydial Genital Infection and Factors Associated with Clearance: Review of Animal Studies

Chlamydia trachomatis is an important cause of sexually transmitted infection that can manifest as acute cervicitis, pelvic inflammatory disease, and most commonly, chronic asymptomatic infection. The basis of this wide spectrum of manifestations and the factors that lead to clearance or chronic infection are poorly understood. We reviewed specific literature pertaining to clearance of primary genital tract infections in animal models, including mice, guinea pigs, pigs, sheep, and nonhuman primates. T helper 1 cell responses involved in cell-mediated immunity are key immune parameters that define efficient clearance in the murine and guinea pig models of chlamydial infection, which are useful for studying C. trachomatis clearance. However, there may be some differences between humans and other animals in innate and adaptive immune responses to chlamydial infection. Studies have suggested that differences in the induced T cell subsets and the species-specific differences in interferon gamma-mediated effector mechanisms may play a significant role in these discrepancies. To close these gaps in knowledge, translational research in humans is a critical next step. However, for questions about specific mechanisms of host-pathogen interaction that cannot be answered feasibly or ethically in humans, animal models will continue to be important. Future research should include use of humanized and nonmurine models that establish prolonged infection to improve understanding of chronic human infections.

Individual Differences in Novelty-Seeking and Behavioral Responses to Nicotine: A Review of Animal Studies

Individual differences in the behavioral responses to a novel environment have been proposed as a research tool to predict responsiveness to other behavioral tasks, response to certain events and individual vulnerability to nicotine addiction. In rats and mice, novelty seeking (defined as enhanced specific exploration of novel situations) is a complex behavior confirmed by a large body of neurochemical, endocrinological and behavioral data. We review the main standardized procedures employed to measure the novelty seeking trait in rodents and the ontogeny of this behavior throughout the life-span taking into account that novelty seeking can be permanently modified as a consequence of particular early experiences, maternal care, and environmental enrichment. Studies in animal models suggest that individual differences in the sensitivity to nicotine depend on different variables such as basal locomotor activity of the experimental subjects, their response to novel environments (open-field, hole-board) and level of impulsivity. It is concluded that these basic findings contribute to a better understanding of smoking behavior and to the establishment of improved pharmacological treatments if individual differences are borne in mind.

Epigenetic Influences on Food Intake and Physical Activity Level: Review of Animal Studies

Epidemiological studies suggest that the perinatal environment can predispose human offspring to develop obesity and type 2 diabetes. Animal models provide a means of assessing the consequences of manipulating the perinatal environment in ways that cannot be done in humans. During the gestational period, maternal malnutrition, obesity, type 1 and type 2 diabetes, and psychological and pharmacological stressors can all promote, while early-onset exercise can ameliorate, offspring obesity and diabetes, especially in genetically predisposed offspring. Many of these perinatal manipulations are associated with reorganization of the central neural pathways which regulate food intake, energy expenditure, and storage in ways that enhance the development of obesity and diabetes in offspring. Both leptin and insulin have strong neurotrophic properties, so altered availability of either during the perinatal period can underlie some of these adverse developmental changes. Because perinatal manipulations can permanently alter the systems which regulate energy homeostasis, it behooves us to identify the responsible factors as a means of stemming the tide of the emerging worldwide obesity epidemic.

Tumor Protection Following Vaccination With Low Doses of Lentivirally Transduced DCs Expressing the Self-antigen erbB2

Gene therapy strategies may accelerate the development of prophylactic immunotherapy against cancer. We synthesized a lentiviral (LV) vector encoding a kinase-deficient form of erbB2 (erbB2tr) to transduce murine dendritic cells (DCs) efficiently. Murine erbB2 models a clinically relevant tumor-associated self-antigen; its human homolog (HER-2/neu) is overexpressed in breast cancer and in 80% of metastatic prostate cancers. Following one infection, approximately 47% of DCs overexpressed erbB2tr. To determine whether low doses of transduced DCs could protect mice from prostate cancer cells, we performed prime/boost vaccinations with 2 x 10(3) or 2 x 10(5) erbB2tr-transduced DCs. Six weeks after vaccination, mice were simultaneously bilaterally challenged with the aggressive RM-1 prostate cancer cell line and an erbB2tr-expressing variant (RM-1-erbB2tr). Whereas control mice developed both tumors, all recipients of 2 x 10(5) erbB2tr-transduced DCs developed only wild-type RM-1 tumors. One-third of mice vaccinated with just 2 x 10(3) erbB2tr-transduced DCs also demonstrated erbB2tr-specific tumor protection. Protection against RM-1-erbB2tr tumors was associated with sustained levels of anti-erbB2tr antibody production and also correlated with erbB2tr-specific Th1 cytokine secretion. Depletion of CD4(+), CD8(+), or natural killer (NK) cells prior to tumor challenge underscored their role in mediating tumor protection. We conclude that administration of DCs expressing a self-antigen through efficient LV-based gene transfer activates cellular and humoral immunity, protecting host animals against specific tumor challenge.

Adenosine receptor antagonists for cognitive dysfunction: a review of animal studies

Over the last decade, adenosine receptors in the central nervous system have been implicated in the modulation of cognitive functions. Despite the general view that endogenous adenosine modulates cognition through the activation of adenosine A1 receptors, evidence is now emerging on a possible role of A2A receptors in learning and memory. The present review attempts to examine results reported in different studies using diverse animal models, to provide a comprehensive picture of the recent evidence of a relationship between adenosinergic function and memory deficits. The present data suggest that caffeine (a nonselective adenosine receptor antagonist) and selective adenosine A2A receptor antagonists can improve memory performance in rodents evaluated through different tasks. They might also afford protection against memory dysfunction elicited in experimental models of aging, Alzheimer's disease, Parkinson's disease and, in spontaneously hypertensive rats (SHR), a putative genetic model of attention deficit hyperactivity disorder (ADHD).

An Updated Weight of the Evidence Evaluation of Reproductive and Developmental Effects of Low Doses of Bisphenol A

There is controversy over whether low doses of bisphenol A (BPA, CAS no. 80-05-7) cause reproductive and developmental effects in humans. We update the 2004 weight-of-evidence assessment of an expert panel convened by Harvard's Center for Risk Analysis by critically evaluating over 50 additional studies published between April 2002 and February 2006 that examine in vivo reproductive and developmental toxicity in mammals at doses ≤5 mg/kg-d. Our findings are consistent with the Harvard study: some statistically significant findings in rats and mice exist but they are generally countered by more numerous studies showing no effect for similar endpoints. No effect is marked or consistent across species, doses, and time points. Some mouse studies report morphological changes in testes and sperm and some non-oral mouse studies report morphological changes in female reproductive organs. Owing to lack of first-pass metabolism, results from non-oral studies are of limited relevance to oral human exposure. Human biomonitoring indicates exposures lower than the “low” doses in the reviewed animal studies. Reports of human health impact are very limited and inconsistent. Taken together, the weight of evidence does not support the hypothesis that low oral doses of BPA adversely affect human reproductive and developmental health.

ORIGINAL RESEARCH—EJACULATORY DISORDERS: On‐Demand SSRI Treatment of Premature Ejaculation: Pharmacodynamic Limitations for Relevant Ejaculation Delay and Consequent Solutions

ABSTRACT Introduction Recently, the idea has emerged that on-demand use of serotonin reuptake inhibitors (SSRIs), particularly short half-life, should be equally effective in delaying ejaculation as daily SSRI treatment of premature ejaculation. Aim To provide evidence that SSRI-induced ejaculation delay is mainly dependent on pharmacodynamic properties of the drug and hardly on pharmacokinetic factors, and that combined SSRI administration with specific 5-hydroxytryptamine (5-HT) receptor antagonism leads acutely to stronger ejaculation delay than acute SSRI monoadministration. Methods We performed a detailed analysis of serotonin neurotransmission and reviewed animal studies with 5-HT1A receptor antagonists. In addition, we critically reviewed existing on-demand SSRI treatments publications and the current debate on a definition of premature ejaculation. Main Outcome Measures Intravaginal ejaculation latency time (IELT). Results Acute SSRI administration leads to only a mild or no increase of 5-HT neurotransmission and concomitant stimulation of postsynaptic 5-HT receptors. Existing on-demand SSRI treatment studies suffer from methodological insufficiencies, and the reported high-fold increases of ejaculation time contradict with neuropharmacological insights from serotonin metabolism. Animal studies show that SSRI coadministration with 5-HT1A receptor antagonists significantly increases the ejaculation time acutely compared to acute SSRI monoadministration. Conclusion On-demand SSRI treatment has less ejaculation-delaying effects than daily SSRI treatment. SSRIs with a short half-life are likely leading to much less ejaculation delay than current registered SSRIs. Combined use of SSRIs with 5-HT1A receptor antagonists increases the likelihood of clinically relevant ejaculation delay after on-demand treatment. On-demand SSRIs with short half-life that insufficiently delay ejaculation in men with IELTs less than 1 minute should be called ejaculation-delaying drugs rather than drugs against premature ejaculation.

Synopsis: 2003 Annual Meeting of the American Society of Andrology.

Synopsis: 2003 Annual Meeting of the American Society of Andrology.

Angiogenic gene therapy for heart disease: a review of animal studies and clinical trials

The current published clinical literature on angiogenic gene therapy for the treatment of myocardial ischemia does not include a single randomized, placebo-controlled trial. Based on current clinical literature, it is an unproven therapy. Successful animal studies combined with published reports of good outcomes in patients enrolled in uncontrolled trials has led to the expectation that angiogenic gene therapy will ultimately become a clinical reality. The next important landmark in the field will be the publication of data showing a favorable effect of angiogenic gene transfer in placebo-controlled, blinded clinical trials.

Genetic dissection of nicotine-related behaviour: a review of animal studies

Nicotine has a broad spectrum of behavioural effects. A considerable body of data has emerged indicating genetic factors regulate the behavioural effects of nicotine. Experimental genetic techniques have been invaluable in generating knowledge on the interelationship of genetic factors and behavioural responsiveness to nicotine. Three different approaches have been invoked to explore the relationship of genetic factors to response to nicotine. Firstly, the classical genetic tool of inbred lines has been exploited to delineate genetic influences in the effects of nicotine. Secondly, the use of selectively bred lines has been profitably employed to reveal genetic differences in behavioural responses, such as cognition and exploration, to nicotine. These approaches have also provided useful information on the contribution of genetic factors influencing nicotinic receptors function. Finally the molecular genetic technique of gene targetting to create mice with null mutations of specific genes in the central nervous system, which is having a tremendous impact in drug addiction research, has also been employed to gain insight into the molecular and cellular basis of nicotine action. These techniques are proving to be invaluable in dissecting the role of different subunits of the nicotinic acetylcholine receptors on behaviour. This paper provides a survey of the animal studies that have used the above mentioned techniques to gain insight into genetic basis of the behavioural effects of nicotine.

Neuroprotection against cerebral ischemia. A review of animal studies and correlation with human trial results.

Neuroprotection against cerebral ischemia. A review of animal studies and correlation with human trial results.

Progesterone withdrawal I: pro-convulsant effects

Pro-convulsant withdrawal properties have been reported for a variety of GABA-modulatory drugs, such as the benzodiazepines (BDZs, [S.E. File, The history of BDZ dependence: a review of animal studies, Neurosci. Biobehav. Rev. 14 (1990) 135–146; P.R. Finley, P.E. Nolan, Precipitation of BDZ withdrawal following sudden discontinuation of midazolam, DICP 23 (1989) 151–152]), barbiturates and ethanol [N. Kokka, D.E. Sapp, U. Witte, R.W. Olsen, Sex differences in sensitivity to pentylenetetrazol but not in GABA A receptor binding, Pharm. Biochem. Behav. 43 (1992) 441–447]. In this report, we test the hypothesis that pro-convulsant effects are produced by withdrawal from the GABA-modulatory neurosteroid 3α-OH-5α-pregnan-20-one (3α,5α-THP) after sustained exposure to elevated circulating levels of its parent compound progesterone (P). Seizure activity was precipitated by picrotoxin or with the BDZ inverse agonist n-methyl-β-carboline-3-carboxamide (β-CC), and a seizure rating determined 24 h after abrupt discontinuation of P following a multiple withdrawal/chronic administration paradigm. In some cases, a pseudopregnant rat model was employed to produce increased ovarian production of P prior to withdrawal (ovariectomy). Rats undergoing P withdrawal exhibited greater seizure-like activity than vehicle-treated controls, and received seizure scores in the same range as rats undergoing BDZ withdrawal. Administration of a 5α-reductase blocker, MK-906, along with P, prevented this pro-convulsant effect of P withdrawal, suggesting that the GABA-modulatory 3α,5α-THP is the active compound responsible for this withdrawal effect. Combined administration of P and diazepam produced synergistic effects upon withdrawal and produced a seizure score higher than observed after withdrawal from either agent alone. These results suggest that P exhibits withdrawal properties via the neuroactive steroid 3α,5α-THP, that include exacerbation of seizure activity. These results may have clinical relevance, as increased incidence and severity of seizures has been reported in susceptible women during times of declining circulating levels of P across the menstrual cycle [T. Backstrom, B. Zetterlund, S. Blom, M. Romano, Effects of intravenous progesterone infusions on the epileptic discharge frequency in women with partial epilepsy, Acta Neurol. Scand. 69 (1984) 240–248; A.G. Herzog, Progesterone therapy in women with complex partial and secondary generalized seizures, Neurology 45 (1995) 1660–1662].

Chronic diffuse interstitial fibrosis of the lung in uranium miners.

Many uranium miners have been disabled by and died of pulmonary fibrosis that was not recognized as an occupational disease. A review of animal studies, complications from whole body irradiation, pulmonary function, and mortality studies of uranium miners led us to suspect radiation-induced chronic diffuse interstitial fibrosis in miners who had inhaled excessive radon progeny. A selected group of uranium miners (22) with severe respiratory disease (but no rounded nodules in chest films) were studied. Lung tissue from five disclosed severe diffuse interstitial fibrosis, with "honeycomb lung" in all. Some also had small anthrasilicotic nodules and birefringent crystals. Although quartz crystals probably contributed, we concluded that the predominant injurious agent in these cases was alpha particles from radon progeny. This disease, after a long latent period, usually results in pulmonary hypertension, shortness of breath, and death by cardiopulmonary failure.

S-50-2 - Naltrexone: Critical review of studies in animals for their relevance to alcoholism treatment

S-50-2 - Naltrexone: Critical review of studies in animals for their relevance to alcoholism treatment

Review of Animal Studies on Antimicrobial Catheters to Prevent Catheter-related Infections

Various experimental models have been developed to investigate the pathogenesis of intravascular catheter-related infections. Catheters are implanted either subcutaneously or intravenously, and the test animals are inoculated via either the subcutaneous tissue near the catheter exit site or the bloodstream. Catheters containing antimicrobial agents were investigated in various test models and their efficacy in inhibiting bacterial colonisation and reducing catheter-related infections was demonstrated.