An animal model with relevance to schizophrenia: sex-dependent cognitive deficits in osteogenic disorder-Shionogi rats induced by glutathione synthesis and dopamine uptake inhibition during development

Low glutathione levels have been observed in the prefrontal cortex and the cerebrospinal fluid of schizophrenic patients, possibly enhancing the cerebral susceptibility to oxidative stress. We used osteogenic disorder Shionogi mutant rats, which constitute an adequate model of the human redox regulation because both are unable to synthesize ascorbic acid. To study the long-term consequences of a glutathione deficit, we treated developing rats with L-buthionine-(S,R)-sulfoximine (BSO), an inhibitor of glutathione synthesis, and later investigated their behavior until adulthood. Moreover, some rats were treated with the dopamine uptake inhibitor GBR 12909 in order to elevate dopamine extracellular levels, thereby mimicking the dopamine hyperactivity proposed to be involved in schizophrenia. BSO and GBR 12909 alone or in combination minimally affected the development of spontaneous alternation or basic sensory and motor skills. A major effect of BSO alone or in combination with GBR 12909 was the induction of cataracts in both sexes, whereas GBR 12909 induced an elevation of body weight in females only. Sex and age-dependent effects of the treatments were observed in a test of object recognition. At postnatal day 65, whereas male rats treated with both BSO and GBR 12909 failed to discriminate between familiar and novel objects, females were not affected. At postnatal day 94, male object recognition capacity was diminished by BSO and GBR 12909 alone or in combination, whereas females were only affected by the combination of both drugs.Inhibition of brain glutathione synthesis and dopamine uptake in developing rats induce long-term cognitive deficits occurring in adulthood. Males are affected earlier and more intensively than females, at least concerning object recognition. The present study suggests that the low glutathione levels observed in schizophrenic patients may participate in the development of some of their cognitive deficit

New model of glutathione deficit during development: effect on lipid peroxidation in the rat brain

Glutathione is a major regulator of the redox equilibrium, so its deficit weakens tissue resistance to oxidants. The nervous system is particularly susceptible to oxidative insults and is therefore very dependent on its glutathione content, especially during development, when brain metabolism and growth are maximal. In addition, various pathologies affecting the nervous system involve oxidative stress, possibly associated with a diminution of glutathione concentrations. To study the involvement of glutathione in brain redox homeostasis, we set up an experimental model of chronic glutathione deficit. Developing rats were treated daily with L-buthionine-(S,R)-sulfoximine (BSO), an inhibitor of glutathione synthesis, and their brain levels of glutathione and lipid peroxidation products (TBARS) were measured. BSO induced a 40-50% glutathione deficit in the cortex, diencephalon, and pons/medulla. Despite the glutathione deficit induced by BSO, we did not observe any signs of oxidative stress. Because it is known that rats compensate for a glutathione deficit by enhancing their synthesis and tissue levels of ascorbic acid (AA), we performed the same experiment in osteogenic-disorder Shionogi (ODS) rats, a mutant strain that cannot synthetize AA. Although BSO induced a glutathione deficit of comparable intensity in the two strains of rats, it elevated TBARS levels in the diencephalon and pons/medulla only in ODS and not in nonmutant rats. These results suggest that ODS rats, which closely mimic the human redox regulation, will allow study of the long-term consequences of chronic glutathione deficit observed in various clinical situation

Dual role of the NF-kappaB transcription factor in the death of immature neurons

Using the INTERMED, a system for classifying case complexity, the authors evaluated patients admitted to a general internal medicine ward on length of stay (LOS), number of medicines prescribed during the hospital stay, and whether they had received specialist medical consults. Using the patients' INTERMED scores, the authors divided the patients into three clusters of patients: standard (n=41), chronic (n=26), and complex (n=18). A comparison of the three clusters indicated that patients who had scored within the complex cluster were at risk of requiring complex care and an increased LOS. The findings suggest that the INTERMED detects complex patients at admission and may, therefore, be used for early integral case management. Key Words: Case Complexity ; Health Care Utilization

Low brain glutathione and ascorbic acid associated with dopamine uptake inhibition during rat's development induce long-term cognitive deficit: relevance to schizophrenia

Schizophrenia is associated with a cerebral glutathione deficit, which may leave the brain susceptible to oxidants. To study the consequences of a glutathione deficit, we treated developing rats with L-buthionine-(S,R)-sulfoximine (BSO), an inhibitor of glutathione synthesis, and later investigated their behaviour until adulthood. Since rodents may in some occasions compensate for a glutathione deficit by ascorbic acid (AA), we used Osteogenic Disorder Shionogi (ODS) mutant rats, which like humans, cannot synthetize ascorbic acid. Moreover, as hyperactivity of the dopaminergic system may be associated with schizophrenia, some rats were treated with the dopamine uptake inhibitor GBR 12909. Whereas ODS rats treated with either BSO or GBR 12909 alone had normal behaviour, rats treated with both BSO and GBR 12909 failed to discriminate between familiar and novel objects although other behaviours proved to be normal. In contrast, nonmutant rats were not affected by treatment with BSO and GBR 12909. Our results suggest that low brain glutathione and ascorbic acid levels associated with a perturbation of the dopaminergic system actively participate in the development of some cognitive deficits affecting schizophrenic patient

Evaluation of Temozolomide and Fingolimod Treatments in Glioblastoma Preclinical Models

Glioblastomas are malignant brain tumors which remain lethal due to their aggressive and invasive nature. The standard treatment combines surgical resection, radiotherapy, and chemotherapy using Temozolomide, albeit with a minor impact on patient prognosis (15 months median survival). New therapies evaluated in preclinical translational models are therefore still required to improve patient survival and quality of life. In this preclinical study, we evaluated the effect of Temozolomide in different models of glioblastoma. We also aimed to investigate the efficacy of Fingolimod, an immunomodulatory drug for multiple sclerosis also described as an inhibitor of the sphingosine-1-phosphate (S1P)/S1P receptor axis. The effects of Fingolimod and Temozolomide were analyzed with in vitro 2D and 3D cellular assay and in vivo models using mouse and human glioblastoma cells implanted in immunocompetent or immunodeficient mice, respectively. We demonstrated both in in vitro and in vivo models that Temozolomide has a varied effect depending on the tumor type (i.e., U87MG, U118MG, U138MG, and GL261), demonstrating sensitivity, acquired resistance, and purely resistant tumor phenotypes, as observed in patients. Conversely, Fingolimod only reduced in vitro 2D tumor cell growth and increased cytotoxicity. Indeed, Fingolimod had little or no effect on 3D spheroid cytotoxicity and was devoid of effect on in vivo tumor progression in Temozolomide-sensitive models. These results suggest that the efficacy of Fingolimod is dependent on the glioblastoma tumor microenvironment. Globally, our data suggest that the response to Temozolomide varies depending on the cancer model, consistent with its clinical activity, whereas the potential activity of Fingolimod may merit further evaluation

A Face-To-Face Comparison of Tumor Chicken Chorioallantoic Membrane (TCAM) In Ovo with Murine Models for Early Evaluation of Cancer Therapy and Early Drug Toxicity

Ethical considerations, cost, and time constraints have highlighted the need to develop alternatives to rodent in vivo models for evaluating drug candidates for cancer. The tumor chicken chorioallantoic membrane (TCAM) model provides an affordable and fast assay that permits direct visualization of tumor progression. Tumors from multiple species including rodents and human cell lines can be engrafted. In this study, we engrafted several tumor models onto the CAM and demonstrated that the TCAM model is an alternative to mouse models for preliminary cancer drug efficacy testing and toxicity analysis. Tumor cells were deposited onto CAM, and then grown for up to an additional 10 days before chronic treatments were administered. The drug response of anticancer therapies was screened in 12 tumor cell lines including glioblastoma, melanoma, breast, prostate, colorectal, liver, and lung cancer. Tumor-bearing eggs and tumor-bearing mice had a similar chemotherapy response (cisplatin and temozolomide) in four human and mouse tumor models. We also demonstrated that lethality observed in chicken embryos following chemotherapies such as cisplatin and cyclophosphamide were associated with corresponding side-effects in mice with body weight loss. According to our work, TCAM represents a relevant alternative model to mice in early preclinical oncology screening, providing insights for both the efficacy and the toxicity of anticancer drugs