Thiamme2-G, A Novel O-GlcNAcase Inhibitor, Reduces Tau Hyperphosphorylation and Rescues Cognitive Impairment in Mice

Background: Abnormal hyperphosphorylation of microtubule-associated protein tau plays a pivotal role in Alzheimer’s disease (AD). We previously found that O-GlcNAcylation inversely correlates to hyperphosphorylation of tau in AD brain, and downregulation of brain O-GlcNAcylation promotes tau hyperphosphorylation and AD-like neurodegeneration in mice. Objective: Herein we investigated the effect of increasing O-GlcNAcylation by using intermittent dosing with low doses of a potent novel O-GlcNAcase (OGA) inhibitor on AD-like brain changes and cognitive function in a mouse model of sporadic AD (sAD) induced by intracerebroventricular (ICV) injection of streptozotocin (STZ). Methods: STZ was injected into the lateral ventricle of C57BL/6J mice. From the second day, Thiamme2-G (TM2G) or saline, as a vehicle control, was orally administered to the ICV-STZ mice three times per week for five weeks. A separate group of ICV-saline mice treated with saline was used as a baseline control. Behavioral tests, including open field and novel object recognition, were conducted three weeks after the first dose of the TM2G or saline. Protein O-GlcNAcylation, tau hyperphosphorylation, synaptic proteins, and neuroinflammation in the mouse brain were assessed by western blotting. Results: ICV-STZ caused decreased protein O-GlcNAcylation. Enhancement of O-GlcNAcylation to moderate levels by using low-dose OGA inhibitor in ICV-STZ mice prevented STZ-induced body weight loss, rescued cognitive impairments, and restored AD-like pathologies, including hyperphosphorylation of tau and abnormalities in synaptic proteins and neuroinflammation. Conclusion: These findings suggest that moderately increasing protein O-GlcNAcylation by using low doses of OGA inhibitor may be a suitable therapeutic strategy for sAD.

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Mice with Induced Pulmonary Comorbidities Display Severe Lung Inflammation and Mortality following Exposure to SARS-CoV-2

10.1101/2020.10.28.358614 ◽

2020 ◽

Author(s):

Reut Falach ◽

Liat Bar-On ◽

Shlomi Lazar ◽

Tamar Kadar ◽

Ohad Mazor ◽

...

Keyword(s):

Lung Inflammation ◽

Low Dose ◽

Severe Disease ◽

Body Weight Loss ◽

Mortality Rates ◽

Passive Transfer ◽

Cell Entry ◽

Low Doses ◽

Viral Cell Entry ◽

Severe Lung

AbstractSevere manifestations of COVID-19 are mostly restricted to people with comorbidities. Here we report that induced mild pulmonary morbidities render SARS-CoV-2-refractive CD-1 mice to be susceptible to this virus. Specifically, SARS-CoV-2 infection after application of low-doses of the acute-lung-injury stimulants bleomycin or ricin caused a severe disease in CD-1 mice, manifested by sustained body weight loss and mortality rates of >50%. Further studies revealed markedly higher levels of viral RNA in the lungs, heart and serum of low-dose-ricin pretreated, as compared to non-pretreated mice. Notably, the deleterious effects of SARS-CoV-2 infection were effectively alleviated by passive transfer of polyclonal or monoclonal antibodies generated against SARS-CoV-2 RBD. Thus, viral cell entry in the sensitized mice seems to involve viral RBD binding, albeit by a mechanism other than the canonical ACE2-mediated uptake route. In summary, we present a novel mice-based animal model for the study of comorbidity-dependent severe COVID-19.

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Single Low Dose of Cocaine–Structural Brain Injury Without Metabolic and Behavioral Changes

Frontiers in Neuroscience ◽

10.3389/fnins.2020.589897 ◽

2021 ◽

Vol 14 ◽

Author(s):

Camilla Nicolucci ◽

Mariana Lapo Pais ◽

A. C. Santos ◽

Fabiana M. Ribeiro ◽

Pedro M. C. C. Encarnação ◽

...

Keyword(s):

Structural Damage ◽

Low Dose ◽

Brain Activity ◽

High Morbidity ◽

Low Doses ◽

Positron Emission ◽

Chronic Cocaine ◽

Field Activity ◽

Brain Changes ◽

Brain Metabolic Activity

Chronic cocaine use has been shown to lead to neurotoxicity in rodents and humans, being associated with high morbidity and mortality rates. However, recreational use, which may lead to addictive behavior, is often neglected. This occurs, in part, due to the belief that exposure to low doses of cocaine comes with no brain damage risk. Cocaine addicts have shown glucose metabolism changes related to dopamine brain activity and reduced volume of striatal gray matter. This work aims to evaluate the morphological brain changes underlying metabolic and locomotor behavioral outcome, in response to a single low dose of cocaine in a pre-clinical study. In this context, a Balb-c mouse model has been chosen, and animals were injected with a single dose of cocaine (0.5 mg/kg). Control animals were injected with saline. A behavioral test, positron emission tomography (PET) imaging, and anatomopathological studies were conducted with this low dose of cocaine, to study functional, metabolic, and morphological brain changes, respectively. Animals exposed to this cocaine dose showed similar open field activity and brain metabolic activity as compared with controls. However, histological analysis showed alterations in the prefrontal cortex and hippocampus of mice exposed to cocaine. For the first time, it has been demonstrated that a single low dose of cocaine, which can cause no locomotor behavioral and brain metabolic changes, can induce structural damage. These brain changes must always be considered regardless of the dosage used. It is essential to alert the population even against the consumption of low doses of cocaine.

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Increased Thromboxane Biosynthesis in Essential Thrombocythemia

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649916 ◽

1995 ◽

Vol 74 (05) ◽

pp. 1225-1230 ◽

Cited By ~ 71

Author(s):

Bianca Rocca ◽

Giovanni Ciabattoni ◽

Raffaele Tartaglione ◽

Sergio Cortelazzo ◽

Tiziano Barbui ◽

...

Keyword(s):

Platelet Count ◽

Platelet Activation ◽

Essential Thrombocythemia ◽

Therapeutic Strategy ◽

Low Dose ◽

Thrombotic Risk ◽

Dose Aspirin ◽

Gender And Age ◽

Low Dose Aspirin

SummaryIn order to investigate the in vivo thromboxane (TX) biosynthesis in essential thromboeythemia (ET), we measured the urinary exeretion of the major enzymatic metabolites of TXB2, 11-dehydro-TXB2 and 2,3-dinor-TXB2 in 40 ET patients as well as in 26 gender- and age-matched controls. Urinary 11-dehydro-TXB2 was significantly higher (p <0.001) in thrombocythemic patients (4,063 ± 3,408 pg/mg creatinine; mean ± SD) than in controls (504 ± 267 pg/mg creatinine), with 34 patients (85%) having 11-dehydro-TXB2 >2 SD above the control mean. Patients with platelet number <1,000 × 109/1 (n = 25) had significantly higher (p <0.05) 11 -dehydro-TXB2 excretion than patients with higher platelet count (4,765 ± 3,870 pg/mg creatinine, n = 25, versus 2,279 ± 1,874 pg/mg creatinine, n = 15). Average excretion values of patients aging >55 was significantly higher than in the younger group (4,784 ± 3,948 pg/mg creatinine, n = 24, versus 2,405 ± 1,885 pg/mg creatinine, n = 16, p <0.05). Low-dose aspirin (50 mg/d for 7 days) largely suppressed 11-dehydro-TXB2 excretion in 7 thrombocythemic patients, thus suggesting that platelets were the main source of enhanced TXA2 biosynthesis. The platelet count-corrected 11-dehydro-TXB2 excretion was positively correlated with age (r = 0.325, n = 40, p <0.05) and inversely correlated with platelet count (r = -0.381, n = 40, p <0.05). In addition 11 out of 13 (85%) patients having increased count-corrected 11-dehydro-TXB2 excretion, belonged to the subgroup with age >55 and platelet count <1,000 × 1099/1. We conclude that in essential thrombocythemia: 1) enhanced 11-dehydro-TXB2 excretion largely reflects platelet activation in vivo;2) age as well as platelet count appear to influence the determinants of platelet activation in this setting, and can help in assessing the thrombotic risk and therapeutic strategy in individual patients.

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AB1335-HPR HEALTH PROFESSIONALS’ PERSPECTIVE ON THE BENEFITS AND RISKS OF LOW-DOSE GLUCOCORTICOIDS IN RHEUMATOID ARTHRITIS – AN INTERNATIONAL SURVEY OF 444 HEALTH PROFESSIONALS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.3277 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1955.1-1956

Author(s):

T. Santiago ◽

M. Voshaar ◽

M. De Wit ◽

P. Carvalho ◽

M. Boers ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Adverse Events ◽

Health Professionals ◽

Patient Perspective ◽

Online Survey ◽

Low Dose ◽

Low Doses ◽

Research Support ◽

Serious Adverse Events ◽

Patient Organizations

Background:The Glucocorticoid Low-dose Outcome in Rheumatoid Arthritis Study (GLORIA) is an international investigator-initiated pragmatic randomized trial designed to study the effects of low-dose glucocorticoids (GCs) in elderly patients with Rheumatoid Arthritis (RA).The research team is also committed to promote a better understanding of the risks and benefits of these drugs among health professionals and patients. In order to achieve these goals, it is important to assess the current ideas and concerns of patients regarding GCs.Objectives:To evaluate the current patient perspective on the efficacy and risks of GCs in RA patients who are or have been treated with GCs.Methods:Patients with RA completed an online survey (with 5 closed questions regarding efficacy and safety) presented in their native language. RA patients were recruited through a variety of patient organizations representing three continents. Patients were invited to participate through national patient organizations. In the USA, patients were also invited to participate through MediGuard.org. Participants were asked for their level of agreement on a 5-point Likert scale.Results:1344 RA patients with exposure to GCs, from Brazil, USA, UK, Portugal, Netherlands, Germany and 24 other countries** participated: 89% female, mean age (SD) 52 (14) years and mean disease duration 13 (11) years. The majority of participants (84%) had ≥10 years of education. The duration of GCs exposure was 1.6 (4.2) years. The majority of participants had read articles or pamphlets on the benefits or harms of GC therapy.Regarding GCs efficacy (table 1), high levels of endorsement were found: about 2/3 of patients considered that GCs as very useful in their case, more than half considered that GCs were effective even at low doses, and agreed that GC improved RA symptoms within days.Regarding safety (table 1), 1/3 of the participants reported having suffered some form of serious adverse events (AEs) due to GCs, and 9% perceived this as “life-threatening. Adverse events had a serious impact on quality of life, according to about 1/3 of the respondents.Conclusion:Patients with RA exposed to GC report a strong conviction that GCs are very useful and effective for the treatment of their RA, even at low doses. This is accompanied by an important prevalence of serious AEs. Understanding the patient perspective can improve shared decision-making between patient and rheumatologist.Funding statement:This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 634886.Disclosure of Interests:Tânia Santiago: None declared, Marieke Voshaar Grant/research support from: part of phd research, Speakers bureau: conducting a workshop (Pfizer), Maarten de Wit Grant/research support from: Dr. de Wit reports personal fees from Ely Lilly, 2019, personal fees from Celgene, 2019, personal fees from Pfizer, 2019, personal fees from Janssen-Cilag, 2017, outside the submitted work., Consultant of: Dr. de Wit reports personal fees from Ely Lilly, 2019, personal fees from Celgene, 2019, personal fees from Pfizer, 2019, personal fees from Janssen-Cilag, 2017, outside the submitted work., Speakers bureau: Dr. de Wit reports personal fees from Ely Lilly, 2019, personal fees from Celgene, 2019, personal fees from Pfizer, 2019, personal fees from Janssen-Cilag, 2017, outside the submitted work., Pedro Carvalho: None declared, Maarten Boers: None declared, Maurizio Cutolo Grant/research support from: Bristol-Myers Squibb, Actelion, Celgene, Consultant of: Bristol-Myers Squibb, Speakers bureau: Sigma-Alpha, Frank Buttgereit Grant/research support from: Amgen, BMS, Celgene, Generic Assays, GSK, Hexal, Horizon, Lilly, medac, Mundipharma, Novartis, Pfizer, Roche, and Sanofi., José Antonio P. da Silva Grant/research support from: Pfizer, Abbvie, Consultant of: Pfizer, AbbVie, Roche, Lilly, Novartis

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Sorafenib is a potent inhibitor of FIP1L1-PDGFRα and the imatinib-resistant FIP1L1-PDGFRα T674I mutant

Blood ◽

10.1182/blood-2006-02-004457 ◽

2006 ◽

Vol 108 (4) ◽

pp. 1374-1376 ◽

Cited By ~ 101

Author(s):

Els Lierman ◽

Cedric Folens ◽

Elizabeth H. Stover ◽

Nicole Mentens ◽

Helen Van Miegroet ◽

...

Keyword(s):

Low Dose ◽

Potent Inhibitor ◽

Growth Factor Receptor ◽

Platelet Derived Growth Factor ◽

Low Doses ◽

Chronic Eosinophilic Leukemia ◽

Nanomolar Concentration ◽

Imatinib Resistant ◽

Factor Receptor Alpha ◽

Induced Apoptosis

Abstract The FIP1L1-PDGFRA oncogene is a common cause of chronic eosinophilic leukemia (CEL), and encodes an activated tyrosine kinase that is inhibited by imatinib. FIP1L1-PDGFRA–positive patients with CEL respond to low-dose imatinib therapy, but resistance due to acquired T674I mutation has been observed. We report here the identification of sorafenib as a potent inhibitor of the FIP1 like 1–platelet-derived growth factor receptor alpha (FIP1L1-PDGFRα) (T674I) mutant. Sorafenib inhibited the proliferation of FIP1L1-PDGFRα and FIP1L1-PDGFRα(T674I)–transformed Ba/F3 cells and induced apoptosis of the EOL-1 cell line at a low nanomolar concentration. Western blot analysis confirmed that these effects were due to a direct effect on FIP1L1-PDGFRα and FIP1L1-PDGFRα(T674I). Sorafenib was recently approved for the treatment of renal cell carcinoma. Our data suggest that low doses of sorafenib could be efficient for the treatment of FIP1L1-PDGFRA–positive CEL and could be used to overcome resistance to imatinib associated with the T674I mutation.

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Ripk3 Signaling Regulates Hematopoietic Stem Cell Number and Function during Stress

Blood ◽

10.1182/blood-2019-131332 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3714-3714

Author(s):

Lei Zhang ◽

Huacheng Luo ◽

Jing Li ◽

Hong-Min Ni ◽

Mark Sellin ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Low Dose ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

High Dose ◽

Low Doses ◽

Hematopoietic Stem ◽

Increased Risk ◽

Leukemia Development ◽

Serial Transplantation

Background: Among all tissues, bone marrow (BM) is the most sensitive tissue to ionizing radiation (IR)-induced acute tissue damage (ATD) and chronic long-term residual damage (LT-RD). BM failure and a significant reduction in blood cells (pancytopenia) often occurs within days after exposure to IR due to the massive death of proliferative hematopoietic progenitor cells (HPCs). However, due to their quiescent cell cycle status and reduced fidelity of DNA repair feature, many hematopoietic stem cells (HSCs) cannot fully eliminate such damage and enter senescence; this results in LT-RD. Abnormal dysplastic hematopoiesis is the most common LT-RD in most victims of IR, followed by an increased risk of leukemia/lymphoma development. Thus IR exposure is an established cause of BM failure and leukemia. A significant increase in the production of inflammatory cytokines is induced by IR which contributes to the pathogenesis of both ATD and LT-RD. Such inflammatory cytokines induce the activation of Ripk3-Mlkl-mediated necroptotic signaling in HSCs. However, the role of Ripk3-Mlkl signaling in IR-induced damage has not studied. Experimental procedures: The self-renewal capacity of HSCs among Ripk3-/-, Mlkl-/- and WT mice were examined and compared by serial transplantation assay. The phenotypes of ATD and LT-RD induced by different dosages of IR were compared among Ripk3-/-, Mlkl-/- and WT mice. The mechanism by which Ripk3 signaling prevents IR-induced leukemia development was studied. Results: Ripk3-Mlkl signaling is not required for hematopoiesis during homeostatic condition. However, during serial transplantation, inactivation of such signaling prevents stress-induced loss of HSCs. Interestingly, Ripk3 signaling also induces an Mlkl-independent ROS-p38-p16-mediated senescence in HSCs. Thus Ripk3-/- HSCs showed better competitive hematopoietic ability compared to Mlkl-/- and WT HSCs during serial transplantation. A sub-lethal dosage of IR (6Gy) induces Ripk3-dependent NF-κB activation and pro-survival gene expression in HSCs, which is necessary for the survival of damaged HSCs. After 6Gy IR, although DNA damage is repaired in most HSCs within 2 days, a proportion of HSCs in WT and Mlkl-/- mice fail to fully repair the damage and undergo p53-p21-dependent senescence. However such cells in Ripk3-/- mice die from apoptosis. Thus the remaining HSCs in Ripk3-/- mice should be functionally normal, while a proportion of the remaining HSCs in Mlkl-/- and WT mice remain damaged but senescent, all as demonstrated by competitive hematopoietic reconstitution assay. Multiple low-doses of IR (1.75Gy once week × 4) induce HSC exhaustion in WT mice but not in Ripk3-/- and Mlkl-/- mice. Interestingly, almost all Ripk3-/- mice develop acute lymphoblastic leukemia within 200 days after such low dose IR, while 45% of WT and 60% of Mlkl-/- mice develop thymomas within 360 days (see Figure). Mechanistically, such low-dose IR stimulates chronic inflammatory cytokine production. Such cytokines induce Ripk3-Mlkl-mediated necroptosis in response to HSC exhaustion observed in WT mice. These cytokines also induce Ripk3-ROS-p38-p16-mediated senescence in response to impaired HSC functioning observed in both WT and Mlkl-/- mice. In Ripk3-/- mice, due to the lack of both necroptotic and senescent signaling, mutant HSCs accumulate and leukemia development is accelerated. Conclusion: Ripk3 signaling plays distinct roles in HSCs in response to different doses of IR. High-dose IR induces Ripk3-dependent NF-κB/survival signaling, which is required for the survival of HSCs which fail to repair the damage. Thus temporal inhibition of Ripk3-NF-κB signaling might help to remove the damaged HSCs thus preventing the occurrence of LT-RD. However multiple low-doses of IR induces Ripk3 activation in HSCs which represses leukemia development by inducing both ROS-p38-p16-mediated senescence and Ripk3-Mlkl-mediated necroptosis. Induced activation of Mlkl-necroptosis might help to repress leukemia development by removing damaged HSCs. Disclosures No relevant conflicts of interest to declare.

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Proteins as targets for high dilutions of drugs: Interaction between ?-amylase and mercuric chloride.

International Journal of High Dilution Research - ISSN 1982-6206 ◽

10.51910/ijhdr.v17i2.920 ◽

2021 ◽

Vol 17 (2) ◽

pp. 24-25

Author(s):

Nirmal Chandra Sukul ◽

Tandra Sarkar ◽

Atheni Konar ◽

Anirban Sukul

Keyword(s):

Mercuric Chloride ◽

Binding Sites ◽

Low Dose ◽

Soluble Starch ◽

Low Doses ◽

Substrate Interaction ◽

Enzyme Substrate ◽

High Dilutions ◽

High Doses ◽

Mother Tincture

Background: High dilutions of drugs, used in homeopathy, are usually applied by oral route or foliar spray. These dilutions first come in contact with membrane or circulating proteins. Ultra low doses of mercuric chloride, called potencies, promote activity of diastase or ?-amylase in terms of breakdown of starch, a polysaccharide into a disaccharide maltose in a cell-free medium in test tubes. Merc cor or HgCl2 in high doses inhibits the enzyme activity. Aims: To see (i) whether the high and ultra low dose effects of HgCl2 involve different binding sites of the enzyme and (ii) to find an explanation for the low dose effect of HgCl2 in spite of absence of its original molecules. Methodology: Merc cor mother tincture (147 mM HgCl2) in distilled water was used undiluted in this experiment. Merc cor 200c and 1000c were prepared from the mother tincture (MT) by successive dilution with water 1:100 followed by succussion in 200 and 1000 steps, respectively, and finally preserved in 90% EtOH. These potencies and blank 90% ethanol, were diluted with deionized, distilled (DD) water 1:1000 to minimize ethanol content in test solutions. Each test solution or control was mixed with the enzyme 1:10 just before experiment. The control consisted of DD water. An isothermal calorimetry (ITC) instrument was used to measure the interaction between soluble starch and ?-amylase mixed with each potency (200c/1000c) of Merc cor, its mother tincture, ethanol and control. ITC is a thermodynamic technique which helps in measuring directly very small amount of heat evolved during chemical reaction. Soluble starch 90 µM was injected into 300 µl of 15µM ?-amylase at 2 µl / injection. Twenty injections, one every 2 min, were given. The enzyme substrate interaction in terms of heat released (exothermic) or absorbed (endothermic) were monitored by the ITC instrument. All ITC measurements were calculated and analyzed statistically by an in-built software Origin 7. Results and discussion: The data are presented in figures. While Merc cor MT shows endothermic reaction, all its potencies, ethanol and water control show exothermic reactions. There is wide variation in enthalpy (?H), entropy (?S), binding constant (K) and Gibbs free energy change (?G) among the treatments with Merc cor MT, potencies, ethanol and also control. The results indicate that Merc cor MT and its potencies act on different binding sites of the enzyme. The variation in thermodynamic parameters suggest difference in binding interaction between the drug solutions and the enzyme. This in turn influences the enzyme substrate interaction as reported in earlier studies. The potencies are virtually water modified by the starting substance HgCl2. Conclusion: The mother tincture and potencies of mercuric chloride produce different effects on the enzyme substrate interaction. Potencies show wide variation in ?H, ?S, K and ?G values. It appears from the results that the drugs used in homeopathy produce dual action on proteins. At high doses they act on a binding site(s) but at ultra low doses they act on a different binding site(s). Proteins in an organism may serve as targets for initiation of action of homeopathic potencies.

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Abstract 528: Dose- And Salt-dependency Of Angiogenesis Inhibition-induced Blood Pressure Rise And Renal Toxicity

Hypertension ◽

10.1161/hyp.64.suppl_1.528 ◽

2014 ◽

Vol 64 (suppl_1) ◽

Author(s):

Stephanie Lankhorst ◽

Mariëtte H Kappers ◽

Stefan Sleijfer ◽

A H Danser ◽

Anton H van den Meiracker

Keyword(s):

Low Dose ◽

Renal Toxicity ◽

Pressure Rise ◽

High Salt ◽

High Dose ◽

Low Doses ◽

High Salt Diet ◽

Salt Diet ◽

Angiogenesis Inhibition ◽

Cystatine C

Angiogenesis inhibition with the VEGF inhibitor sunitinib is an established anti-cancer therapy, inducing hypertension and nephrotoxicity. We explored the dose- and salt-dependency of these side effects. In male WKY rats, mean arterial pressure (MAP) was monitored telemetrically during oral treatment with a high (27.5 mg/kg.day, n=14), an intermediate (14 mg/kg.day, n=6) and low dose (7 mg/kg.day, n=6) of sunitinib or vehicle (n=8) after normal salt diet for 2 weeks. The low dose-model was also combined with a high salt diet (8% NaCl and saline water). Eight days after administration rats were sacrificed and blood and 24h urine samples collected for biochemical measurements. With the high dose of sunitinib, MAP increased from 94.7±0.9 mmHg to 125.8±1.5 mmHg (Δ31.1±0.9 mmHg, p<0.001). The intermediate and low doses induced MAP rises of 24.3±2.7 mmHg (p<0.001) and 13.4±3.3 mmHg (p<0.001), respectively. The low dose of sunitinib with high salt, induced a MAP rise of 43.5±2.2 mmHg (p<0.001 compared to normal salt). With the high dose, circulating ET-1 increased from 0.6±0.1 pg/ml to 1.6±0.2 pg/ml (p<0.01) and serum cystatine-C from 4.5±0.1 mg/L to 6.6±0.3 mg/L (p<0.001). Comparable increases in circulating ET-1 were seen with the intermediate and low doses, whereas serum cystatine-C did increase with the intermediate dose (to 6.3±0.1 mg/L, p0.05). Serum cystatine-C levels with low and high salt were identical. With the high dose of sunitinib, proteinuria increased from 7.5±1.3 to 33.3±4.8 mg/day (p<0.05). The rise in proteinuria was attenuated with the intermediate (16.2±2.1 mg/day, p<0.01) and low dose (19.9±3.3 mg/day, p<0.01), but increased to 40.4±30.1 mg/day (p>0.05) with high salt. Angiogenesis inhibition-induced hypertension and nephrotoxicity are dose-dependent with a lower threshold for the rise in BP than for renal toxicity. The BP rise observed with the low dose of sunitinib observed in normotensive rats is comparable to the sunitinib-induced BP rise observed in patients and clearly is salt-sensitive. Since cystatine-C levels during normal and high salt diet were comparable, the BP rise during high salt seems independent of renal dysfunction.

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Global brain volume reductions in a sub-chronic phencyclidine animal model for schizophrenia and their relationship to recognition memory

Journal of Psychopharmacology ◽

10.1177/0269881119844196 ◽

2019 ◽

Vol 33 (10) ◽

pp. 1274-1287 ◽

Cited By ~ 3

Author(s):

Nazanin Doostdar ◽

Eugene Kim ◽

Ben Grayson ◽

Michael K Harte ◽

Joanna C Neill ◽

...

Keyword(s):

Object Recognition ◽

Locomotor Activity ◽

Brain Volume ◽

Perirhinal Cortex ◽

Novel Object Recognition ◽

Novel Object ◽

Object Exploration ◽

Brain Changes ◽

Global Brain ◽

Structural Brain

Background: Cognitive deficits and structural brain changes co-occur in patients with schizophrenia. Improving our understanding of the relationship between these is important to develop improved therapeutic strategies. Back-translation of these findings into rodent models for schizophrenia offers a potential means to achieve this goal. Aims: The purpose of this study was to determine the extent of structural brain changes and how these relate to cognitive behaviour in a sub-chronic phencyclidine rat model. Methods: Performance in the novel object recognition task was examined in female Lister Hooded rats at one and six weeks after sub-chronic phencyclidine (2 mg/kg intra-peritoneal, n=15) and saline controls (1 ml/kg intra-peritoneal, n=15). Locomotor activity following acute phencyclidine challenge was also measured. Brain volume changes were assessed in the same animals using ex vivo structural magnetic resonance imaging and computational neuroanatomical analysis at six weeks. Results: Female sub-chronic phencyclidine-treated Lister Hooded rats spent significantly less time exploring novel objects ( p<0.05) at both time-points and had significantly greater locomotor activity response to an acute phencyclidine challenge ( p<0.01) at 3–4 weeks of washout. At six weeks, sub-chronic phencyclidine-treated Lister Hooded rats displayed significant global brain volume reductions ( p<0.05; q<0.05), without apparent regional specificity. Relative volumes of the perirhinal cortex however were positively correlated with novel object exploration time only in sub-chronic phencyclidine rats at this time-point. Conclusion: A sustained sub-chronic phencyclidine-induced cognitive deficit in novel object recognition is accompanied by global brain volume reductions in female Lister Hooded rats. The relative volumes of the perirhinal cortex however are positively correlated with novel object exploration, indicating some functional relevance.

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