ABSTRACT
OBJECTIVE: Sepsis is the main cause of death in hospitals and the implementation of diagnosis and treatment bundles has shown to improve its evolution. However, there is a lack of evidence about patients attended in conventional units. METHODS: A 3-year retrospective cohort study was conducted. Patients hospitalized in Internal Medicine units with sepsis were included and assigned to two cohorts according to Sepsis Code (SC) activation (group A) or not (B). Baseline and evolution variables were collected. RESULTS: A total of 653 patients were included. In 296 cases SC was activated. Mean age was 81.43 years, median Charlson comorbidity index (CCI) was 2 and 63.25% showed some functional disability. More bundles were completed in group A: blood cultures 95.2% vs 72.5% (p <0.001), extended spectrum antibiotics 59.1% vs 41.4% (p < 0.001), fluid resuscitation 96.62% vs 80.95% (p < 0.001). Infection control at 72 hours was quite higher in group A (81.42% vs 55.18%, odds ratio 3.55 [2.48-5.09]). Antibiotic was optimized more frequently in group A (60.77% vs 47.03%, p 0.008). Mean in-hospital stay was 10.63 days (11.44 vs 8.53 days, p < 0.001). Complications during hospitalization appeared in 51.76% of patients, especially in group B (45.95% vs 56.58%, odds ratio 1.53 [1.12-2.09]). Hospital readmissions were higher in group A (40% vs 24.76%, p < 0.001). 28-day mortality was significantly lower in group A (20.95% vs 42.86%, odds ratio 0.33 [0.23-0.47]). CONCLUSIONS: Implementation of SC seems to be effective in improving short-term outcomes in IM patients, although therapy should be tailored in an individual basis.
Subject(s)
Sepsis , Aged, 80 and over , Cohort Studies , Hospitals , Humans , Length of Stay , Retrospective Studies , Sepsis/diagnosis , Sepsis/drug therapyABSTRACT
Objectives: Ceftazidime/avibactam (CZA) is a third generation cephalosporin and the first non-beta-lactam beta-lactamase inhibitor combination. The main outcome was to assess the effectiveness and safety of CZA in the clinical practice.Methods: It was a retrospective observational study. The inclusion criteria were age >18 years and receipt of >24 hours of CZA between January 2016 and October 2018. Variables studied included demographic, clinical, and treatment.Results: 63 inpatients in treatment with CZA were included, 39 (61.9 %) were male and the mean (SD) age was 64.3 (15.8) years. Thirty-eight (60.3%) patients presented bacteremia and 28 (44.4%) were admitted in Intensive Care Unit (ICU). Klebsiella pneumoniae were isolated in 43 (68.3) patients, and OXA-48 carbapenemase in 51 (81.0%). Concomitant antibiotic was used in 40 (63.5%) patients. Mortality at 14 and 30 days were 6 (9.5%) and 4 (6.3%) patients, respectively.Thirty-five (55.6%) patients reached microbiological cure and 47 (74.6%) clinical cure. Infection recurrence evaluated at 90 days was achieved in 23 (36.5%) patients. ICU admission and bacteremia showed decreased in clinical cure (p=0.023 and p=0.01, respectively). Only ICU admission had a diminution in microbiological cure (p=0.035) and bacteremia a higher recurrence evaluated at 90 days (p=0.003). Only 3 (4.8%) patients interrupted treatment because of the adverse events.Conclusions: ICU admission had demonstrated a microbiological and clinical cure decreasing. Recurrence evaluated a 90 days was statically significant higher in patients with bacteremia. CZA was a security antibiotic, with a very low incidence of treatment interruptions. (AU)
Objetivo: Ceftazidima/avibactam (CZA) es una cefalosporina de tercera generación y el primer inhibidor de beta-lactamasas no beta-lactámico. El objetivo principal fue evaluar su efectividad y seguridad en la práctica clínica.Métodos: Se realizó un estudio observacional retrospectivo. Los criterios de inclusión fueron: edad >18 años y administración de >24 horas de CZA entre enero de 2016 y octubre de 2018. Las variables estudiadas incluyeron demograficas, clínicas y de tratamiento.Resultados: Se incluyeron 63 pacientes con CZA, 39 (61,9 %) fueron hombres, media (SD) de edad de 64,3 (15,8) años. 38 (60,3%) pacientes presentaron bacteriemia y 28 (44,4%) fueron ingresados en la Unidad de Cuidados Intensivos (UCI). Klebsiella pneumoniae se aisló en 43 (68,3) pacientes y OXA-48 carbapenemasa en 51 (81,0%). 40 (63,5%) pacientes recibieron antibiótico concomitante. La mortalidad a los 14 y 30 días fue de 6 (9,5%) y 4 (6,3%), respectivamente.Treinta y cinco (55,6%) alcanzaron curación microbiológica y 47 (74,6%) curación clínica. Recurrencia de la infección a los 90 días sucedió en 23 (36,5%). El ingreso en UCI y la bacteriemia demostraron una disminución de la curación clínica (p-0,023 y p-0,01, respectivamente). El ingreso en UCI tuvo una disminución en curación microbiológica (p-0,035) y la bacteriemia en una mayor recurrencia a los 90 días (p-0,003). 3 (4,8%) interrumpieron el tratamiento por toxicidad.Conclusiones: El ingreso en UCI se relacionó con disminución de curación microbiológica y clínica. La recurrencia a los 90 días fue mayor en pacientes con bacteriemia. CZA presenta una incidencia baja de interrupciones del tratamiento. (AU)
Subject(s)
Humans , Adolescent , Enterobacteriaceae Infections , Penicillinase , Klebsiella pneumoniae , PatientsABSTRACT
BACKGROUND: Lymphedema induced by mTOR inhibitors is a side-effect rarely reported to date. PATIENTS AND METHODS: Long-lasting bilateral lower-limb lymphedema with left predominance developed in a 71-year-old stable renal transplant recipient after 40 months of sirolimus treatment. Although no change in lymphedema was observed after 21 months despite dosage reduced, it improved markedly after changeover to tacrolimus. DISCUSSION: Regardless of the individual drug, mTOR inhibitors can cause lymphedema. This effect may be countered through substitution with tacrolimus. CONCLUSION: Physicians should be aware of lymphedema as a side-effect of mTOR inhibitors. It can be improved by substitution with tacrolimus. However, early withdrawal of mTOR inhibitors is recommended before irreversible lymphedema occurs.
Subject(s)
Immunosuppressive Agents/adverse effects , Lymphedema/chemically induced , Sirolimus/adverse effects , Tacrolimus/therapeutic use , Aged , Female , Humans , Kidney Transplantation , Sirolimus/therapeutic use , Transplant RecipientsABSTRACT
BACKGROUND AND PURPOSE: In the search for safer and effective anti-inflammatory agents, we investigated the effect of methyl indoline-3-propionate and indoline-3-(3-aminopropyl) carbamates on LPS-induced lung injury and pro-inflammatory cytokines in mice. Their mechanism of action was determined in murine peritoneal macrophages. EXPERIMENTAL APPROACH: Lung injury was induced by intratracheal infusion of LPS and assessed by the change in lung weight and structure by light microscopy after staining by haematoxylin and eosin. In LPS-activated macrophages, MAPK proteins and IκBα were measured by Western blotting and the transcription factors, AP-1 and NF-κB by electromobility shift assay. Cytokines in the plasma and spleen of mice injected with LPS were measured by elisa-based assay. KEY RESULTS: AN917 and AN680 (1-10 pM) decreased TNF-α protein in macrophages by inhibiting phosphorylation of p38 MAPK, IκBα degradation and activation of AP-1 and NF-κB without affecting cell viability. In vivo, these compounds (10 µmol · kg(-1)) markedly decreased lung injury induced by LPS and the elevation of TNF-α and IL-6 in lung, plasma and spleen. Activation of α-7nACh receptors contributed to the reduction of TNF-α by AN917, which inhibited AChE in the spleen by 35%. CONCLUSION AND IMPLICATIONS: Indoline carbamates are potent inhibitors of pro-inflammatory mediators in murine macrophages and in mice injected with LPS, acting via the p38 MAPK, AP-1 and NF-κB cascades. Indirect α-7nACh receptor activation by AN917, through inhibition of AChE, contributes to its anti-inflammatory effect. Indoline carbamates may have therapeutic potential for lung injury and other diseases associated with chronic inflammation without causing immunosuppression.
Subject(s)
Acute Lung Injury/drug therapy , Carbamates/pharmacology , Carbamates/therapeutic use , Cytokines/immunology , Indoles/pharmacology , Indoles/therapeutic use , Acute Lung Injury/immunology , Animals , Cell Line , Cells, Cultured , Cholinesterases/metabolism , Female , Lipopolysaccharides , Macrophages, Peritoneal/drug effects , Macrophages, Peritoneal/immunology , Male , Mice, Inbred BALB C , Mice, Inbred C57BL , Receptors, NicotinicABSTRACT
OBJECTIVES: The French ENT Society (SFORL) created a workgroup to draw up guidelines for the management of immunodeficient patients with head and neck cancer of cutaneous origin. The present guidelines cover diagnostic and therapeutic management and prevention of head and neck cancer of cutaneous origin in immunodeficient patients, and in particular in transplant patients and those with HIV infection. MATERIALS AND METHODS: The present guidelines were based on a critical multidisciplinary reading of the literature. Immunosuppression and its varieties are defined. The usual risk factors for skin cancer and those specific to immunodeficiency are presented. The prevention, assessment and management of cutaneous carcinoma, melanoma, Kaposi's sarcoma and lymphoma are dealt with. The level of evidence of the source studies was assessed so as to grade the various guidelines. When need be, expert opinions are put forward. RESULTS: Immunodeficient patients are at higher risk of head and neck skin tumors. The level of risk depends on the type of deficiency; there is an especially high risk of squamous cell carcinoma in transplant patients and of Kaposi's sarcoma in HIV-positive subjects. Various viruses are associated with skin cancers. Skin tumors are often evolutive in case of immunodeficiency, requiring rapid treatment. Management is generally the same as in immunocompetent subjects and should be discussed in a multidisciplinary team meeting. Immunosuppression may need to be modulated. In organ transplant patients, the only class of immunosuppressants with proven antitumoral efficacy are mTOR inhibitors, particularly in cutaneous squamous cell carcinoma. The rhythm of clinical surveillance should be adapted according to the risk of recurrence. Preventive measures should be undertaken. CONCLUSION: Skin cancers in immunodeficiency are highly evolutive, requiring the earliest possible treatment. Immunosuppression may need modulating. As the risk of recurrence may be elevated, careful surveillance should be implemented. Preventive measures should also be undertaken.
Subject(s)
Head and Neck Neoplasms/diagnosis , Head and Neck Neoplasms/therapy , Immunologic Deficiency Syndromes/complications , Immunosuppression Therapy/adverse effects , Skin Neoplasms/diagnosis , Skin Neoplasms/therapy , Head and Neck Neoplasms/immunology , Humans , Skin Neoplasms/immunologyABSTRACT
The effect of daily varied stress from days 13-21 of gestation in Wistar rats was investigated by tests of learning and memory and anxiogenic behaviour in the 60-day-old offspring of both sexes. Prenatal stress decreased the anogenital distance in males at 1 day of age. Anxiogenic behaviour in the elevated plus maze was seen in prenatally-stressed rats of both genders. There was no significant gender difference in the rate of spatial learning in the Morris water maze but prenatal stress only slowed that of males. In the object recognition test with an inter-trial interval of 40 min, females but not males, discriminated between a familiar and novel object. Prenatal stress did not affect object discrimination in females but feminised that in males. Maternal adrenalectomy with replacement of basal corticosterone levels in the drinking fluid prevented all of the above effects of prenatal stress in the offspring. To mimic the peak corticosterone levels and time course of elevation in response to stress, corticosterone (3 mg/kg) was injected twice (0 and 30 min) on days 13-16 and once on days 17-20 of gestation to adrenalectomised mothers. This treatment re-instated anxiogenic behaviour similar to that induced by prenatal stress, indicating that it is mediated by exposure of the foetal brain to raised levels of corticosterone. However, steroid administration to adrenalectomised dams did not decrease anogenital distance, feminise object recognition memory or slow spatial learning in their male offspring. The findings indicate that other adrenal hormones are necessary to induce these effects of prenatal stress.
Subject(s)
Corticosterone/physiology , Prenatal Exposure Delayed Effects/physiopathology , Stress, Psychological/physiopathology , Stress, Psychological/psychology , Adrenalectomy/methods , Animals , Birth Weight/drug effects , Birth Weight/physiology , Corticosterone/blood , Corticosterone/pharmacology , Discrimination, Psychological/drug effects , Discrimination, Psychological/physiology , Female , Litter Size/drug effects , Litter Size/physiology , Male , Maze Learning/drug effects , Maze Learning/physiology , Pregnancy , Rats , Rats, Wistar , Recognition, Psychology/drug effects , Recognition, Psychology/physiology , Sex Characteristics , Stress, Psychological/bloodABSTRACT
Histoplasma capsulatum var. capsulatum is a thermally dimorphic fungus that causes histoplasmosis. Fungal hemagglutination activity and cases of reactive hemophagocytic syndrome (RHS) have been reported in the disseminated form of disease. In the present study, soluble components of H. capsulatum var. capsulatum have been investigated for hemagglutinin activity and the capacity to induce hemophagocytosis in the mouse system. To analyze hemagglutinating activity, mouse red blood cells (RBC) (1% v/v in PBS) were incubated (37 degrees C, 1 h) with cell-free antigen (CFAg) from H. capsulatum var. capsulatum (isolate IMT/HC128) (RBC-CFAg) or previously heated CFAg (56 degrees C, 30 min) (RBC-hCFAg) or as control with PBS (RBC-PBS). Hemophagocytosis was analyzed by incubating BALB/c mouse peritoneal phagocytic cells (5 x 10(6) cells) with syngeneic RBC, sensitized or not with CFAg. In addition, mouse polyclonal antibodies were raised against syngeneic RBC-CFAg (anti-RBC-CFAg) and used to analyze CFAg chromatographic fractions (Sephadex G75/120) by immunoenzymatic assay (ELISA). Hemagglutinin activity was observed with RBC-CFAg, but not with RBC-hCFAg or RBC. Also, hemophagocytosis was observed with RBC-CFAg, but not with RBC. The anti-RBC-CFAg antibodies reacted with CFAg fractions corresponding to a molecular mass (MM) higher than 150 kDa. In conclusion, the yeast form of H. capsulatum var. capsulatum releases thermolabile soluble components with hemagglutinin activity and it has been demonstrated for the first time that soluble components of the same fungus induce syngeneic hemophagocytosis in the in vitro mouse system. Also, indirect analysis with antibodies suggests that high-MM components (>150 kDa) are responsible for the interaction with RBC.
Subject(s)
Fungal Proteins/immunology , Fungal Proteins/isolation & purification , Hemagglutination , Histoplasma/chemistry , Phagocytosis , Animals , Enzyme-Linked Immunosorbent Assay , Fungal Proteins/chemistry , Macrophages, Peritoneal/immunology , Mice , Mice, Inbred BALB C , Molecular WeightABSTRACT
Las enfermedades cardiovasculares constituyen la primera causa de muerte en España.Mientras que su peso relativo en la mortalidad está disminuyendo, aumenta como causageneradora de morbilidad, hospitalización y discapacidad. Hasta ahora el abordaje deestos pacientes había sido unifactorial; sin embargo, el objetivo actual de la prevencióncardiovascular es reducir el riesgo absoluto, es decir, disminuir la probabilidad de unevento cardiovascular de cualquier tipo en cualquier territorio vascular. De esta formaes el riesgo general lo que determina el tipo y la intensidad de la intervención. Los pacientesque más se benefi cian del control de los factores son aquellos que presentan unalto riesgo cardiovascular; éstos son, según las últimas guías, los pacientes en prevenciónsecundaria, los que tienen varios factores de riesgo cardiovascular o un solo factor muyelevado, los diabéticos y los pacientes con síndrome metabólico. El control de los factoresde riesgo cardiovascular en todos los ámbitos de la sanidad es defi citario, incluso enlas poblaciones de alto riesgo, aunque la tendencia en el tiempo es favorable. El manejointensivo y general del riesgo cardiovascular mejora el pronóstico de estos pacientes(AU)
Cardiovascular diseases are the fi rst cause of death in Spain. Although its relative weighin mortality is decreases, it is increases as a generating cause of morbidity, hospitalizationand disability. Up to now, the approach to these patients has been unifactorial. However,the current objective of cardiovascular prevention is to reduce the absolute risk, that is,decrease the likelihood of a cardiovascular event of any type in any vascular territory. Thus, the global risk is that what determines the type and intensity of the intervention.Those patients who benefi t the most from the control of factors are those who presenthigh cardiovascular risk. These are, according to the last guidelines, patients in secondaryprevention, those who have several cardiovascular risk factors or a one single very highfactor, diabetics and patients with metabolic syndrome. Control of cardiovascular riskfactor in all the health care settings, even in high risk populations, is defi cient, eventhough the current tendency is favorable. Intensive and global management ofcardiovascular risk improves the prognosis of these patients(AU)
Subject(s)
Humans , Cardiovascular Diseases/prevention & control , Risk Factors , Cardiovascular Diseases/epidemiology , Disease Prevention , Risk Groups , PrognosisABSTRACT
Ladostigil is a novel drug that inhibits acetyl and butyrylcholinesterase, and monoamine oxidase (MAO) A and B selectively in the brain. It reverses memory deficits induced by chronic inhibition of cortical cytochrome oxidase in rats and has anxiolytic and antidepressant-like activity in prenatally-stressed rats. Ladostigil also prevents oxidative-nitrative stress induced in astrocytes in the hippocampal CA1 region following icv injection of STZ in rats which also impairs their episodic memory. The unique combination of ChE and MAO enzyme inhibition combined with neuroprotection makes ladostigil a potentially useful drug for the treatment of dementia in subjects that also have extrapyramidal dysfunction and depression.
Subject(s)
Cholinesterase Inhibitors/therapeutic use , Dementia/complications , Dementia/drug therapy , Indans/therapeutic use , Monoamine Oxidase Inhibitors/therapeutic use , Parkinson Disease/complications , Anti-Anxiety Agents , Antidepressive Agents , HumansABSTRACT
We studied the functional role of the Escherichia coli ADPglucose pyrophosphorylase's N-terminus in allosteric regulation, and the particular effects caused by its length. Small truncated mutants were designed, and those lacking up to 15-residues were active and highly purified for further kinetic analyses. Ndelta3 and Ndelta7 did not change the kinetic parameters with respect to the wild-type. Ndelta11 and Ndelta15 enzymes were insensitive to allosteric regulation and highly active in the absence of the activator. Co-expression of two polypeptides corresponding to the N- and C-termini generated an enzyme with activation properties lower than those of the wild-type [C.M. Bejar, M.A. Ballicora, D.F. Gómez Casati, A.A. Iglesias, J. Preiss, The ADPglucose pyrophosphorylase from Escherichia coli comprises two tightly bound distinct domains, FEBS Lett. 573 (2004) 99-104]. Here, we characterized a Ndelta15 co-expression mutant, in which the allosteric regulation was restored to wild-type levels. Unusual allosteric effects caused by either an N-terminal truncation or co-expression of individual domains may respond to structural changes favoring an up-regulated or a down-regulated conformation rather than specific activator or inhibitor sites' disruption.
Subject(s)
Escherichia coli Proteins/chemistry , Escherichia coli/enzymology , Glucose-1-Phosphate Adenylyltransferase/chemistry , Allosteric Regulation/genetics , Amino Acid Sequence , Escherichia coli Proteins/genetics , Escherichia coli Proteins/metabolism , Glucose-1-Phosphate Adenylyltransferase/genetics , Glucose-1-Phosphate Adenylyltransferase/metabolism , Molecular Sequence Data , Protein Conformation , Sequence DeletionABSTRACT
Objetivos: Demostrar que la mosca doméstica (Musca domestica) es un vector mecánico de bacterias enteropatógenas en distritos de Lima y Callao. Materiales y Métodos: Estudio de tipo descriptivo transversal. Unidad de estudio: Musca domestica. Entre mayo de 2004 y julio de 2005 se realizó un muestreo en diferentes distritos de las provincias de Lima y el Callao teniendo en cuenta el índice de infestación de cada zona elegida. Se recolectaron moscas de mercados, periferia y basurales aledaños. En el laboratorio fueron procesadas en medios de cultivo para aislamientode enterobacterias y su identificación. Resultados: De un total de 780 moscas domésticas se aisló Escherichia coli enteropatógena, Salmonella typhi, Shigella flexneri y Yersinia enterocolitica. Se estableció una relación directa entre el hallazgo de bacterias enteropatógenas y las zonas de mayor grado de infestación (>20 moscas/hora de observación). Conclusión: El aislamiento de bacterias enteropatógenas en Musca domestica permitió demostrar su papel vector
Objectives: To prove that domestic fly (Musca domestica) is a mechanic vector for enteropathogenic bacteria in Lima and Callao districts. Materials and methods: Cross sectional descriptive study. Between May 2004 and July 2005 a sampling was performed in different districts in Lima and Callao, considering the infestation index in each selected area. Flies from markets, peripheral areas and surrounding junkyards were collected. The insects were later processed in the laboratory for isolation and identification of enterobacteria. Results: Out of 780 flies, enteropathogenic Escherichia coli, Salmonella typhi, Shigella flexneri, and Yersinia enterocolitica were isolated. A direct relationship between finding enteropathogenic bacteria and the areas with greatest infestation indexes (>20 flies/hour in observation). Conclusion: The isolation of enteropathogenic bacteria in Musca domestica allowed us to prove its role as a vector.
Subject(s)
Houseflies , PeruABSTRACT
The effect of colostral maternal antibodies (Abs), acquired via colostrum, on passive protection and development of systemic and mucosal immune responses against rotavirus was evaluated in neonatal calves. Colostrum-deprived (CD) calves, or calves receiving one dose of pooled control colostrum (CC) or immune colostrum (IC), containing an IgG1 titer to bovine rotavirus (BRV) of 1:16,384 or 1:262,144, respectively, were orally inoculated with 105.5 FFU of IND (P[5]G6) BRV at 2 days of age. Calves were monitored daily for diarrhea, virus shedding and anti-BRV Abs in feces by ELISA. Anti-rotavirus Ab titers in serum were evaluated weekly by isotype-specific ELISA and virus neutralization (VN). At 21 days post-inoculation (dpi), all animals were euthanized and the number of anti-BRV antibody secreting cells (ASC) in intestinal and systemic lymphoid tissues were evaluated by ELISPOT. After colostrum intake, IC calves had significantly higher IgG1 serum titers (GMT=28,526) than CC (GMT=1195) or CD calves (GMT<4). After BRV inoculation, all animals became infected with a mean duration of virus shedding between 6 and 10 days. However, IC calves had significantly fewer days of diarrhea (0.8 days) compared to CD and CC calves (11 and 7 days, respectively). In both groups receiving colostrum there was a delay in the onset of diarrhea and virus shedding associated with IgG1 in feces. In serum and feces, CD and CC calves had peak anti-BRV IgM titers at 7 dpi, but IgA and IgG1 responses were significantly lower in CC calves. Antibody titers detected in serum and feces were associated with circulation of ASC of the same isotype in blood. The IC calves had only an IgM response in feces. At 21 dpi, anti-BRV ASC responses were observed in all analyzed tissues of the three groups, except bone marrow. The intestine was the main site of ASC response against BRV and highest IgA ASC numbers. There was an inverse relationship between passive IgG1 titers and magnitude of ASC responses, with fewer IgG1 ASC in CC calves and significantly lower ASC numbers of all isotypes in IC calves. Thus, passive anti-BRV IgG1 negatively affects active immune responses in a dose-dependent manner. In ileal Peyer's patches, IgM ASC predominated in calves receiving colostrum; IgG1 ASC predominated in CD calves. The presence in IC calves of IgG1 in feces in the absence of an IgG1 ASC response is consistent with the transfer of serum IgG1 back into the gut contributing to the protection of the intestinal mucosa.
Subject(s)
Cattle Diseases/immunology , Cattle Diseases/virology , Colostrum/immunology , Gastrointestinal Diseases/veterinary , Immunity, Maternally-Acquired/immunology , Rotavirus Infections/veterinary , Rotavirus/immunology , Animals , Animals, Newborn , Antibodies, Viral/blood , Cattle , Diarrhea/immunology , Diarrhea/veterinary , Diarrhea/virology , Enzyme-Linked Immunosorbent Assay/veterinary , Feces/virology , Gastrointestinal Diseases/immunology , Gastrointestinal Diseases/virology , Immunoglobulin G/immunology , Intestinal Mucosa/immunology , Intestinal Mucosa/virology , Male , Neutralization Tests/veterinary , Random Allocation , Rotavirus Infections/immunology , Rotavirus Infections/virology , Virus Shedding/immunologyABSTRACT
BACKGROUND: Chronic antidepressant treatment causes alterations in several hippocampal genes, which participate in neuronal plasticity. However the full picture of their mechanism of action is not known. The advent of genomics enables to identify a broader mechanism of action and identify novel targets for antidepressant development. METHODS: The present study examined the cDNA microarray gene expression profile in the hippocampus induced by chronic antidepressant treatment, in rats exposed to the forced swim test. Animals were treated for 2 weeks with moclobemide, clorgyline and amitriptyline. RESULTS: The three antidepressants significantly reduced immobility in the forced swim test and initiated significant homologous changes in gene expressions. These include up regulation of cAMP response element binding protein and down regulation of corticotrophin releasing hormone. Other gene changes noted were those related to neuropeptides, neurogenesis and synaptogenesis, including synaptophysin and neogenin. Some 89 genes were changed by at least 2 drugs, out of which 53 were changed oppositely by forced swim test. Confirmation of gene changes, have come from real time RT-PCR. CONCLUSIONS: A significant number and homology in gene expression were observed with the three antidepressants. Many of the genes were associated with neurogenesis and synaptogenesis, including synaptophysin and neogenin.
Subject(s)
Antidepressive Agents/pharmacology , DNA-Binding Proteins , Hippocampus/drug effects , Oligonucleotide Array Sequence Analysis , Signal Transduction/drug effects , Activating Transcription Factor 1 , Amitriptyline/pharmacology , Animals , Behavior, Animal/drug effects , Clorgyline/pharmacology , Cyclic AMP/metabolism , DNA Primers , DNA, Complementary/analysis , Male , Moclobemide/pharmacology , Rats , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/physiology , Transcription Factors/metabolismABSTRACT
It has been reported that intracerebroventricular (icv) injection of streptozotocin (STZ) impairs spatial memory by disrupting glucose utilization through an insulin-dependent mechanism in the cerebral cortex and hippocampus. However, evidence of septal damage and microglosis induced by icv STZ suggested that its neurotoxic effects could contribute to the memory impairment. The present study examined the histopathological changes in adult rats following three icv STZ injections (0.25 mg into each lateral ventricle) and their effects on spatial memory in a Morris water maze task. STZ retarded acquisition of reference learning (progressive reduction in escape latency) and disrupted working memory (difference in escape latency between the two swims within a daily session). STZ caused selective injury to myelin and axons in the fornix and hippocampus in association with activation of microglia. The 3rd ventricle was enlarged by 100-150% because of a loss of ependymal cells and damage to hypothalamic periventricular myelin but the process involved in these changes is unclear. Our findings provide an alternative explanation for the decrease in glucose utilization in the hippocampus and cortex and the impairment of spatial memory induced by STZ. These could result from a disruption of the communication through myelinated axons in the fornix connecting the septum and the hippocampus, and through other myelinated axons adjacent to the ventricles. The selective damage to myelin may well result from oxidative stress.
Subject(s)
Antibiotics, Antineoplastic/administration & dosage , Memory Disorders/physiopathology , Myelin Sheath/drug effects , Neurons/drug effects , Streptozocin/administration & dosage , Animals , Injections, Intraventricular , Lateral Ventricles/drug effects , Lateral Ventricles/pathology , Lateral Ventricles/physiopathology , Male , Maze Learning/drug effects , Maze Learning/physiology , Memory/drug effects , Memory/physiology , Memory Disorders/chemically induced , Myelin Sheath/pathology , Neurons/pathology , Oxidative Stress , Rats , Rats, Sprague-Dawley , Spatial Behavior/drug effects , Spatial Behavior/physiologyABSTRACT
TV3326, (N-propargyl-(3R)-aminoindan-5-yl-ethyl,methyl carbamate) was prepared in order to combine the neuroprotective effects of rasagiline, a selective inhibitor of monoamine oxidase (MAO)-B with the cholinesterase (ChE) inhibitory activity of rivastigmine as a potential treatment for Alzheimer's disease. The study reported here examined the neuroprotective effects of TV3326 against various insults in vitro and in vivo. TV3326 caused a dose related (10-500 microM) reduction in death induced in NGF differentiated rat pheochromocytoma (PC12) cells by 3-4 hour exposure to oxygen-glucose deprivation. A single s.c. injection of TV3326 given five minutes after closed head injury in mice significantly reduced the cerebral edema, and accelerated the recovery of motor function and spatial memory several days later. Unilateral icv injection of streptozotocin (STZ) 1.5 mg in rats, caused specific damage to myelinated neurones in the fornix and corpus callosum accompanied by microgliosis. Three bilateral injections of STZ, 0.25 mg each, caused more widespread damage, and a marked impairment in spatial memory. Chronic oral treatment with TV3326 (75 mumols/kg) reduced the neuronal damage and microgliosis and almost completely prevented the memory impairment. The neuroprotective effect in PC12 cells may be due to a combination of ChE inhibition and antiapoptotic activity. The latter does not result from ChE inhibition. It is associated with the presence of the propargyl group, since it occurs with other propargylamines that do not inhibit MAO, but not with drugs that inhibit only ChE.
Subject(s)
Cholinesterase Inhibitors/pharmacology , Indans/pharmacology , Memory/drug effects , Neuroprotective Agents/pharmacology , Reaction Time/drug effects , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Animals , Anti-Bacterial Agents , Brain Injuries/drug therapy , Brain Injuries/metabolism , Cell Death/drug effects , Cell Death/physiology , Cell Hypoxia/drug effects , Cell Hypoxia/physiology , Cholinesterase Inhibitors/therapeutic use , Cholinesterases/drug effects , Cholinesterases/metabolism , Indans/therapeutic use , Male , Memory/physiology , Mice , Monoamine Oxidase/drug effects , Monoamine Oxidase/metabolism , Neuroprotective Agents/therapeutic use , PC12 Cells , Rats , Rats, Sprague-Dawley , Reaction Time/physiology , StreptozocinABSTRACT
This study compared the effect of rivastigmine on cholinesterase (ChE) activity in different brain regions, heart, skeletal muscle and plasma and on the cognitive impairment induced by scopolamine (0.5 mg/kg) in male and female rats. Rats were injected s.c. with saline or rivastigmine (0.75-2.5 mg/kg) or physostigmine (0.05 mg/kg) and killed 30-120 min later. Amelioration of scopolamine-induced memory deficits by rivastigmine (0.75 mg/kg) was assessed in the Morris water maze. There were no gender differences in spatial memory or basal ChE activity in the brain or other organs. Rivastigmine (0.75 and 1.5 mg/kg) and physostigmine (0.05 mg/kg) caused significantly greater ChE inhibition in females than in males (P<0.01) in the cerebral cortex, hippocampus and striatum, but not in the periphery 30 and 60 min after injection. Rivastigmine was also more effective in antagonising the scopolamine-induced spatial memory impairment in female than in male rats. Ovariectomy did not affect the degree of enzyme inhibition by rivastigmine in any brain area. Orchidectomy completely abolished the difference in enzyme inhibition. It is concluded that a testicular hormone suppresses the effect of rivastigmine, by reducing the amount of drug reaching the brain or its interaction with ChE.
Subject(s)
Brain/drug effects , Carbamates/pharmacology , Cholinesterase Inhibitors/pharmacology , Cholinesterases/drug effects , Memory/drug effects , Phenylcarbamates , Animals , Brain/enzymology , Cholinesterases/metabolism , Female , Male , Memory/physiology , Memory Disorders/chemically induced , Muscarinic Antagonists , Muscle, Skeletal/drug effects , Muscle, Skeletal/enzymology , Myocardium/enzymology , Orchiectomy , Ovariectomy , Physostigmine/pharmacology , Rats , Rats, Sprague-Dawley , Rivastigmine , Scopolamine , Sex FactorsABSTRACT
TV3326, [(N-propargyl-(3R) aminoindan-5-yl)-ethyl methyl carbamate] is a novel aminoindan derivative of the selective irreversible monoamine oxidase (MAO)-B inhibitor, rasagiline (N-propargyl-(1R)-aminoindan), possessing both cholinesterase (ChE) and MAO-inhibitory activity. In doses of 35-100 micromoles/kg administered orally to rats, it inhibits ChE by 25-40% and antagonises scopolamine-induced impairments in spatial memory. After daily administration of 75 micromoles/kg for 2 weeks, TV3326 does not show any motor stimulant effects but significantly reduces immobility in the forced swim test, an action consistent with that of known antidepressants. This could result from more than 70% inhibition of both MAO-A and B in the brain that occurs under these conditions, since it is not shared by the S-isomer, TV3279, which does not block MAO. TV3326 also shows selectivity for brain MAO, even after 2 months of daily administration, with little or no effect on the enzyme in the intestinal tract and liver. This reduces the likelihood of it producing the "cheese effect" if administered with tyramine-containing foods or beverages. TV3326 and TV3279 protect against ischemia-induced cytotoxicity in PC12 cells and reduce the oedema, deficits in motor function and memory after closed head injury in mice. These neuroprotective effects do not result from MAO inhibition. The pharmacological actions of TV3326 could be of clinical importance for the treatment of AD, and the drug is currently in development for this purpose.
Subject(s)
Alzheimer Disease/drug therapy , Alzheimer Disease/enzymology , Cholinesterase Inhibitors/pharmacology , Indans/agonists , Indans/pharmacology , Monoamine Oxidase Inhibitors/pharmacology , Neuroprotective Agents/pharmacology , Acetylcholinesterase/drug effects , Acetylcholinesterase/metabolism , Alzheimer Disease/physiopathology , Animals , Brain Injuries/complications , Brain Injuries/drug therapy , Male , Memory Disorders/chemically induced , Memory Disorders/drug therapy , Monoamine Oxidase/drug effects , Monoamine Oxidase/metabolism , Motor Activity/drug effects , Motor Activity/physiology , Rats , Rats, Sprague-Dawley , Scopolamine/antagonists & inhibitorsABSTRACT
The effect of rivastigmine on memory impairments induced in rats by scopolamine (0.5 mg/kg) was assessed in the Morris water maze and passive avoidance tests and compared with that of tacrine (2.5-17.7 mg/kg). Rivastigmine, (0.5-2.5 mg/kg) inhibited cholinesterase in the cortex and hippocampus by 21-60% and antagonised the deficits in working and reference memory. Tacrine (12.5 and 17.7 mg/kg) produced significantly less inhibition of cholinesterase in the hippocampus but more in the striatum than rivastigmine (0.75 and 1.5 mg/kg) and only antagonised the deficit in reference memory. Rivastigmine (1.5 and 2.5 mg/kg) or tacrine (12.5 mg/kg), injected immediately after completion of the acquisition trial in the passive avoidance test, antagonised the deficit induced by scopolamine (1 mg/kg) in memory retention. The inability of higher doses of the cholinesterase inhibitors to antagonise memory deficits induced by scopolamine may be related to excessive cholinergic stimulation in the central nervous system.