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1.
Sci Rep ; 10(1): 16130, 2020 09 30.
Artículo en Inglés | MEDLINE | ID: mdl-32999377

RESUMEN

Cardiovascular and renal complications are the predominant causes of morbidity and mortality amongst patients with diabetes. Development of novel treatments have been hampered by the lack of available animal models recapitulating the human disease. We hypothesized that experimental diabetes in rats combined with a cardiac or renal stressor, would mimic diabetic cardiomyopathy and nephropathy, respectively. Diabetes was surgically induced in male Sprague Dawley rats by 90% pancreatectomy (Px). Isoprenaline (Iso, 1 mg/kg, sc., 10 days) was administered 5 weeks after Px with the aim of inducing cardiomyopathy, and cardiac function and remodeling was assessed by echocardiography 10 weeks after surgery. Left ventricular (LV) fibrosis was quantified by Picro Sirius Red and gene expression analysis. Nephropathy was induced by Px combined with uninephrectomy (Px-UNx). Kidney function was assessed by measurement of glomerular filtration rate (GFR) and urine albumin excretion, and kidney injury was evaluated by histopathology and gene expression analysis. Px resulted in stable hyperglycemia, hypoinsulinemia, decreased C-peptide, and increased glycated hemoglobin (HbA1c) compared with sham-operated controls. Moreover, Px increased heart and LV weights and dimensions and caused a shift from α-myosin heavy chain (MHC) to ß-MHC gene expression. Isoprenaline treatment, but not Px, decreased ejection fraction and induced LV fibrosis. There was no apparent interaction between Px and Iso treatment. The superimposition of Px and UNx increased GFR, indicating hyperfiltration. Compared with sham-operated controls, Px-UNx induced albuminuria and increased urine markers of kidney injury, including neutrophil gelatinase-associated lipocalin (NGAL) and podocalyxin, concomitant with upregulated renal gene expression of NGAL and kidney injury molecule 1 (KIM-1). Whereas Px and isoprenaline separately produced clinical endpoints related to diabetic cardiomyopathy, the combination of the two did not accentuate disease development. Conversely, Px in combination with UNx resulted in several clinical hallmarks of diabetic nephropathy indicative of early disease development.


Asunto(s)
Cardiomiopatías Diabéticas/patología , Nefropatías Diabéticas/patología , Pancreatectomía/métodos , Albuminuria/complicaciones , Animales , Péptido C/metabolismo , Diabetes Mellitus Experimental/metabolismo , Modelos Animales de Enfermedad , Fibrosis , Tasa de Filtración Glomerular , Corazón/fisiopatología , Isoproterenol/farmacología , Riñón/metabolismo , Lipocalina 2/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Insuficiencia Renal/complicaciones
2.
Psychopharmacology (Berl) ; 193(2): 225-33, 2007 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-17406859

RESUMEN

RATIONALE: In humans, the N-methyl-D-aspartate antagonist phencyclidine (PCP) induces behavioral changes that mimic schizophrenia symptoms, including positive and negative symptoms as well as cognitive deficits. In clinic, the cognitive deficits are closely associated with functional outcome. Thus, improvement of cognition may have high impact on patients' daily life. OBJECTIVE: In the present study, three second-generation antipsychotics (sertindole, risperidone, and clozapine) as well as the classical antipsychotic haloperidol were tested for the ability to reverse PCP-induced cognitive deficits in the Morris' water maze. RESULTS: The second-generation antipsychotics reversed the PCP-induced cognitive impairment: sertindole (0.63-2.5 mg/kg, s.c.), risperidone (0.04 mg/kg, s.c.; whereas 0.08 and 0.16 mg/kg were without significant effect), and clozapine (0.63 mg/kg, s.c.; while 1.3 mg/kg was without significant effect). The significant effect of sertindole was observed from day 2 onwards, while clozapine and risperidone only had significant effect at day 3. The classical antipsychotic haloperidol (0.010-0.020 mg/kg, s.c.) was ineffective. No compounds influenced swimming speed at the doses used, indicating that motor function was preserved. CONCLUSION: These results confirm that repeated PCP administration induces marked cognitive deficits. Further, second-generation antipsychotics like sertindole, clozapine, and risperidone within a certain, often narrow, dose range are able to reverse the impairment and thus might improve cognitive deficits in schizophrenic patients, whereas classical compounds like haloperidol lack this effect. The receptor mechanisms involved in the reversal of PCP's disruptive effect are discussed and likely include a delicate balance between effects on dopamine D(2), 5-HT(2A/6), alpha-adrenergic, muscarinic, and histaminergic H(1) receptors.


Asunto(s)
Antipsicóticos/uso terapéutico , Trastornos del Conocimiento/tratamiento farmacológico , Aprendizaje por Laberinto/efectos de los fármacos , Análisis de Varianza , Animales , Conducta Animal/efectos de los fármacos , Clozapina/uso terapéutico , Trastornos del Conocimiento/inducido químicamente , Trastornos del Conocimiento/psicología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Haloperidol/uso terapéutico , Imidazoles/uso terapéutico , Indoles/uso terapéutico , Masculino , Fenciclidina , Ratas , Ratas Wistar , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Risperidona/uso terapéutico , Psicología del Esquizofrénico
3.
J Diabetes Res ; 2016: 7484601, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26953152

RESUMEN

The cytokine interleukin-1ß (IL-1ß) is known to stimulate proinflammatory immune responses and impair ß-cell function and viability, all critical events in the pathogenesis of type 1 diabetes (T1D). Here we evaluate the effect of SER140, a small peptide IL-1ß receptor antagonist, on diabetes progression and cellular pancreatic changes in female nonobese diabetic (NOD) mice. Eight weeks of treatment with SER140 reduced the incidence of diabetes by more than 50% compared with vehicle, decreased blood glucose, and increased plasma insulin. Additionally, SER140 changed the endocrine and immune cells dynamics in the NOD mouse pancreas. Together, the data suggest that SER140 treatment postpones the onset of diabetes in female NOD mice by interfering with IL-1ß activated pathways.


Asunto(s)
Diabetes Mellitus/prevención & control , Hipoglucemiantes/farmacología , Células Secretoras de Insulina/efectos de los fármacos , Interleucina-1beta/metabolismo , Péptidos/farmacología , Receptores de Interleucina-1/antagonistas & inhibidores , Animales , Biomarcadores/sangre , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Diabetes Mellitus/sangre , Diabetes Mellitus/patología , Femenino , Insulina/sangre , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Ratones Endogámicos NOD , Oligopéptidos/farmacología , Receptores de Interleucina-1/metabolismo , Transducción de Señal/efectos de los fármacos , Factores de Tiempo
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