Nilotinib restores memory function by preventing dopaminergic neuron degeneration in a mouse model of Alzheimer's Disease

What happens precociously to the brain destined to develop Alzheimer's Disease (AD) still remains to be elucidated and this is one reason why effective AD treatments are missing. Recent experimental and clinical studies indicate that the degeneration of the dopaminergic (DA) neurons in the Ventral Tegmental Area (VTA) could be one of the first events occurring in AD. However, the causes of the increased vulnerability of DA neurons in AD are missing. Here, we deeply investigate the physiology of DA neurons in the VTA before, at the onset, and after onset of VTA neurodegeneration. We use the Tg2576 mouse model of AD, overexpressing a mutated form of the human APP, to identify molecular targets that can be manipulated pharmacologically. We show that in Tg2576 mice, DA neurons of the VTA at the onset of degeneration undergo slight but functionally relevant changes in their electrophysiological properties and cell morphology. Importantly, these changes are associated with accumulation of autophagosomes, suggestive of a dysfunctional autophagy, and with enhanced activation of c-Abl, a tyrosine kinase previously implicated in the pathogenesis of neurodegenerative diseases. Chronic treatment of Tg2576 mice with Nilotinib, a validated c-Abl inhibitor, reduces c-Abl phosphorylation, improves autophagy, reduces A\u3b2 levels and - more importantly - prevents degeneration as well as functional and morphological alterations in DA neurons of the VTA. Interestingly, the drug prevents the reduction of DA outflow to the hippocampus and ameliorates hippocampal-related cognitive functions. Our results strive to identify early pathological brain changes in AD, to provide a rational basis for new therapeutic interventions able to slow down the disease progression

In Preclinical Model of Ovarian Cancer, the SGK1 Inhibitor SI113 Counteracts the Development of Paclitaxel Resistance and Restores Drug Sensitivity

Ovarian cancer is the second most common gynecological malignancy worldwide. Paclitaxel is particularly important in the therapy of ovarian carcinomas, but the treatment efficacy is counteracted by the development of resistance to chemotherapy. The identification of target molecules that can prevent or control the development of chemoresistance might provide important tools for the management of patients affected by ovarian cancer. Serum-and glucocorticoid-regulated kinase 1 (SGK1) appears to be a key determinant of resistance to chemo- and radiotherapy. Specifically, SGK1 affects paclitaxel sensitivity in RKO colon carcinoma cells by modulating the specificity protein 1 (SP1)-dependent expression of Ran-specific GTPase-activating protein (RANBP1), a member of the GTP-binding nuclear protein Ran (RAN) network that is required for the organization and function of the mitotic spindle. SGK1 inhibition might thus be useful for counteracting the development of paclitaxel resistance. Here, we present in vitro data obtained using ovarian carcinoma cell lines that indicate that the SGK1 inhibitor SI113 inhibits cancer cell proliferation, potentiates the effects of paclitaxel-based chemotherapy, counteracts the development of paclitaxel resistance, and restores paclitaxel sensitivity in paclitaxel-resistant A2780 ovarian cancer cells. The results were corroborated by preclinical studies of xenografts generated in nude mice through the implantation of paclitaxel-resistant human ovarian cancer cells. The SGK1 inhibitor SI113 synergizes with paclitaxel in the treatment of xenografted ovarian cancer cells. Taken together, these data suggest that SGK1 inhibition should be investigated in clinical trials for the treatment of paclitaxel-resistant ovarian cancer

Resilience to anhedonia-passive coping induced by early life experience is linked to a long-lasting reduction of Ih current in VTA dopaminergic neurons: Altered Ih current in the VTA of adult resilient-to-depression mice

Exposure to aversive events during sensitive developmental periods can affect the preferential coping strategy adopted by individuals later in life, leading to either stress-related psychiatric disorders, including depression, or to well-adaptation to future adversity and sources of stress, a behavior phenotype termed “resilience”. We have previously shown that interfering with the development of mother-pups bond with the Repeated Cross Fostering (RCF) stress protocol can induce resilience to depression-like phenotype in adult C57BL/6J female mice. Here, we used patch-clamp recording in midbrain slice combined with both in vivo and ex vivo pharmacology to test our hypothesis of a link between electrophysiological modifications of dopaminergic neurons in the intermediate Ventral Tegmental Area (VTA) of RCF animals and behavioral resilience. We found reduced hyperpolarization-activated (Ih) cation current amplitude and evoked firing in VTA dopaminergic neurons from both young and adult RCF female mice. In vivo, VTA-specific pharmacological manipulation of the Ih current reverted the pro-resilient phenotype in adult early-stressed mice or mimicked behavioral resilience in adult control animals. This is the first evidence showing how pro-resilience behavior induced by early events is linked to a long-lasting reduction of Ih current and excitability in VTA dopaminergic neurons

Bordetella holmesii in children suspected of pertussis in Argentina

Fil: Bottero, D. Instituto de Biotecnología y Biología Molecular. Laboratoria VacSal; Argentina.Fil: Griffith, M. US Centre for Disease Control and Prevention. Office of Infectious Diseases. National Center for Immunization and Respiratory Diseases. Division of Bacterial Diseases. Meningitis and Vaccine Preventable Diseases; Estados Unidos.Fil: Lara, Claudia. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Infecciosas. Servicio de Bacteriología Clínica; Argentina.Fil: Flores, D. Instituto de Biotecnología y Biología Molecular. Laboratoria VacSal; Argentina.Fil: Pianciola, Luis. Subsecretaria de Salud de Neuquén. Laboratorio Central; Argentina.Fil: Gaillard, M. E. Instituto de Biotecnología y Biología Molecular. Laboratoria VacSal; Argentina.Fil: Mazzeo, Melina. Subsecretaria de Salud de Neuquén. Laboratorio Central; Argentina.Fil: Zamboni, M. I. Dirección de Servicios de Laboratorios y Análisis Clínicos de la Secretaria de Salud Pública de la Municipalidad de Rosario. Centro de Especialidades Médicas Ambulatorias de Rosario; Argentina.Fil: Spoleti, M. J. Hospital de Niños Zona Norte; Rosario, Argentina.Fil: Anchart, E. Dirección Provincial de Farmacia, Bioquímica y Droguería Central del Ministerio de Salud de la Provincia de Santa Fe; Argentina.Fil: Ruggeri, D. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Infecciosas. Servicio de Bacteriología Clínica; Argentina.Fil: Sorhouet Pereira, Cecilia. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Infecciosas. Servicio de Bacteriología Clínica; Argentina.Fil: Fiori, S. Instituto de Biotecnología y Biología Molecular. Laboratoria VacSal; Argentina.Fil: Galas, Marcelo F. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Infecciosas. Servicio de Bacteriología Clínica; Argentina.Fil: Tondella, M. L. US Centre for Disease Control and Prevention. Office of Infectious Diseases. National Center for Immunization and Respiratory Diseases. Division of Bacterial Diseases. Meningitis and Vaccine Preventable Diseases; Estados Unidos.Fil: Hozbor, Daniela. Instituto de Biotecnología y Biología Molecular. Laboratoria VacSal; Argentina.We describe nine patients (eight aged <1 year) clinically diagnosed with pertussis yet laboratory-confirmed with Bordetella holmesii infections, a human pathogen normally isolated from blood. Most patients reported cough and cold symptoms. No death was reported. We report B. holmesii isolation in infants with respiratory symptoms in Argentina