116 results on '"Iñigo Azcoitia"'
Search Results
2. THE IMPACT OF SEX CHROMOSOME COMPLEMENT IN COGNITIVE BEHAVIOR AND HIPPOCAMPAL NETWORK ACTIVITY
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Rut De La Vega Ruiz, Alicia Hernández-Vivanco, Iñigo Azcoitia, and Pablo Méndez
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Published
- 2023
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3. Prenatal stress induces long-term effects in cell turnover in the hippocampus-hypothalamus-pituitary axis in adult male rats.
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Eva Baquedano, Cristina García-Cáceres, Yolanda Diz-Chaves, Natalia Lagunas, Isabel Calmarza-Font, Iñigo Azcoitia, Luis M Garcia-Segura, Jesús Argente, Julie A Chowen, and Laura M Frago
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Medicine ,Science - Abstract
Subchronic gestational stress leads to permanent modifications in the hippocampus-hypothalamus-pituitary-adrenal axis of offspring probably due to the increase in circulating glucocorticoids known to affect prenatal programming. The aim of this study was to investigate whether cell turnover is affected in the hippocampus-hypothalamus-pituitary axis by subchronic prenatal stress and the intracellular mechanisms involved. Restraint stress was performed in pregnant rats during the last week of gestation (45 minutes; 3 times/day). Only male offspring were used for this study and were sacrificed at 6 months of age. In prenatally stressed adults a decrease in markers of cell death and proliferation was observed in the hippocampus, hypothalamus and pituitary. This was associated with an increase in insulin-like growth factor-I mRNA levels, phosphorylation of CREB and calpastatin levels and inhibition of calpain -2 and caspase -8 activation. Levels of the anti-apoptotic protein Bcl-2 were increased and levels of the pro-apoptotic factor p53 were reduced. In conclusion, prenatal restraint stress induces a long-term decrease in cell turnover in the hippocampus-hypothalamus-pituitary axis that might be at least partly mediated by an autocrine-paracrine IGF-I effect. These changes could condition the response of this axis to future physiological and pathophysiological situations.
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- 2011
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4. Supplementary Figures 1 - 10, Tables 1 - 2 from CX3CL1 Promotes Breast Cancer via Transactivation of the EGF Pathway
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Santos Mañes, Sergio A. Lira, Iñigo Azcoitia, Miguel Quintela-Fandino, Anna M. Feijoo, Miguel A. García-Cabezas, Emilia Mira, and Manuel Tardáguila
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PDF file - 1052K, S1. CX3CL1 staining in mammary glands of WT and WT and CX3CL1+ mice. S2. Staining of CX3CR1 in tumors and mammary glands of Tg-neu mice. S3. Effects of Ad-CX3CL1or Ad-LacZ injection in tumor proliferation, apoptosisand angiogenesis. S4. CX3CL1 overexpression increases breast carcinogenesis in Tg-neu mice. S5. CX3CL1 or CX3CR1 mRNA expression in breast cancer cell lines with distinct metastatic potential. S6. CX3CL1 expression in a panel of breast cancer cell lines. S7. CX3CL1 induces EMT in breast cancer cells. S8. Lack of lymphoid metastases in Ad-CX3CL1-injected Tg-neu mice. S9. CX3CL1 induces transactivation of the EGF pathway. S10. ErbB ligand expression in T47D cells. S11. CX3CL1 deficiency does not affect the structure and composition of the mammary gland in Tg-neu mice. S12. Hemizygous CX3CL1 mRNA expression in T-neu-CX3CL1+/-. Supplemental Table 1. Media used to culture the cancer cell lines. Supplemental Table 2. Primers and annealing conditions used for PCR.
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- 2023
5. Sex-specific regulation of inhibition and network activity by local aromatase in the mouse hippocampus
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Nuria Cano Adamuz, Pablo Mendez, Liset Menendez de la Prida, Alberto Rodríguez Fernández, Iñigo Azcoitia, Alicia Hernández Vivanco, Alba González Alonso, Alberto Sánchez-Aguilera López, Ministerio de Ciencia e Innovación (España), and Agencia Estatal de Investigación (España)
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Male ,Multidisciplinary ,Estradiol ,General Physics and Astronomy ,General Chemistry ,Hippocampus ,General Biochemistry, Genetics and Molecular Biology ,Mice ,Aromatase ,Parvalbumins ,Interneurons ,Synapses ,Animals ,Female - Abstract
Cognitive function relies on a balanced interplay between excitatory and inhibitory neurons (INs), but the impact of estradiol on IN function is not fully understood. Here, we characterize the regulation of hippocampal INs by aromatase, the enzyme responsible for estradiol synthesis, using a combination of molecular, genetic, functional and behavioral tools. The results show that CA1 parvalbumin-expressing INs (PV-INs) contribute to brain estradiol synthesis. Brain aromatase regulates synaptic inhibition through a mechanism that involves modification of perineuronal nets enwrapping PV-INs. In the female brain, aromatase modulates PV-INs activity, the dynamics of network oscillations and hippocampal-dependent memory. Aromatase regulation of PV-INs and inhibitory synapses is determined by the gonads and independent of sex chromosomes. These results suggest PV-INs are mediators of estrogenic regulation of behaviorally-relevant activity., We thank E. Jiménez, A. Arroyo, and C. Sanmartín Segovia for help with image analysis; C. Sánchez for Python data processing scripts, J.G. Yagüe and M.A. Arévalo for production and validation of aromatase antibody; A.P. Arnold (UCLA, USA) for the kind gift of the FCG mice and A. Bacci (ICM, Paris, France) and L.M. García-Segura (Cajal Institute, Madrid, Spain) for helpful discussions on the manuscript. This work was supported by grants: RYC-2015-18545 (to P.M.), funded by MCIN/AEI/ 10.13039/501100011033 by “ESF Investing in your future”, BFU2017-84490-P (to P.M.) and RTI2018-098581-B-I00 (to L.M.P.) funded by MCIN/AEI/ 10.13039/501100011033 by “ERDF A way of making Europe” and PID2020-112824GB-100 (to P.M.) funded by MCIN/AEI/ 10.13039/501100011033. N.C.-A. is supported by the Ph.D. fellowship PRE2018-084857 funded by MCIN/AEI/10.13039/501100011033 by “ESF Investing in your future”. A.S.-A. is supported by the Juan de la Cierva program FJCI-2017-32719 funded by MCIN/AEI/10.13039/501100011033.
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- 2022
6. The endocannabinoid 2-AG enhances spontaneous remyelination by targeting microglia
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Francisco J. Carrillo-Salinas, Ana Feliú, Miriam Mecha, Carmen Guaza, V.W. Yong, Leyre Mestre, Iñigo Azcoitia, Natalia Yanguas-Casás, Ministerio de Economía y Competitividad (España), Red Española de Esclerosis Múltiple, and Instituto de Salud Carlos III
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Male ,0301 basic medicine ,Multiple Sclerosis ,Phagocytosis ,Immunology ,Mice, Inbred Strains ,Endogeny ,Arachidonic Acids ,TMEV ,Corpus Callosum ,Glycerides ,Mice ,03 medical and health sciences ,Behavioral Neuroscience ,Myelin ,0302 clinical medicine ,Theilovirus ,medicine ,Animals ,Axon ,Remyelination ,Myelin Sheath ,Oligodendrocyte Precursor Cells ,Biología celular ,Microglia ,Endocrine and Autonomic Systems ,Chemistry ,Multiple sclerosis ,Cell Differentiation ,medicine.disease ,Endocannabinoid system ,Axons ,Disease Models, Animal ,Oligodendroglia ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,Female ,Neuroscience ,030217 neurology & neurosurgery ,Demyelinating Diseases ,Endocannabinoids - Abstract
Remyelination is an endogenous process by which functional recovery of damaged neurons is achieved by reinstating the myelin sheath around axons. Remyelination has been documented in multiple sclerosis (MS) lesions and experimental models, although it is often incomplete or fails to affect the integrity of the axon, thereby leading to progressive disability. Microglia play a crucial role in the clearance of the myelin debris produced by demyelination and in inflammation-dependent OPC activation, two processes necessary for remyelination to occur. We show here that following corpus callosum demyelination in the TMEV-IDD viral murine model of MS, there is spontaneous and partial remyelination that involves a temporal discordance between OPC mobilization and microglia activation. Pharmacological treatment with the endocannabinoid 2-AG enhances the clearance of myelin debris by microglia and OPC differentiation, resulting in complete remyelination and a thickening of the myelin sheath. These results highlight the importance of targeting microglia during the repair processes in order to enhance remyelination., This work was supported by grants from the Ministerio de Economía y Competitividad (MINECO SAF2013-42784-R, SAF2016 76449-R), and the Red Española de Esclerosis Múltiple (REEM: RD12/0032/0008, RD16/0015/0021) sponsored by the Fondo de Investigación Sanitaria (FIS).
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- 2019
7. 86 - Envejecimiento del sistema nervioso
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Segura, Luis Miguel García and Elías, Íñigo Azcoitia
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- 2020
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8. Sex differences in the phagocytic and migratory activity of microglia and their impairment by palmitic acid
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María L. de Ceballos, Luis M. Garcia-Segura, Julie A. Chowen, Andrea Crespo-Castrillo, María Ángeles Arévalo, Natalia Yanguas-Casás, and Iñigo Azcoitia
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Male ,0301 basic medicine ,Senescence ,Offspring ,Phagocytosis ,Palmitic Acid ,Motility ,Biology ,Palmitic acid ,Interferon-gamma ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Prosencephalon ,0302 clinical medicine ,Cell Movement ,medicine ,Animals ,RNA, Messenger ,Rats, Wistar ,Cognitive decline ,Cells, Cultured ,Neuroinflammation ,Inflammation ,Sex Characteristics ,Microglia ,030104 developmental biology ,medicine.anatomical_structure ,Neurology ,chemistry ,Immunology ,Female ,030217 neurology & neurosurgery - Abstract
Sex differences in the incidence, clinical manifestation, disease course, and prognosis of neurological diseases, such as autism spectrum disorders or Alzheimer's disease, have been reported. Obesity has been postulated as a risk factor for cognitive decline and Alzheimer's disease and, during pregnancy, increases the risk of autism spectrum disorders in the offspring. Obesity is associated with increased serum and brain levels of free fatty acids, such as palmitic acid, which activate microglial cells triggering a potent inflammatory cascade. In this study, we have determined the effect of palmitic acid in the inflammatory profile, motility, and phagocytosis of primary male and female microglia, both in basal conditions and in the presence of a pro-inflammatory stimulus (interferon-γ). Male microglia in vitro showed higher migration than female microglia under basal and stimulated conditions. In contrast, female microglia had higher basal and stimulated phagocytic activity than male microglia. Palmitic acid did not affect basal migration or phagocytosis, but abolished the migration and phagocytic activity of male and female microglia in response to interferon-γ. These findings extend previous observations of sex differences in microglia and suggest that palmitic acid impairs the protective responses of these cells.
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- 2017
9. Notch signaling in astrocytes mediates their morphological response to an inflammatory challenge
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Estefania Acaz-Fonseca, María Ángeles Arévalo, Iñigo Azcoitia, Luis M. Garcia-Segura, Ana Ortiz-Rodriguez, Agencia Estatal de Investigación (España), Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (España), Instituto de Salud Carlos III, and Federación Española de Enfermedades Raras
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0301 basic medicine ,MAPK/ERK pathway ,Nervous system ,Cancer Research ,Immunology ,Notch signaling pathway ,Stimulus (physiology) ,lcsh:RC254-282 ,Article ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Mediator ,Downregulation and upregulation ,medicine ,lcsh:QH573-671 ,Biología celular ,Chemistry ,lcsh:Cytology ,Cell Biology ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Phenotype ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Astrocyte - Abstract
In the nervous system, Notch pathway has a prominent role in the control of neuronal morphology and in the determination of the astrocyte fate. However, the role of Notch in morphological astrocyte plasticity is unknown. Here, we have explored the role of Notch activity on the morphological reactivity of primary astrocytes in response to LPS, an inflammatory stimulus. We found that LPS induces reactive astrocyte morphology by the inhibition of Notch signaling via NFκB activation and Jagged upregulation. In contrast, IGF-1, an anti-inflammatory molecule, inhibits LPS-induced reactive astrocyte morphological phenotype by enhancing Notch signaling through the inhibition of NFκB and the activation of MAPK. Therefore, Notch signaling pathway emerges as a mediator of the regulation of astrocyte morphology by inflammatory and anti-inflammatory stimuli., We thank Elisa Baides Rosell for excellent technical assistance. This work was supported by grants from Agencia Estatal de Investigación, Spain (grant number BFU2017-82754-R), Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain and Fondos FEDER.
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- 2019
10. Estrogenic Regulation of Neuroprotective and Neuroinflammatory Mechanisms: Implications for Depression and Cognition
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Luis M. Garcia-Segura, Iñigo Azcoitia, Natalia Yanguas-Casás, Maria Elvira Brocca, and María Ángeles Arévalo
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medicine.anatomical_structure ,Microglia ,Synaptic plasticity ,Central nervous system ,medicine ,biology.protein ,Estrogen receptor ,Biology ,Aromatase ,Neuroprotection ,Neuroscience ,Tissue homeostasis ,Neuroinflammation - Abstract
Glial cells, such as astrocytes and microglia, contribute to maintain tissue homeostasis in the brain and are involved in the control of neuronal function, synaptic plasticity, and neuroinflammation. In the aged brain and under neurodegenerative conditions, microglial cells acquire a senescent reactive phenotype, which involves a dysregulated inflammatory response that affects the normal function and metabolism of neurons and other cell types, including astrocytes. The impaired function of astrocytes and microglia in the aged brain increases neuroinflammation, which is associated with depressive disorders and cognitive deficits. Estradiol, from gonadal origin or locally produced in the brain, exerts anti-inflammatory actions in the central nervous system, regulating the reactive phenotype of astrocytes and microglia. In addition, estrogen receptor signaling exerts direct neuroprotective actions on neurons and interacts with the signaling of other neuroprotective and anti-inflammatory factors in the brain. These actions of estradiol and estrogen receptors contribute to maintain a proper neuronal information processing, promoting cognitive function and preventing affective disorders. The effects of estradiol are imitated by synthetic estrogenic compounds, such as some selective estrogen receptor modulators and tibolone.
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- 2019
11. The Synthetic Steroid Tibolone Decreases Reactive Gliosis and Neuronal Death in the Cerebral Cortex of Female Mice After a Stab Wound Injury
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Iñigo Azcoitia, George E. Barreto, Luis M. Garcia-Segura, Andrea Crespo-Castrillo, María Ángeles Arévalo, Natalia Yanguas-Casás, Ministerio de Economía, Industria y Competitividad (España), Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (España), European Commission, and Instituto de Salud Carlos III
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0301 basic medicine ,Cell Count ,Tibolone ,0302 clinical medicine ,Neuroinflammation ,Image Processing, Computer-Assisted ,Gliosis ,Cerebral Cortex ,Neurons ,Cell Death ,Glial fibrillary acidic protein ,biology ,Microglia ,Microfilament Proteins ,Nuclear Proteins ,Neuroprotection ,DNA-Binding Proteins ,Phenotype ,medicine.anatomical_structure ,Neurology ,Cerebral cortex ,Ovariectomized rat ,Female ,Steroid receptors ,medicine.symptom ,medicine.drug ,medicine.medical_specialty ,Norpregnenes ,Neuroscience (miscellaneous) ,Nerve Tissue Proteins ,Wounds, Stab ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Brain trauma ,Internal medicine ,Glial Fibrillary Acidic Protein ,medicine ,Animals ,business.industry ,Macrophages ,Calcium-Binding Proteins ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,Brain Injuries ,Astrocytes ,biology.protein ,business ,030217 neurology & neurosurgery - Abstract
Previous studies have shown that estradiol reduces reactive gliosis after a stab wound injury in the cerebral cortex. Since the therapeutic use of estradiol is limited by its peripheral hormonal effects, it is of interest to determine whether synthetic estrogenic compounds with tissue-specific actions regulate reactive gliosis. Tibolone is a synthetic steroid that is widely used for the treatment of climacteric symptoms and/or the prevention of osteoporosis. In this study, we have assessed the effect of tibolone on reactive gliosis in the cerebral cortex after a stab wound brain injury in ovariectomized adult female mice. By 7 days after brain injury, tibolone reduced the number of glial fibrillary acidic protein (GFAP) immunoreactive astrocytes, the number of ionized calcium binding adaptor molecule 1 (Iba1) immunoreactive microglia, and the number of microglial cells with a reactive phenotype in comparison to vehicle-injected animals. These effects on gliosis were associated with a reduction in neuronal loss in the proximity to the wound, suggesting that tibolone exerts beneficial homeostatic actions in the cerebral cortex after an acute brain injury., This work was supported by grants from Ministerio de Economía, Industria y Competitividad (MINECO), Spain (grant numbers BFU2014–51836-C2-1-R and BFU2017-82754-R), Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), and Instituto de Salud Carlos III, Madrid, Spain and Fondos Feder.
- Published
- 2018
12. Signaling mechanisms mediating the regulation of synaptic plasticity and memory by estradiol
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María Ángeles Arévalo, Luis M. Garcia-Segura, Ignacio González-Burgos, and Iñigo Azcoitia
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Male ,Aging ,Dendritic spine ,Estrogen receptor ,Hippocampus ,Estrogen receptors ,Prefrontal cortex ,Synaptic plasticity ,Dendritic spines ,Behavioral Neuroscience ,Cognition ,Endocrinology ,Memory ,Metaplasticity ,Animals ,Humans ,Brain-derived neurotrophic factor ,Neuronal Plasticity ,Estradiol ,Endocrine and Autonomic Systems ,Wnt signaling pathway ,Brain ,Object recognition ,Receptors, Estrogen ,Female ,Signal transduction ,Growth factors ,Psychology ,Neuroscience ,hormones, hormone substitutes, and hormone antagonists ,Signal Transduction - Abstract
© 2015 Elsevier Inc.. This article is part of a Special Issue >Estradiol and Cognition>.Estradiol participates in the regulation of the function and plasticity of synaptic circuits in key cognitive brain regions, such as the prefrontal cortex and the hippocampus. The mechanisms elicited by estradiol are mediated by the regulation of transcriptional activity by nuclear estrogen receptors and by intracellular signaling cascades activated by estrogen receptors associated with the plasma membrane. In addition, the mechanisms include the interaction of estradiol with the signaling of other factors involved in the regulation of cognition, such as brain derived neurotrophic factor, insulin-like growth factor-1 and Wnt. Modifications in these signaling pathways by aging or by a long-lasting ovarian hormone deprivation after menopause may impair the enhancing effects of estradiol on synaptic plasticity and cognition.
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- 2015
13. Interaction of sex chromosome complement, gonadal hormones and neuronal steroid synthesis on the sexual differentiation of mammalian neurons
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María Julia Cambiasso, María Ángeles Arévalo, Isabel Ruiz-Palmero, Iñigo Azcoitia, Carla D. Cisternas, Luis M. Garcia-Segura, María Julia Scerbo, Agencia Nacional de Promoción Científica y Tecnológica (Argentina), Consejo Nacional de Investigaciones Científicas y Técnicas (Argentina), Universidad de Córdoba (España), Consejo Superior de Investigaciones Científicas (España), Ministerio de Economía, Industria y Competitividad (España), Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (España), Instituto de Salud Carlos III, and European Commission
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0301 basic medicine ,Male ,medicine.medical_specialty ,endocrine system ,Sex Differentiation ,Neurite ,Otras Ciencias Biológicas ,Neurogenesis ,AROMATASE ,Estrogen receptor ,Estrogen receptors ,Hippocampal formation ,Ciencias Biológicas ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Mice ,0302 clinical medicine ,Aromatase ,Downregulation and upregulation ,Internal medicine ,Genetics ,medicine ,Neurites ,Animals ,ESTROGEN RECEPTORS ,ESTRADIOL ,Neuritogenesis ,Neurons ,Sexual differentiation ,Sex Chromosomes ,Neurogenin 3 ,biology ,Estradiol ,ANDROGEN RECEPTOR ,Chromosome ,Androgen receptor ,030104 developmental biology ,Endocrinology ,nervous system ,biology.protein ,Female ,NEURITOGENESIS ,NEUROGENIN 3 ,CIENCIAS NATURALES Y EXACTAS ,030217 neurology & neurosurgery ,hormones, hormone substitutes, and hormone antagonists - Abstract
Female mouse hippocampal and hypothalamic neurons growing in vitro show a faster development of neurites than male mouse neurons. This sex difference in neuritogenesis is determined by higher expression levels of the neuritogenic factor neurogenin 3 in female neurons. Experiments with the four core genotype mouse model, in which XX and XY animals with male gonads and XX and XY animals with female gonads are generated, indicate that higher levels of neurogenin 3 in developing neurons are determined by the presence of the XX chromosome complement. Female XX neurons express higher levels of estrogen receptors than male XY neurons. In female XX neurons, neuronal derived estradiol increases neurogenin 3 expression and neuritogenesis. In contrast, neuronal-derived estradiol is not able to upregulate neurogenin 3 in male XY neurons, resulting in decreased neuritogenesis compared to female neurons. However, exogenous testosterone increases neurogenin 3 expression and neuritogenesis in male XY neurons. These findings suggest that sex differences in neuronal development are determined by the interaction of sex chromosomes, neuronal derived estradiol and gonadal hormones., This work was supported by Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT), Argentina [grant number PICT 2015 No. 1333]; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina (PIP 2013–2015); Secretaría de Investigación, Ciencia y Tecnología, Universidad de Córdoba (SECyT-UNC), Argentina (2016–2017); Programa CSIC de Cooperación Científica para el Desarrollo I-COOP +2013 [grant number COOPA20038]; Ministerio de Economia, Industria y Competitividad, Spain [grant number BFU2014-51836-C2-1-R]; Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable [CIBERFES; CB16/10/00383], Instituto de Salud Carlos III, Madrid, Spain and Fondos FEDER.
- Published
- 2017
14. Neuroactive steroid treatment modulates myelin lipid profile in diabetic peripheral neuropathy
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Donatella Caruso, Emma De Fabiani, Nico Mitro, Luis M. Garcia-Segura, Elisabetta Brioschi, Federico Abbiati, Iñigo Azcoitia, Matteo Audano, Silvia Giatti, Roberto Cosimo Melcangi, Maurizio Crestani, and Gaia Cermenati
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Male ,medicine.medical_specialty ,Neuroactive steroid ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Real-Time Polymerase Chain Reaction ,Biochemistry ,Diabetes Mellitus, Experimental ,Rats, Sprague-Dawley ,Myelin ,Anabolic Agents ,Endocrinology ,Diabetic Neuropathies ,Tandem Mass Spectrometry ,Diabetes mellitus ,Internal medicine ,medicine ,Animals ,RNA, Messenger ,Liver X receptor ,Molecular Biology ,Myelin Sheath ,medicine.diagnostic_test ,Reverse Transcriptase Polymerase Chain Reaction ,Chemistry ,Peripheral Nervous System Diseases ,Cell Biology ,medicine.disease ,Androstane-3,17-diol ,Lipids ,Sciatic Nerve ,20-alpha-Dihydroprogesterone ,Rats ,medicine.anatomical_structure ,Peripheral neuropathy ,Dihydroprogesterone ,Lipogenesis ,Molecular Medicine ,Progestins ,Lipid profile ,Biomarkers ,Chromatography, Liquid - Abstract
Diabetic peripheral neuropathy causes a decrease in the levels of dihydroprogesterone and 5α-androstane-3α,17β-diol (3α-diol) in the peripheral nerves. These two neuroactive steroids exert protective effects, by mechanisms that still remain elusive. We have previously shown that the activation of Liver X Receptors improves the peripheral neuropathic phenotype in diabetic rats. This protective effect is accompanied by the restoration to control values of the levels of dihydroprogesterone and 3α-diol in peripheral nerves. In addition, activation of these receptors decreases peripheral myelin abnormalities by improving the lipid desaturation capacity, which is strongly blunted by diabetes, and ultimately restores the myelin lipid profile to non-diabetic values. On this basis, we here investigate whether dihydroprogesterone or 3α-diol may exert their protective effects by modulating the myelin lipid profile. We report that both neuroactive steroids act on the lipogenic gene expression profile in the sciatic nerve of diabetic rats, reducing the accumulation of myelin saturated fatty acids and promoting desaturation. These changes were associated with a reduction in myelin structural alterations. These findings provide evidence that dihydroprogesterone and 3α-diol are protective agents against diabetic peripheral neuropathy by regulating the de novo lipogenesis pathway, which positively influences myelin lipid profile.
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- 2014
15. Neural-derived estradiol regulates brain plasticity
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María Ángeles Arévalo, Luis M. Garcia-Segura, and Iñigo Azcoitia
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0301 basic medicine ,medicine.medical_specialty ,Neuroactive steroid ,Neurogenesis ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Internal medicine ,Neuroplasticity ,medicine ,Animals ,Humans ,Aromatase ,Long-term depression ,Testosterone ,Neurons ,Neuronal Plasticity ,biology ,Estradiol ,Cholesterol side-chain cleavage enzyme ,Brain ,Long-term potentiation ,030104 developmental biology ,Endocrinology ,Synaptic plasticity ,biology.protein ,hormones, hormone substitutes, and hormone antagonists ,030217 neurology & neurosurgery - Abstract
In addition to be an ovarian hormone, estradiol is a neurosteroid synthesized by neural cells. The brain is a steroidogenic tissue that metabolizes testosterone to estradiol. The last step in the synthesis of estradiol is catalyzed by the enzyme aromatase, which is widely expressed in the brain of male and female animals and humans. Studies that have manipulated the expression or the activity of aromatase have revealed that brain-derived estradiol acts as a neuromodulator and regulates different forms of brain plasticity in male and female animals. The regulation of neuroplastic events by brain-derived estradiol probably participates in the effects of brain aromatase on behavior and cognition.
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- 2016
16. Molecular mechanisms and cellular events involved in the neuroprotective actions of estradiol. Analysis of sex differences
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Iñigo Azcoitia, Luis M. Garcia-Segura, George E. Barreto, Agencia Estatal de Investigación (España), Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (España), and Federación Española de Enfermedades Raras
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Male ,0301 basic medicine ,Cell signaling ,Neurogenesis ,Neurociencias ,Excitotoxicity ,Estrogen receptor ,Apoptosis ,Mitochondrion ,Biology ,medicine.disease_cause ,Neuroprotection ,03 medical and health sciences ,0302 clinical medicine ,Neuroinflammation ,Glia ,Autophagy ,medicine ,Animals ,Humans ,Inflammation ,Sex Characteristics ,Brain plasticity ,Neuronal Plasticity ,Estradiol ,Biología celular ,Endocrine and Autonomic Systems ,Neuroregeneration ,Mitochondria ,Cell biology ,030104 developmental biology ,Receptors, Estrogen ,Female ,030217 neurology & neurosurgery ,Signal Transduction ,Cell signalling - Abstract
Estradiol, either from peripheral or central origin, activates multiple molecular neuroprotective and neuroreparative responses that, being mediated by estrogen receptors or by estrogen receptor independent mechanisms, are initiated at the membrane, the cytoplasm or the cell nucleus of neural cells. Estrogen-dependent signaling regulates a variety of cellular events, such as intracellular Ca levels, mitochondrial respiratory capacity, ATP production, mitochondrial membrane potential, autophagy and apoptosis. In turn, these molecular and cellular actions of estradiol are integrated by neurons and non-neuronal cells to generate different tissue protective responses, decreasing blood-brain barrier permeability, oxidative stress, neuroinflammation and excitotoxicity and promoting synaptic plasticity, axonal growth, neurogenesis, remyelination and neuroregeneration. Recent findings indicate that the neuroprotective and neuroreparative actions of estradiol are different in males and females and further research is necessary to fully elucidate the causes for this sex difference., Authors acknowledge funding from Agencia Estatal de Investigación (BFU2017-82754-R), CIBERFES and Fondos FEDER.
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- 2019
17. Colaboradores
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Abizanda Soler, Pedro, Agudo Mena, José Luis, Aguilar, Adriana B., Alarcón Alarcón, Teresa, Albrecht Junghanns, Rodolfo Emmanuel, Alfaro Acha, Ana, Almaida Pagán, Pedro Francisco, Alonso Bouzón, Cristina, Alonso Fernández, Teresa, Alvira Rasal, Berta, Andradas Aragonés, Elena, Andrés Lacueva, Cristina, Angulo Frutos, Javier, Arche Coto, José Miguel, Ariza Zafra, Gabriel, Arriola Manchola, Enrique, Avellana Zaragoza, Juan Antonio, Avendaño Céspedes, Almudena, Defez, José Manuel Azaña, Elías, Íñigo Azcoitia, Balducci, Lodovico, Bardales Mas, Yadira, Baztán Cortés, Juan José, Varea, Ángel Belenguer, Bermeo Serrato, Sandra Milena, Menéndez de la Granda, Manuel Bermúdez, Borrás Blasco, Consuelo, Burcet Pérez, Silvia, Mora, María Ángeles Caballero, Cabré Roure, Mateu, Calcaterra, Laura, Camilo Beltrán, Jonathan, Cano Gutiérrez, Carlos Alberto, Casas Agustench, Patricia, Herrero, Álvaro Casas, Castro Rodríguez, Marta, Cebollero Ribas, Pilar, Celaya Cifuentes, Sara, Cesari, Matteo, Chavarro Carvajal, Diego Andrés, Chaves, Paulo H.M., Chodzko-Zajko, Wojtek, Clavé Civit, Pere, Contreras Escámez, Beatriz, Contreras Luque, Claudia Patricia, Santiago, Dámaso Crespo, Allue, Ramón Cristófol, Cristofori, Giovanna, María Cuervo, Ana, Cuesta Triana, Federico, Curcio Borrero, Carmen Lucía, de Costa Ruiz, Jorge, Rey, Mónica de la Fuente del, de la Fuente Gutiérrez, Carlos, Martín, María de la Puente, del Pozo Guerrero (D.E.P.), Francisco, Domínguez Martín, Laura, Duque Naranjo, Gustavo, Durio Calero, Enrique Antonio, Enfedaque Montes, Belén, Escobar Gómez, Lina María, Esquinas Requena, José Luis, Esteve Arríen, Ainhoa, Estrella Cazalla, Juan de Dios, Fernández, Agustín F., Fernández, Iñaki Fernández de Trocóniz, Fernández Fernández, María, Fernández Martínez, Nuria, Fernández Minaya, Dionis Carolina, Fernández Rodríguez, Esperanza, Fernández Viadero, Carlos, Flores Ruano, Teresa, Fraga, Mario F., Galmés Belmonte, Ignacio, Gambini Buchón, Juan, Garatachea Vallejo, Nuria, Garcia Cifuentes, Elkin, García Esquinas, Esther, García García, Francisco José, García Navarro, José Augusto, García Sánchez, Sergio, García Segura, Luis Miguel, Garreta Buriel, Marisa, Garrido Cid, María Jesús, Gil Gregorio, Pedro, Gimeno Mallench, Lucía, Gómez Fernández, Marisol, Gómez Montes, Fernando, Gómez Pavón, Javier, González-Colaço Harmand, Magali, González García, Paloma, González Guerrero, José Luis, González Montalvo, Juan Ignacio, Gramunt Fombuena, Nina, Grande Martín, Alberto, Guerrero Díaz, María Teresa, Luis Guerrero Solano, José, Gutiérrez Robledo, Luis Miguel, Gutiérrez Rodríguez, José, Hendry, Anne, Heras Benito, Manuel, Hernández Zamora, Paulo, Hernández Zegarra, Pablo Alberto, Hoogendijk, Emiel O., Hornillos Calvo, Mercedes, Huedo Rodenas, Isabel, Pérez de Heredia, Javier Hueto, Ibarzábal Aramberri, Xabier, Inzitari, Marco, Izquierdo Redín, Mikel, Jiménez Muela, Francisco, Jiménez Rojas, Concepción, Jiménez Segura, José Daniel, Jordán Bueso, Joaquín, Jové Font, Mariona, Júdez Navarro, Enrique, Juncos Martínez, Gema, Laosa Zafra, Olga, León Ortiz, Matilde, Limón Ramírez, Esther, Linge Martín, Magdalena, Arrieta, Jesús María López, Chicharro, José Luis López, López-Dóriga Bonnardeaux, Pedro, López García, Esther, López Jiménez, Esther, Sáez de Asteasu, Mikel López, López Utiel, Melisa, Lozano Berrio, Vicente, Lozano Montoya, Isabel, Lucía Mulas, Alejandro, Luengo Márquez, Carmen, Madrid Pérez, Juan Antonio, Manzarbeitia Arambarri, Jorge, Fuentes, Ángel Martín, Martín Martínez, Alberto, Martín Sanz, Eduardo, Sebastiá, Asunción Martín, Martín Sebastiá, Elena, Luz Martínez, Iveris, Martínez Antón, Miguel Ángel, Montandón, Álvaro Martínez, Martínez Ramírez, Alicia, Martínez Reig, Marta, Velilla, Nicolás Martínez, Mas Bergas, Miquel Àngel, Mas Romero, Marta, Matheu, Ander, Mazoteras Muñoz, Virginia, Miguel Alhambra, Luciana, Millor Muruzábal, Nora, Basseda, Ramón Miralles, Mohedano Molano, Julia, Garrido, María José Molina, Molina Olivas, Marta, Guix, José Luis Molinuevo, Montero Moreno, Javier Antonio, Montero-Odasso, Manuel, Morales Martínez, Fernando, Moreno Cugnon, Leire, Moreno Valladares, Manuel, Mosquera Gorostidi, Carmen, Negrín Mena, Natalia, Noguerón García, Alicia, Ochando Ibernón, Gemma, Olaso González, Gloria, Oliva Moreno, Juan, Carbonell, José Luis Oliver, Ortega Fernández, Omar, Pamplona Gras, Reinald, Fernández, José Manuel Pardal, Pareja Galeano, Helios, Pareja Sierra, Teresa, García, José Francisco Parodi, Pedraza Sepúlveda, Laura, Peláez, Martha B., Peña Longobardo, Luz María, Pérez Bazán, Laura Mónica, Pérez-Jara Carrera, Javier, Pérez Rodríguez, Rodrigo, Pérez Rojo, Gema, Petidier Torregrossa, Roberto, Pradas Barriga, Irene, Villanueva, Begoña Prado, Prieto Prieto, Fernando, Puertas Cuesta, Francisco Javier, Puyol Antolín, Rafael, Ramos Bacco, Mauricio, Rangel Selvera, Omar, Rexach Cano, Lourdes, Rodríguez Artalejo, Fernando, Rodríguez Mañas, Leocadio, Rodríguez Sánchez, Beatriz, Rodríguez Sánchez, Isabel, Rodríguez Solís, Juan, Lama, María Ángeles Rol de, Romero Macías, Juan Ramón, Romero Rizos, Luis, Ruiz Medrano, Jorge, Ruiz-Moreno, José María, Ruiz Sáenz, Pedro Luis, Salas Carrillo, Mario, Cristóbal Velasco, Esther San, Sánchez Castellano, Carmen, Sánchez Jurado, Pedro Manuel, Nievas, Ginés Sánchez, Escudero, José Manuel Santacruz, Sanz Fernández, Ricardo, Schwingel, Andiara, Scuteri, Angelo, Sierra, Marta I., Sinclair, Alan J., Solano Jaurrieta, Juan José, Soler Moratalla, Isabel, Rodríguez, María del Carmen Soriano, Tarazona Santabalbina, Francisco, Tardáguila García, Noelia, Tasset, Inmaculada, Dorta, Agustín Tejera, Ucha Domingo, Marisol, Urpi Sarda, Mireia, van Leeuwen, Mara, Vega García, Enrique, Verdejo Bravo, Carlos, Verduga Vélez, Rosario, Vial Escolano, Raquel, Vilches Moraga, Arturo, Ribes, José Viña, Walston, Jeremy, Yubero Pancorbo, Raquel, Zambom-Ferraresi, Fabrício, and Zúñiga Gil, Clemente Humberto
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- 2020
- Full Text
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18. Interactions of Estradiol and Insulin‐Like Growth Factor‐I in Neuroprotection: Implications for Brain Aging and Neurodegeneration
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Luis M. Garcia-Segura, María Ángeles Arévalo, and Iñigo Azcoitia
- Subjects
medicine.medical_specialty ,Insulin-like growth factor ,Endocrinology ,Internal medicine ,medicine.medical_treatment ,Neurodegeneration ,medicine ,Biology ,medicine.disease ,Neuroprotection ,Brain aging - Published
- 2011
19. Role of astroglia in the neuroplastic and neuroprotective actions of estradiol
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Luis M. Garcia-Segura, María Ángeles Arévalo, María Santos-Galindo, and Iñigo Azcoitia
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General Neuroscience ,Neurodegeneration ,Estrogen receptor ,Biology ,medicine.disease ,Neuroprotection ,Astrogliosis ,Neurotrophic factors ,Synaptic plasticity ,medicine ,biology.protein ,Signal transduction ,Aromatase ,Neuroscience ,hormones, hormone substitutes, and hormone antagonists - Abstract
Astrocyte-neuron cross-talk is an essential component of the mechanisms involved in the neuroendocrine and neuroprotective actions of estradiol. Astrocytes express estrogen receptors, show morphological and functional modifications in response to estradiol and participate in the hormonal regulation of synaptic plasticity and neuroendocrine events. In addition, estradiol interferes with the activation of astrocytes under pathological conditions, modulating the release of neurotrophic factors and inflammatory molecules by these cells. Furthermore, under neurodegenerative conditions, astrocytes synthesize estradiol, which acts as a local neuroprotectant. The actions of estradiol on astrocytes can be imitated by selective estrogen receptor modulators. Some of these molecules, which are free of the peripheral risks associated with estrogen therapy, exert estradiol-like anti-inflammatory actions on astrocytes and are potential therapeutic candidates for the control of reactive astrogliosis.
- Published
- 2010
20. Response of transcription factor NFATc3 to excitotoxic and traumatic brain insults: Identification of a subpopulation of reactive astrocytes
- Author
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Pedro Tranque, Soledad Calvo, Iñigo Azcoitia, Eva Cano, Cecilia F. Vaquero, María C. Serrano-Pérez, and Eduardo D. Martín
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Blotting, Western ,Excitotoxicity ,Brain damage ,Biology ,medicine.disease_cause ,Glial scar ,Mice ,Cellular and Molecular Neuroscience ,Glial Fibrillary Acidic Protein ,medicine ,Animals ,Neuroinflammation ,Neurons ,Analysis of Variance ,Kainic Acid ,Microscopy, Confocal ,Cell Death ,NFATC Transcription Factors ,Microglia ,Reverse Transcriptase Polymerase Chain Reaction ,Brain ,NFAT ,medicine.disease ,Immunohistochemistry ,Astrogliosis ,medicine.anatomical_structure ,Neurology ,Astrocytes ,Brain Injuries ,medicine.symptom ,Neuroscience ,Astrocyte - Abstract
Astrocytes react to brain injury triggering neuroinflammatory processes that determine the degree of neuronal damage. However, the signaling events associated to astrocyte activation remain largely undefined. The nuclear factor of activated T-cells (NFAT) is a transcription factor family implicated in activation of immune cells. We previously characterized the expression of NFAT isoforms in cultured astrocytes, and NFAT activation in response to mechanical lesion. Here we analyze NFATc3 in two mouse models of inflammatory brain damage: hippocampal excitotoxicity induced by intracerebral kainic acid (KA) injection and cortical mechanical lesion. Immunofluorescence results demonstrated that NFATc3 is specifically induced in a subset of reactive astrocytes, and not in microglia or neurons. In KA-treated brains, NFATc3 expression is transient and NFATc3-positive astrocytes concentrate around damaged neurons in areas CA3 and CA1. Complementary Western blot and RT-PCR analysis revealed an NFAT-dependent induction of RCAN1-4 and COX-2 in hippocampus as soon as 6 h after KA exposure, indicating that NFAT activation precedes NFATc3 over-expression. Moreover, activation of NFAT by ATP increased NFATc3 mRNA levels in astrocyte cultures, suggesting that NFATc3 expression is controlled through an auto-regulatory loop. Meanwhile, stab wound enhanced NFATc3 expression specifically in a subclass of reactive astrocytes confined within the proximal layer of the glial scar, and GFAP immunoreactivity was attenuated in NFATc3-expressing astrocytes. In conclusion, our work establishes NFATc3 as a marker of activation for a specific population of astrocytes in response to brain damage, which may have consequences for neuronal survival.
- Published
- 2010
21. Actions of estrogens on glial cells: Implications for neuroprotection
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Iñigo Azcoitia, María-José Bellini, Luis M. Garcia-Segura, María Santos-Galindo, and María Ángeles Arévalo
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medicine.medical_specialty ,Cell Survival ,Extracellular glutamate ,Biophysics ,Glutamic Acid ,Brain Edema ,Estrogenic Compounds ,Biochemistry ,Neuroprotection ,Myelin ,Internal medicine ,medicine ,Animals ,Humans ,Remyelination ,Molecular Biology ,Myelin Sheath ,Inflammation ,Neurons ,Microglia ,Chemistry ,Estrogens ,Oligodendroglia ,Neuroprotective Agents ,medicine.anatomical_structure ,Endocrinology ,nervous system ,Selective estrogen receptor modulator ,Astrocytes ,Brain Injuries ,Intercellular Signaling Peptides and Proteins ,Edema formation ,hormones, hormone substitutes, and hormone antagonists - Abstract
Glial cells are directly or indirectly affected by estradiol and by different estrogenic compounds, such as selective estrogen receptor modulators. Acting on oligodendrocytes, astrocytes and microglia, estrogens regulate remyelination, edema formation, extracellular glutamate levels and the inflammatory response after brain injury. In addition, estradiol induces the expression and release of growth factors by glial cells that promote neuronal survival. Therefore, glial cells are important players in the neuroprotective and reparative mechanisms of estrogenic compounds. © 2009 Elsevier B.V.
- Published
- 2010
22. Sex-specific regulation of inhibition and network activity by local aromatase in the mouse hippocampus
- Author
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Alicia Hernández-Vivanco, Nuria Cano-Adamuz, Alberto Sánchez-Aguilera, Alba González-Alonso, Alberto Rodríguez-Fernández, Íñigo Azcoitia, Liset Menendez de la Prida, and Pablo Méndez
- Subjects
Science - Abstract
Using a combination of molecular, genetic, functional and behavioural tools, this study describes the impact of brain synthesized estrogen in inhibitory neuronal function, network oscillations and hippocampal dependent memory.
- Published
- 2022
- Full Text
- View/download PDF
23. Selective Estrogen Receptor Modulators Decrease Reactive Astrogliosis in the Injured Brain: Effects of Aging and Prolonged Depletion of Ovarian Hormones
- Author
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Yolanda Diz-Chaves, Luis M. Garcia-Segura, Olga Pernía, Iñigo Azcoitia, Paloma Carrero, George E. Barreto, and María Santos-Galindo
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Selective Estrogen Receptor Modulators ,Aging ,medicine.medical_specialty ,medicine.drug_class ,Ovariectomy ,Endocrinology ,Internal medicine ,medicine ,Animals ,Vimentin ,Raloxifene ,Rats, Wistar ,Estradiol ,business.industry ,Brain ,Estrogens ,medicine.disease ,Rats ,Astrogliosis ,Tamoxifen ,Gliosis ,Selective estrogen receptor modulator ,Estrogen ,Astrocytes ,Brain Injuries ,Raloxifene Hydrochloride ,Ovariectomized rat ,Female ,medicine.symptom ,business ,medicine.drug ,Hormone - Abstract
After brain injury, astrocytes acquire a reactive phenotype characterized by a series of morphological and molecular modifications, including the expression of the cytoskeletal protein vimentin. Previous studies have shown that estradiol down-regulates reactive astrogliosis. In this study we assessed whether raloxifene and tamoxifen, two selective estrogen receptor modulators, have effects similar to estradiol in astrocytes. We also assessed whether aging and the timing of estrogenic therapy after ovariectomy influence the action of the estrogenic compounds. Four groups of animals were studied: 1) young rats, ovariectomized at 2 months of age; 2) middle-aged rats, ovariectomized at 8 months of age; 3) aged rats, ovariectomized at 18 months of age; and 4) aged rats, ovariectomized at 2 months and sham operated at 18 months of age. Fifteen days after ovariectomy or sham surgery, animals received a stab wound brain injury and the treatment with the estrogenic compounds. The number of vimentin-immunoreactive astrocytes after injury was significantly higher in the hippocampus of aged rats after a long-term ovariectomy compared with aged animals after a short-term ovariectomy and middle-aged rats. In addition, reactive astrocytes were more numerous in the two groups of aged animals than in young animals. Despite these differences, the estrogenic compounds reduced reactive astrogliosis in all animal groups. These findings indicate that estradiol, raloxifene, and tamoxifen are potential candidates for the control of astrogliosis in young and older individuals and after a prolonged depletion of ovarian hormones. Copyright © 2009 by The Endocrine Society.
- Published
- 2009
24. Testosterone decreases reactive astroglia and reactive microglia after brain injury in male rats: role of its metabolites, oestradiol and dihydrotestosterone
- Author
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Daniel Garcia-Ovejero, Sergio Veiga, Luis M. Garcia-Segura, George E. Barreto, and Iñigo Azcoitia
- Subjects
medicine.medical_specialty ,Microglia ,General Neuroscience ,Biology ,medicine.disease ,Neuroprotection ,Astrogliosis ,Androgen receptor ,Endocrinology ,medicine.anatomical_structure ,Gliosis ,Internal medicine ,Dihydrotestosterone ,medicine ,medicine.symptom ,Testosterone ,Hormone ,medicine.drug - Abstract
Previous studies have shown that the neuroprotective hormone, testosterone, administered immediately after neural injury, reduces reactive astrogliosis. In this study we have assessed the effect of early and late therapy with testosterone or its metabolites, oestradiol and dihydrotestosterone, on reactive astroglia and reactive microglia after a stab wound brain injury in orchidectomized Wistar rats. Animals received daily s.c. injections of testosterone, oestradiol or dihydrotestosterone on days 0-2 or on days 5-7 after injury. The number of vimentin immunoreactive astrocytes and the volume fraction of major histocompatibility complex-II (MHC-II) immunoreactive microglia were estimated in the hippocampus in the lateral border of the wound. Both early and delayed administration of testosterone or oestradiol, but not dihydrotestosterone, resulted in a significant decrease in the number of vimentin-immunoreactive astrocytes. The volume fraction of MHC-II immunoreactive microglia was significantly decreased in the animals that received testosterone or oestradiol in both early and delayed treatments and in animals that received early dihydrotestosterone administration. Thus, both early and delayed administration of testosterone reduces reactive astroglia and reactive microglia and these effects may be at least in part mediated by oestradiol, while dihydrotestosterone may mediate part of the early effects of testosterone on reactive microglia. In conclusion, testosterone controls reactive gliosis and its metabolites, oestradiol and dihydrotestosterone, may be involved in this hormonal effect. The regulation of gliosis may be part of the neuroprotective mechanism of testosterone.
- Published
- 2007
25. In search of neuroprotective therapies based on the mechanisms of estrogens
- Author
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Lydia L. DonCarlos, Luis M. Garcia-Segura, and Iñigo Azcoitia
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medicine.drug_class ,Endocrinology, Diabetes and Metabolism ,Estrogen receptor ,Estrogenic Compounds ,Biology ,Pharmacology ,Neuroprotection ,Estrogen ,Basic research ,Selective estrogen receptor modulator ,medicine ,biology.protein ,Aromatase ,hormones, hormone substitutes, and hormone antagonists ,Estrogen receptor beta - Abstract
Although estradiol is a neuroprotective factor, estrogen therapy in older women increases the risk of adverse cognitive outcomes and poses additional peripheral risks, requiring careful use of estrogenic compounds as treatments for neurodegenerative conditions or neural injury. Potential alternatives to estrogen therapy to promote neuroprotection might include treatment with molecules that are able to interact with estrogen receptors, with alternative mechanisms of action, or with molecules that induce local estradiol synthesis in the brain, or a combination of all. However, before considering the broad clinical applications, more basic research is required to clarify the mechamsms of action and potential risks of some of these estrogen-based treatments. © 2007 Future Drugs Ltd.
- Published
- 2007
26. The lipogenic regulator Sterol Regulatory Element Binding Factor-1c is required to maintain peripheral nerve structure and function
- Author
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Iñigo Azcoitia, Silvia Giatti, Luis M. Garcia-Segura, Enrique Saez, Gaia Cermenati, Maurizio Crestani, Maurizio D'Antonio, Donatella Caruso, Guido Cavaletti, Matteo Audano, Emma De Fabiani, Nico Mitro, Roberto Cosimo Melcangi, Mitro, N, Cermenati, G, Audano, M, Giatti, S, D'Antonio, M, De Fabiani, E, Crestani, M, Saez, E, Azcoitia, I, Cavaletti, G, Garcia-Segura, L, Melcangi, R, and Caruso, D
- Subjects
medicine.medical_specialty ,Peripheral neuropathy ,Regulator ,Peroxisome proliferator-activated receptor ,010501 environmental sciences ,Biology ,01 natural sciences ,03 medical and health sciences ,chemistry.chemical_compound ,Myelin ,metabolism, Peripheral neuropathy,Schwann cells ,Internal medicine ,Phosphatidylcholine ,medicine ,Schwann cells ,030304 developmental biology ,0105 earth and related environmental sciences ,Lecture Presentation ,chemistry.chemical_classification ,0303 health sciences ,Multidisciplinary ,Catabolism ,Fatty acid ,medicine.disease ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Nuclear receptor ,metabolism - Abstract
Myelin is a membrane characterized by high lipid content to facilitate impulse propagation. Changes in myelin fatty acid (FA) composition have been associated with peripheral neuropathy [1], but the specific role of peripheral nerve FA synthesis in myelin formation and function is poorly understood. We explored the extent to which lack of the key regulator of FA synthesis as Sterol Regulatory Element Binding Factor-1c (Srebf-1c) could result in the development of peripheral neuropathy. We found that Srebf-1c null mice display a neuropathic phenotype consisting in hypermyelinated small caliber fibers, the result of changes in myelin periodicity. Unexpectedly, transcriptomics and metabolomics revealed activation of peroxisome proliferator activated receptor α (Pparα) signaling in Srebf-1c null peripheral nerve as a result of increased levels of two distinct phosphatidylcholine-based Pparα ligands, PC-C16:0/C18:1 and PC-C18:0/C18:1 [2, 3]. Pparα is a nuclear receptor that directs uptake, utilization and catabolism of FAs [4]. As a consequence of abnormal local Pparα activation, Srebf-1c null peripheral nerve exhibit increased fatty acid utilization, a detrimental condition leading to peripheral neuropathy. Treatment with a Pparα antagonist rescues the neuropathy of Srebf-1c null mice. These findings reveal the importance of FA synthesis to sustain peripheral nerve structure and function.
- Published
- 2015
27. The neuroprotective actions of oestradiol and oestrogen receptors
- Author
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María Ángeles Arévalo, Luis M. Garcia-Segura, and Iñigo Azcoitia
- Subjects
Male ,endocrine system ,Cell type ,medicine.medical_specialty ,Molecular neuroscience ,Biology ,Neuroprotection ,receptors (ERs) ,Neurotrophic factors ,Internal medicine ,polycyclic compounds ,medicine ,Animals ,Humans ,Neuroprostanes ,skin and connective tissue diseases ,Receptor ,Brain Diseases ,Estradiol ,General Neuroscience ,Neurodegeneration ,Brain ,medicine.disease ,Hormones ,Endocrinology ,Receptors, Estrogen ,Female ,Neuroscience ,hormones, hormone substitutes, and hormone antagonists ,Signalling cascades ,Hormone - Abstract
Hormones regulate homeostasis by communicating through the bloodstream to the body's organs, including the brain. As homeostatic regulators of brain function, some hormones exert neuroprotective actions. This is the case for the ovarian hormone 17ß-oestradiol, which signals through oestrogen receptors (ERs) that are widely distributed in the male and female brain. Recent discoveries have shown that oestradiol is not only a reproductive hormone but also a brain-derived neuroprotective factor in males and females and that ERs coordinate multiple signalling mechanisms that protect the brain from neurodegenerative diseases, affective disorders and cognitive decline
- Published
- 2015
28. Aromatase expression in the human temporal cortex
- Author
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Alberto Muñoz, Luis M. Garcia-Segura, Josue G. Yague, Iñigo Azcoitia, P. de Monasterio-Schrader, and Javier DeFelipe
- Subjects
Adult ,Male ,Calcium-binding proteins ,Transcription, Genetic ,Pyramidal neurons ,Polymerase Chain Reaction ,Calbindin ,Exon ,Aromatase ,Interneurons ,medicine ,Humans ,Promoter Regions, Genetic ,Aged ,DNA Primers ,Temporal cortex ,Base Sequence ,Estradiol ,biology ,General Neuroscience ,Alternative splicing ,Temporal Lobe ,Cell biology ,medicine.anatomical_structure ,nervous system ,Cerebral cortex ,Astrocytes ,biology.protein ,RNA ,Autopsy ,Calretinin ,Neuroscience ,Parvalbumin - Abstract
13 pages, 8 figures, 2 tables.-- PMID: 16426763 [PubMed]., The expression of the human cyp19 gene, encoding P450 aromatase, the key enzyme for estrogen biosynthesis, involves alternative splicing of multiple forms of exon I regulated by different promoters. Aromatase expression has been detected in the human cerebral cortex, although the precise cellular distribution and promoter regulation are not fully characterized. We examined the variants of exon I of cyp19 by PCR analysis and the cellular distribution of the enzyme using immunohistochemistry in the human temporal cortex. We detected four different variants of exon I, suggesting a complex regulation of cyp19 in the cerebral cortex. In addition, the enzyme was localized mainly in a large subpopulation of pyramidal neurons and in a subpopulation of astrocytes. However, the majority of GABAergic interneurons identified by their expression of the calcium-binding proteins calbindin, calretinin and parvalbumin, did not display aromatase immunoreactivity. The broad range of potential modulators of the cyp19 gene in the cortex and the widespread expression of the protein in specific neuronal and glial subpopulations suggest that local estrogen formation may play an important role in human cortical function., This study has been carried out with financial support from Ministerio de Ciencia y Tecnología, Spain (SAF 2002–00652, SAF 2005–00272, BFI2003-02745 and BFI2003-01018).
- Published
- 2006
29. Reduced Progesterone Metabolites Protect Rat Hippocampal Neurones From Kainic Acid ExcitotoxicityIn Vivo
- Author
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Iratxe Ciriza, Iñigo Azcoitia, and Luis M. Garcia-Segura
- Subjects
medicine.medical_specialty ,Kainic acid ,Endocrinology, Diabetes and Metabolism ,Excitotoxicity ,Kainate receptor ,Pregnanolone ,Hippocampal formation ,Biology ,medicine.disease_cause ,Neuroprotection ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Endocrinology ,Internal medicine ,Excitatory Amino Acid Agonists ,medicine ,Animals ,Rats, Wistar ,Progesterone ,Neurons ,Kainic Acid ,Cell Death ,Endocrine and Autonomic Systems ,GABAA receptor ,Dentate gyrus ,Glutamate receptor ,Dihydrotestosterone ,Rats ,Neuroprotective Agents ,nervous system ,chemistry ,Dentate Gyrus ,Female - Abstract
The ovarian hormone progesterone is neuroprotective in some animal models of neurodegeneration. Progesterone actions in the brain may partly be mediated by the locally produced metabolites 5α-dihydroprogesterone and 3α,5α-tetrahydroprogesterone. The neuroprotective effects of these two metabolites of progesterone were assessed in this study. Ovariectomized Wistar rats were injected with kainic acid, to induce excitotoxic neuronal death in the hippocampus, and with different doses of 5α-dihydroprogesterone and 3α,5α-tetrahydroprogesterone. The number of surviving neurones in the hilus of the dentate gyrus of the hippocampus was assessed with the optical dlisector method. The administration of kainic acid resulted in a significant decrease in the number of hilar neurones and in the induction of vimentin expression in reactive astrocytes, a sign of neural damage. Low doses of 5α-dihydroprogesterone (0.25 and 0.5 mg/kg body weight, b.w.) prevented the loss of hilar neurones and the appearance of vimentin immunoreactivity in astrocytes. Higher doses (1-2 mg/kg b.w.) were not neuroprotective. By contrast, low doses of 3α,5α-tetrahydroprogesterone (0.25-1 mg/kg b.w.) were unable to protect the hilus from kainic acid while higher doses (2-4 mg/kg b.w.) were protective. The different optimal neuroprotective doses of 5α-dihydroprogesterone and 3α, 5α-tetrahydroprogesterone suggest that these two steroids may protect neurones using different mechanisms. The neuroprotective effects of 3α, 5α-tetrahydroprogesterone may be exerted by the inhibition of neuronal activity via the GABAA receptor. This latter possibility is supported by the observation that 3β,5α-tetrahydroprogesterone, an isomer of 3α,5α-tetrahydroprogesterone that does not bind to GABAA receptor, was not neuroprotective. In summary, our findings suggest that progesterone neuroprotective effects may be, at least in part, mediated by its reduced metabolites 5α-dihydroprogesterone and 3α,5α-tetrahydroprogesterone.
- Published
- 2004
30. Aromatase Expression by Reactive Astroglia Is Neuroprotective
- Author
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Iñigo Azcoitia, Amanda Sierra, Luis M. Garcia-Segura, and Sergio Veiga
- Subjects
medicine.medical_specialty ,Central nervous system ,Endogeny ,Neuroprotection ,Gene Expression Regulation, Enzymologic ,General Biochemistry, Genetics and Molecular Biology ,Aromatase ,History and Philosophy of Science ,Internal medicine ,medicine ,Animals ,Humans ,Testosterone ,Regulation of gene expression ,biology ,General Neuroscience ,Neurodegeneration ,medicine.disease ,Neuroprotective Agents ,Endocrinology ,medicine.anatomical_structure ,Fadrozole ,Astrocytes ,Brain Injuries ,biology.protein ,medicine.drug - Abstract
The enzyme aromatase catalyzes the conversion of testosterone and other C19 steroids to estradiol. Under normal circumstances, the expression of aromatase in the central nervous system of mammals is restricted to neurons. However, the expression of the enzyme is induced in astrocytes in vitro by stressful stimuli. Furthermore, different types of brain injury induce in vivo the expression of aromatase in reactive astrocytes. The expression of aromatase by reactive astrocytes is neuroprotective, because the pharmacological inhibition of the enzyme in the brain exacerbates neuronal death after different forms of mild neurodegenerative stimuli that do not significantly affect neuronal survival under control conditions. These findings indicate that the induction of aromatase in reactive astrocytes, and the consecutive increase in the local production of estradiol in the brain at injured sites, may be an endogenous neural response to reduce the extent of neurodegenerative damage.
- Published
- 2003
31. Neuroprotective and neurotoxic effects of estrogens
- Author
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Ofir Picazo Picazo, Luis M. Garcia-Segura, and Iñigo Azcoitia
- Subjects
medicine.medical_specialty ,Kainic acid ,Ovariectomy ,Neurotoxins ,Excitotoxicity ,Cell Count ,Biology ,medicine.disease_cause ,Neuroprotection ,chemistry.chemical_compound ,In vivo ,Internal medicine ,Excitatory Amino Acid Agonists ,medicine ,Animals ,Neurotoxin ,Rats, Wistar ,Molecular Biology ,Neurons ,Kainic Acid ,Estradiol ,General Neuroscience ,Neurotoxicity ,Estrogens ,medicine.disease ,2-Methoxyestradiol ,Rats ,Neuroprotective Agents ,Endocrinology ,nervous system ,chemistry ,Dentate Gyrus ,Toxicity ,Ovariectomized rat ,Female ,Neurology (clinical) ,Developmental Biology - Abstract
The ovarian hormone 17beta-estradiol (E2) is neuroprotective in animal models of neurodegenerative diseases. Some studies suggest that the neuroprotective effects of 17beta-estradiol are a consequence of its antioxidant activity that depend on the hydroxyl group in the C3 position of the A ring. As in other tissues, 17beta-estradiol is metabolized in the brain to 2-hydroxyestradiol (2OHE2) and 2-methoxyestradiol (2MEOHE2). These two molecules present the hydroxyl group in the A ring and have a higher antioxidant activity than 17beta-estradiol. To test the hypothesis that conversion to 2-hydroxyestradiol and 2-methoxyestradiol may mediate neuroprotective actions of 17beta-estradiol in vivo, we have assessed whether these molecules protect hilar hippocampal neurons from kainic acid toxicity. Ovariectomized Wistar rats received an i.p. injection of 1, 10 or 100 microg 17beta-estradiol, 2-hydroxyestradiol or 2-methoxyestradiol followed by an i.p. injection of kainic acid (7 mg/kg) or vehicle. Treatment with kainic acid resulted in a significant loss of hilar neurons. Only the highest dose tested of 17beta-estradiol (100 microg/rat) prevented kainic acid-induced neuronal loss. 2-Hydroxyestradiol and 2-methoxyestradiol did not protect hilar neurons from kainic acid, suggesting that the mechanism of neuroprotection by 17beta-estradiol in vivo is not mediated by its metabolism to catecholestrogens or methoxycatecholestrogens. Furthermore, 2-methoxyestradiol (100 microg/rat), by itself, resulted in a significant neuronal loss in the hilus that was detected 96 h after the treatment with the steroid. This finding suggests that endogenous metabolism of 17beta-estradiol to 2-methoxyestradiol may counterbalance the neuroprotective effects of the hormone.
- Published
- 2003
32. Progesterone and its derivatives dihydroprogesterone and tetrahydroprogesterone reduce myelin fiber morphological abnormalities and myelin fiber loss in the sciatic nerve of aged rats
- Author
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E. Leonelli, Roberto Cosimo Melcangi, Sergio Veiga, Valerio Magnaghi, Luis M. Garcia-Segura, and Iñigo Azcoitia
- Subjects
Male ,Aging ,medicine.medical_specialty ,medicine.drug_class ,Nerve fiber ,Biology ,Nerve Fibers, Myelinated ,Rats, Sprague-Dawley ,Myelin ,Internal medicine ,medicine ,Animals ,Testosterone ,Gonadal Steroid Hormones ,Progesterone ,General Neuroscience ,Dihydrotestosterone ,Androgen ,Androstane-3,17-diol ,Sciatic Nerve ,20-alpha-Dihydroprogesterone ,Rats ,medicine.anatomical_structure ,Endocrinology ,nervous system ,Axoplasm ,Dihydroprogesterone ,Nerve Degeneration ,Neurology (clinical) ,Sciatic nerve ,Geriatrics and Gerontology ,Developmental Biology ,medicine.drug - Abstract
Previous studies indicate that steroid hormones may be protective for Schwann cells and promote the expression of myelin proteins in the sciatic nerve of adult rats. In this study, we have evaluated the effect of progesterone (P), dihydroprogesterone (DHP), tetrahydroprogesterone (THP), testosterone (T), dihydrotestosterone (DHT) and 5α-androstan-3α, 17β-diol (3α-diol) on the morphological alterations of myelinated fibers in the sciatic nerve of 22-24-month-old male rats. The sciatic nerves of untreated old male rats, showed a general disorganization and a significant reduction in the density of myelinated fibers, compared to nerves from 3-month-old male rats. The effect of aging was particularly evident in myelinated fibers of small caliber (
- Published
- 2003
33. Neuroprotection by the steroids pregnenolone and dehydroepiandrosterone is mediated by the enzyme aromatase
- Author
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Sergio Veiga, Luis M. Garcia-Segura, and Iñigo Azcoitia
- Subjects
Male ,medicine.medical_specialty ,Kainic acid ,Neuroactive steroid ,medicine.drug_class ,Dehydroepiandrosterone ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Aromatase ,Internal medicine ,medicine ,Animals ,Rats, Wistar ,Testosterone ,Aromatase inhibitor ,biology ,Aromatase Inhibitors ,General Neuroscience ,Rats ,Neuroprotective Agents ,Fadrozole ,Endocrinology ,nervous system ,chemistry ,Pregnenolone ,Dentate Gyrus ,biology.protein ,Steroids ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug - Abstract
Pregnenolone and dehydroepiandrosterone (DHEA) are sex hormone precursors and neuroprotective steroids. Effects of pregnenolone and DHEA may be in part mediated by their conversion to testosterone and by the consecutive conversion of testosterone to estradiol by the enzyme aromatase. This enzyme is induced in reactive astrocytes after different forms of neurodegenerative lesions and the resultant local production of estradiol in the brain has been shown to be neuroprotective. The participation of aromatase in the neuroprotective effect of pregnenolone and DHEA has been assessed in this study. The protective effect of different doses (12.5, 25, 50, and 100 mg/kg) of pregnenolone or DHEA, against systemic kainic acid (7 mg/kg b.w.), was assessed on hippocampal hilar neurons in gonadectomized Wistar male rats. To determine whether the neuroprotective effect of pregnenolone and DHEA was dependent on their conversion to estradiol, the aromatase inhibitor fadrozole (4.16 mg/mL) was administered using subcutaneous osmotic minipumps. The number of Nissl-stained neurons in the hilus of the dentate gyrus of the hippocampal formation was estimated by the optical disector method. The administration of kainic acid resulted in a significant decrease in the number of hilar neurons compared to rats injected with vehicles. Pregnenolone and DHEA showed a dose-dependent protective effect of hilar neurons against kainic acid. The administration of the aromatase inhibitor fadrozole blocked the neuroprotective effect of pregnenolone and DHEA. These findings suggest that estradiol formation by aromatase mediates neuroprotective effects of pregnenolone and DHEA against excitotoxic-induced neuronal death in the hippocampus. © 2003 Wiley Periodicals, Inc.
- Published
- 2003
34. Endogenous Estrogen Formation Is Neuroprotective in Model of Cerebellar Ataxia
- Author
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Amanda Sierra, Luis M. Garcia-Segura, and Iñigo Azcoitia
- Subjects
Male ,medicine.medical_specialty ,Cerebellar Ataxia ,Cell Survival ,Pyridines ,medicine.drug_class ,Endocrinology, Diabetes and Metabolism ,Neurotoxins ,Cell Count ,Endogeny ,Olivary Nucleus ,Biology ,Neuroprotection ,chemistry.chemical_compound ,Aromatase ,Endocrinology ,Internal medicine ,medicine ,Animals ,RNA, Messenger ,Rats, Wistar ,Testosterone ,Aromatase inhibitor ,Estradiol ,Fadrozole ,Cerebellar ataxia ,Aromatase Inhibitors ,Reverse Transcriptase Polymerase Chain Reaction ,Estrogen Antagonists ,Immunohistochemistry ,Rats ,Neuroprotective Agents ,Castration ,chemistry ,Nerve Degeneration ,biology.protein ,medicine.symptom ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug - Abstract
The expression of aromatase, the enzyme that transforms testosterone into estradiol, was analyzed by reverse transcriptase polymerase chain reaction in the inferior olive of adult male rats. The expression of this messenger in the inferior olive suggests that this brain area may be able to synthesize estradiol. The neuroprotective role of estradiol in the inferior olive was then assessed in a model of cerebellar ataxia, achieved by the ip administration of 3-acetylpyridine (3-AP). In a first experiment, male Wistar rats were orchidectomized to diminish the plasmatic levels of testosterone, the direct precursor of estradiol. Inmediately after castration, animals were implanted with a silicone tube that was either empty or filled with estradiol. One week later, animals were injected with 3-AP. Estradiol treatment resulted in a significant reduction in neuronal death in the olive. In a second experiment, animals were treated with fadrozole, an aromatase inhibitor, to assess the role of endogenous estradiol formation in neuroprotection. The results show that the inhibition of aromatase activity, and therefore the decrease in endogenous estrogen formation, increases the death in inferior olive. In conclusion, this study indicates that the inferior olive is a steroidogenic tissue and that olivary neurons are protected by exogenous and endogenous estradiol.
- Published
- 2003
35. Lack of sterol regulatory element binding factor-1c imposes glial Fatty Acid utilization leading to peripheral neuropathy
- Author
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Cinzia Ferri, Samuele Scurati, Enrique Saez, Luis M. Garcia-Segura, Donatella Caruso, Emma De Fabiani, Roberto Cosimo Melcangi, Iñigo Azcoitia, Emanuela Pettinato, Matteo Audano, Silvia Giatti, Maurizio D'Antonio, Nico Mitro, Carla Porretta-Serapiglia, Valentina Alda Carozzi, Maurizio Crestani, Guido Cavaletti, Gaia Cermenati, Harvard University, Fondazione Cariplo, Ministero della Salute, Cermenati, G, Audano, M, Giatti, S, Carozzi, V, Porretta Serapiglia, C, Pettinato, E, Ferri, C, D'Antonio, M, De Fabiani, E, Crestani, M, Scurati, S, Saez, E, Azcoitia, I, Cavaletti, G, Garcia Segura, L, Melcangi, R, Caruso, D, and Mitro, N
- Subjects
Physiology ,Blotting, Western ,Endogeny ,Biology ,Real-Time Polymerase Chain Reaction ,Myelin ,Mice ,BIO/16 - ANATOMIA UMANA ,Microscopy, Electron, Transmission ,medicine ,Animals ,Metabolomics ,Glycolysis ,PPAR alpha ,Receptor ,Molecular Biology ,Oxazoles ,Chromatography, High Pressure Liquid ,Myelin Sheath ,chemistry.chemical_classification ,Mice, Knockout ,Analysis of Variance ,Catabolism ,Fatty Acids ,Fatty acid ,Peripheral Nervous System Diseases ,Cell Biology ,Peroxisome ,medicine.disease ,Microarray Analysis ,Cell biology ,medicine.anatomical_structure ,Peripheral neuropathy ,Biochemistry ,chemistry ,Tyrosine ,Sterol Regulatory Element Binding Protein 1 ,Neuroglia - Abstract
Myelin is a membrane characterized by high lipid content to facilitate impulse propagation. Changes in myelin fatty acid (FA) composition have been associated with peripheral neuropathy, but the specific role of peripheral nerve FA synthesis in myelin formation and function is poorly understood. We have found that mice lacking sterol regulatory element-binding factor-1c (Srebf1c) have blunted peripheral nerve FA synthesis that results in development of peripheral neuropathy. Srebf1c-null mice develop Remak bundle alterations and hypermyelination of small-caliber fibers that impair nerve function. Peripheral nerves lacking Srebf1c show decreased FA synthesis and glycolytic flux, but increased FA catabolism and mitochondrial function. These metabolic alterations are the result of local accumulation of two endogenous peroxisome proliferator-activated receptor-α (Pparα) ligands, 1-palmitoyl-2-oleyl-sn-glycerol-3-phosphatidylcholine and 1-stearoyl-2-oleyl-sn-glycerol-3-phosphatidylcholine. Treatment with a Pparα antagonist rescues the neuropathy of Srebf1c-null mice. These findings reveal the importance of peripheral nerve FA synthesis to sustain myelin structure and function., These studies were supported by funding from Giovanni Armenise-Harvard Foundation Career Development Grant (N.M.), Fondazione CARIPLO 2014-0991 (N.M.), Fondazione CARIPLO 2012-0547 (R.C.M.), Italian Ministry of Health GR-2011-02346791 (M.D. and N.M.) and Research Center for the Characterization and Safe Use of Natural Compounds—“Giovanni Galli” directed by D.C. S.S. is an employee and founder of DASP s.r.l.; all other authors declare no competing financial interests.
- Published
- 2014
36. Interactions of estrogens and insulin-like growth factor-I in the brain: implications for neuroprotection
- Author
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Luis M. Garcia-Segura, Gloria Patricia Cardona-Gómez, Iñigo Azcoitia, Pablo Mendez, and Lydia L. DonCarlos
- Subjects
medicine.drug_class ,medicine.medical_treatment ,Estrogen receptor ,Biology ,Neuroprotection ,Receptor, IGF Type 1 ,medicine ,Animals ,Humans ,Insulin-Like Growth Factor I ,Protein kinase B ,Neuronal Plasticity ,General Neuroscience ,Growth factor ,Brain ,Cell Differentiation ,Estrogens ,Rats ,Neuroprotective Agents ,Receptors, Estrogen ,Cytoprotection ,Estrogen ,Synaptic plasticity ,biology.protein ,Female ,Neurology (clinical) ,Signal transduction ,Neuroscience ,Signal Transduction ,Neurotrophin - Abstract
Data from epidemiological studies suggest that the decline in estrogen following menopause could increase the risk of neurodegenerative diseases. Furthermore, experimental studies on different animal models have shown that estrogen is neuroprotective. The mechanisms involved in the neuroprotective effects of estrogen are still unclear. Anti-oxidant effects, activation of different membrane-associated intracellular signaling pathways, and activation of classical nuclear estrogen receptors (ERs) could contribute to neuroprotection. Interactions with neurotrophins and other growth factors may also be important for the neuroprotective effects of estradiol. In this review we focus on the interaction between insulin-like growth factor-I (IGF-I) and estrogen signaling in the brain and on the implications of this interaction for neuroprotection. During the development of the nervous system, IGF-I promotes the differentiation and survival of specific neuronal populations. In the adult brain, IGF-I is a neuromodulator, regulates synaptic plasticity, is involved in the response of neural tissue to injury and protects neurons against different neurodegenerative stimuli. As an endocrine signal, IGF-I represents a link between the growth and reproductive axes and the interaction between estradiol and IGF-I is of particular physiological relevance for the regulation of growth, sexual maturation and adult neuroendocrine function. There are several potential points of convergence between estradiol and IGF-I receptor (IGF-IR) signaling in the brain. Estrogen activates the mitogen-activated protein kinase (MAPK) pathway and has a synergistic effect with IGF-I on the activation of Akt, a kinase downstream of phosphoinositol-3 kinase. In addition, IGF-IR is necessary for the estradiol induced expression of the anti-apoptotic molecule Bcl-2 in hypothalamic neurons. The interaction of ERs and IGF-IR in the brain may depend on interactions between neural cells expressing ERs with neural cells expressing IGF-IR, or on direct interactions of the signaling pathways of alpha and beta ERs and IGF-IR in the same cell, since most neurons expressing IGF-IR also express at least one of the ER subtypes. In addition, studies on adult ovariectomized rats given intracerebroventricular (i.c.v.) infusions with antagonists for ERs or IGF-IR or with IGF-I have shown that there is a cross-regulation of the expression of ERs and IGF-IR in the brain. The interaction of estradiol and IGF-I and their receptors may be involved in different neural events. In the developing brain, ERs and IGF-IR are interdependent in the promotion of neuronal differentiation. In the adult, ERs and IGF-IR interact in the induction of synaptic plasticity. Furthermore, both in vitro and in vivo studies have shown that there is an interaction between ERs and IGF-IR in the promotion of neuronal survival and in the response of neural tissue to injury, suggesting that a parallel activation or co-activation of ERs and IGF-IR mediates neuroprotection.
- Published
- 2001
37. Role of astrocytes in the neuroprotective actions of 17β-estradiol and selective estrogen receptor modulators
- Author
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Iñigo Azcoitia, Luis M. Garcia-Segura, Estefania Acaz-Fonseca, Rebeca Sánchez-González, and María Ángeles Arévalo
- Subjects
Selective Estrogen Receptor Modulators ,medicine.medical_specialty ,Neuroglobin ,Estrogen receptor ,Biochemistry ,Neuroprotection ,Endocrinology ,Neuroinflammation ,Neurotrophic factors ,Internal medicine ,medicine ,Animals ,Humans ,Molecular Biology ,Neurons ,Glutamate transporters ,Estradiol ,business.industry ,Glutamate receptor ,Brain ,Estrogens ,Neuroprotective Agents ,Gliosis ,Receptors, Estrogen ,Selective estrogen receptor modulator ,Astrocytes ,Brain edema ,Reactive astrocytes ,medicine.symptom ,business ,GPER ,hormones, hormone substitutes, and hormone antagonists - Abstract
Neuroprotective actions of 17β-estradiol (estradiol) are in part mediated by direct actions on neurons. Astrocytes, which play an essential role in the maintenance of the homeostasis of neural tissue, express estrogen receptors and are also involved in the neuroprotective actions of estradiol in the brain. Estradiol controls gliosis and regulates neuroinflammation, edema and glutamate transport acting on astrocytes. In addition, the hormone regulates the release of neurotrophic factors and other neuroprotective molecules by astrocytes. In addition, reactive astrocytes are a local source of neuroprotective estradiol for the injured brain. Since estradiol therapy is not free from peripheral risks, alternatives for the hormone have been explored. Some selective estrogen receptor modulators (SERMs), which are already in use in clinical practice for the treatment of breast cancer, osteoporosis or menopausal symptoms, exert similar actions to estradiol on astrocytes. Therefore, SERMs represent therapeutic alternatives to estradiol for the activation of astroglia-mediated neuroprotective mechanisms. © 2014 Elsevier Ireland Ltd.
- Published
- 2013
38. [Untitled]
- Author
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Julie A. Chowen, Luis M. Garcia-Segura, Gloria Patricia Cardona-Gómez, and Iñigo Azcoitia
- Subjects
Histology ,medicine.drug_class ,General Neuroscience ,medicine.medical_treatment ,Estrogen receptor ,Cell Biology ,Pharmacology ,Biology ,Neuroprotection ,Insulin-like growth factor ,Growth factor receptor ,Estrogen ,medicine ,Growth factor receptor inhibitor ,Anatomy ,Receptor ,hormones, hormone substitutes, and hormone antagonists ,Estrogen receptor beta - Abstract
Several in vitro and in vivo studies have shown that estrogen has neuroprotective properties. The neuroprotective effects of estrogen are probably exerted through several mechanisms. It is established that estrogen can provide neuroprotection by actions that are independent of estrogen receptor activation. In addition, in several experimental models, activation of estrogen receptors appears to be indispensable for neuroprotection. This review focuses on neuroprotection mediated by estrogen receptors. The interaction of estrogen with growth factor receptor signaling to induce neuroprotection is discussed. Evidence is presented that estrogen receptors and insulin-like growth factor-I receptors interact in the promotion of neuronal survival and neuroprotection.
- Published
- 2000
39. Localization of estrogen receptor ?-immunoreactivity in astrocytes of the adult rat brain
- Author
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Amanda Sierra, Luis M. Garcia-Segura, and Iñigo Azcoitia
- Subjects
medicine.medical_specialty ,Glial fibrillary acidic protein ,medicine.drug_class ,Estrogen receptor ,Biology ,Cellular and Molecular Neuroscience ,Estrogen-related receptor alpha ,Endocrinology ,medicine.anatomical_structure ,nervous system ,Neurology ,Estrogen ,Internal medicine ,medicine ,biology.protein ,Neuroglia ,Estrogen receptor alpha ,hormones, hormone substitutes, and hormone antagonists ,Estrogen receptor beta ,Astrocyte - Abstract
Estrogen receptors are direct regulators of transcription that function by binding to specific DNA sequences in promoters of target genes. The two cloned forms of estrogen receptors, α and β, are expressed in the central nervous system by different neuronal populations. Astrocytes in vitro are also reported to express estrogen receptor α; however, this expression has not been confirmed in the rat brain in vivo. The apparent absence of estrogen receptors in glia in vivo contrasts with the well-known effects of this hormone on astrocytes of different brain areas, including the hippocampal formation. In this study, the expression of estrogen receptors in the hippocampal formation of adult male rats has been assessed by confocal microscopy. Estrogen receptor α-immunoreactivity was localized in neuronal nuclei in the pyramidal cell layer of CA1-CA3 fields. Estrogen receptor β-immunoreactivity was observed in the perikarya, apical dendrites, and cell nuclei of pyramidal neurons in CA1 and CA2. Furthermore, estrogen receptor β-immunoreactive glia were observed in CA1, CA2, CA3, and in the hilus of the dentate gyrus of male and female rats. Estrogen receptor β-immunoreactivity was localized in glial processes and perikarya and, in some cases, in glial cell nuclei. Double immunocytochemical labeling of estrogen receptor β and the specific astroglial marker glial fibrillary acidic protein revealed that estrogen receptor β-immunoreactive glial cells were astrocytes. Estrogen receptor α was not co-localized with glial fibrillary acidic protein. The presence of estrogen receptor β in astrocytes of adult male and female rats demonstrates a possible mechanism by which estrogen can directly modulate gene expression in these cells. GLIA 26:260–267, 1999. © 1999 Wiley-Liss, Inc.
- Published
- 1999
40. Aromatase expression by astrocytes after brain injury: implications for local estrogen formation in brain repair
- Author
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Luis M. Garcia-Segura, José-Rodrigo Rodríguez, R.E. Hutchison, Andrew Wozniak, John B. Hutchison, and Iñigo Azcoitia
- Subjects
Male ,medicine.medical_specialty ,medicine.drug_class ,Central nervous system ,Wounds, Penetrating ,Neuroprotection ,Mice ,Aromatase ,Internal medicine ,medicine ,Animals ,Rats, Wistar ,Brain Diseases ,Mice, Inbred BALB C ,Wound Healing ,Kainic Acid ,biology ,Glial fibrillary acidic protein ,General Neuroscience ,Brain ,Estrogens ,Rats ,medicine.anatomical_structure ,Endocrinology ,nervous system ,Gliosis ,Estrogen ,Astrocytes ,Brain Injuries ,biology.protein ,Neuroglia ,Female ,medicine.symptom ,Astrocyte - Abstract
Recent evidence indicates that 17β-estradiol may have neuroprotective and neuroregenerative properties. Estradiol is formed locally in neural tissue from precursor androgens. The expression of aromatase, the enzyme that catalyses the conversion of androgens to estrogens, is restricted, under normal circumstances, to specific neuronal populations. These neurons are located in brain areas in which local estrogen formation may be involved in neuroendocrine control and in the modulation of reproductive or sex dimorphic behaviours. In this study the distribution of aromatase immunoreactivity has been assessed in the brain of mice and rats after a neurotoxic lesion induced by the systemic administration of kainic acid. This treatment resulted in the induction of aromatase expression by reactive glia in the hippocampus and in other brain areas that are affected by kainic acid. The reactive glia were identified as astrocytes by co-localization of aromatase with glial fibrillary acidic protein and by ultrastructural analysis. No immunoreactive astrocytes were detected in control animals. The same result, the de novo induction of aromatase expression in reactive astrocytes on the hippocampus, was observed after a penetrating brain injury. Furthermore, using a 3H2O assay, aromatase activity was found to increase significantly in the injured hippocampus. These findings indicate that although astrocytes do not normally express aromatase, the enzyme expression is induced in these glial cells by different forms of brain injury. The results suggest a role for local astroglial estrogen formation in brain repair.
- Published
- 1999
41. [Untitled]
- Author
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Amanda Sierra, Luis M. Garcia-Segura, Iñigo Azcoitia, and Carmen Fernandez-Galaz
- Subjects
Estrous cycle ,endocrine system ,Kainic acid ,medicine.medical_specialty ,Histology ,General Neuroscience ,Excitotoxicity ,Cell Biology ,Biology ,Hippocampal formation ,medicine.disease_cause ,Neuroprotection ,chemistry.chemical_compound ,Endocrinology ,nervous system ,chemistry ,Internal medicine ,Ovariectomized rat ,medicine ,Neurotoxin ,Anatomy ,Hormone - Abstract
The role of endogenous gonadal secretions in neuroprotection has been assessed in a model of hippocampal degeneration induced by the systemic administration of kainic acid to adult male and female rats. A low dose of kainic acid (7 mg/Kg b.w.) induced a significant loss of hilar dentate neurons in castrated males and did not affect hilar neurons in intact males. The effect of kainic acid on hilar neurons in female rats was different depending on the day of the estrous cycle in which the neurotoxin was administered; while no significant effect of kainic acid was observed when it was injected in the morning of estrus, there was a significant loss of hilar neurons when it was injected in the morning of proestrus as well as when it was injected into ovariectomized rats. Estradiol or estradiol plus progesterone prevented hilar neuronal loss when injected simultaneously with kainic acid in ovariectomized rat. Progesterone by itself did not prevent neuronal loss induced by kainic acid and estogen was only effective when it was injected either 24 h before or simultaneously with kainic acid and not when it was injected 24 h after the administration of the toxin. These findings indicate that endogenous gonadal hormones protect hippocampal hilar neurons from excitotoxic degeneration. In addition, the timing of exposure to ovarian hormones and the natural fluctuation of ovarian hormones during the estrous cycle may influence the vulnerability of hilar neurons to excitotoxicity. These findings are relevant to possible modifications in neurodegenerative risk in humans as endogenous levels of gonadal hormones change during the menstrual cycle and during aging.
- Published
- 1999
42. Viral Superantigen-Induced Negative Selection of TCR Transgenic CD4+ CD8+ Thymocytes Depends on Activation, but not Proliferation
- Author
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Isabel Ferrero, H. Robson MacDonald, Fabienne Anjuère, Carlos Ardavín, Toufic Renno, and Iñigo Azcoitia
- Subjects
Immunology ,T-cell receptor ,Cell Biology ,Hematology ,T lymphocyte ,Biology ,Biochemistry ,Clonal deletion ,Cell biology ,Thymocyte ,Negative selection ,Superantigen ,Cell activation ,CD8 - Abstract
T-cell negative selection, a process by which intrathymic immunological tolerance is induced, involves the apoptosis-mediated clonal deletion of potentially autoreactive T cells. Although different experimental approaches suggest that this process is triggered as the result of activation-mediated cell death, the signal transduction pathways underlying this process is not fully understood. In the present report we have used an in vitro system to analyze the cell activation and proliferation requirements for the deletion of viral superantigen (SAg)-reactive Vβ8.1 T-cell receptor (TCR) transgenic (TG) thymocytes. Our results indicate that in vitro negative selection of viral SAg-reactive CD4+ CD8+thymocytes is dependent on thymocyte activation but does not require the proliferation of the negatively signaled thymocytes.
- Published
- 1998
43. Viral Superantigen-Induced Negative Selection of TCR Transgenic CD4+ CD8+ Thymocytes Depends on Activation, but not Proliferation
- Author
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Ferrero I, Anjuère F, Iñigo Azcoitia, Renno T, Hr, Macdonald, and Ardavín C
- Subjects
Mice, Inbred BALB C ,Superantigens ,CD8 Antigens ,Receptors, Antigen, T-Cell, alpha-beta ,T-Lymphocytes ,Immunology ,Mice, Transgenic ,Cell Biology ,Hematology ,Biochemistry ,Mice ,Mammary Tumor Virus, Mouse ,CD4 Antigens ,Animals ,Antigens, Viral ,Cell Division - Abstract
T-cell negative selection, a process by which intrathymic immunological tolerance is induced, involves the apoptosis-mediated clonal deletion of potentially autoreactive T cells. Although different experimental approaches suggest that this process is triggered as the result of activation-mediated cell death, the signal transduction pathways underlying this process is not fully understood. In the present report we have used an in vitro system to analyze the cell activation and proliferation requirements for the deletion of viral superantigen (SAg)-reactive Vβ8.1 T-cell receptor (TCR) transgenic (TG) thymocytes. Our results indicate that in vitro negative selection of viral SAg-reactive CD4+ CD8+thymocytes is dependent on thymocyte activation but does not require the proliferation of the negatively signaled thymocytes.
- Published
- 1998
44. CX3CL1 promotes breast cancer via transactivation of the EGF pathway
- Author
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Miguel Quintela-Fandino, Manuel Tardaguila, Emilia Mira, Miguel Ángel García-Cabezas, Sergio A. Lira, Santos Mañes, Iñigo Azcoitia, and Anna M. Feijoo
- Subjects
Transcriptional Activation ,Cancer Research ,Epithelial-Mesenchymal Transition ,Carcinogenesis ,Receptor, ErbB-2 ,Breast Neoplasms ,Mammary Neoplasms, Animal ,Mice, Transgenic ,Biology ,medicine.disease_cause ,Article ,ErbB Receptors ,Transactivation ,Mice ,Mammary Glands, Animal ,ErbB ,Cell Line, Tumor ,medicine ,Animals ,Humans ,CX3CL1 ,skin and connective tissue diseases ,Cell Proliferation ,Mammary tumor ,Tumor microenvironment ,Epidermal Growth Factor ,Chemokine CX3CL1 ,Mammary Neoplasms, Experimental ,medicine.disease ,Primary tumor ,Mice, Inbred C57BL ,Oncology ,Lymphatic Metastasis ,Cancer research ,MCF-7 Cells ,Female ,Receptors, Chemokine ,Lymph Nodes ,Signal Transduction - Abstract
Chemokines are relevant molecules in shaping the tumor microenvironment, although their contributions to tumorigenesis are not fully understood. We studied the influence of the chemokine CX3CL1/fractalkine in de novo breast cancer formation using HER2/neu transgenic mice. CX3CL1 expression was downmodulated in HER2/neu tumors, yet, paradoxically, adenovirus-mediated CX3CL1 expression in the tumor milieu enhanced mammary tumor numbers in a dose-dependent manner. Increased tumor multiplicity was not a consequence of CX3CL1-induced metastatic dissemination of the primary tumor, although CX3CL1 induced epithelial-to-mesenchymal transition in breast cancer cells in vitro. Instead, CX3CL1 triggered cell proliferation by induction of ErbB receptors through the proteolytic shedding of an ErbB ligand. This effect was important insofar as mammary tumorigenesis was delayed and tumor multiplicity was reduced by genetic deletion of CX3CL1 in HER2/neu mice, but not in polyoma middle T-antigen oncomice. Our findings support the conclusion that CX3CL1 acts as a positive modifier of breast cancer in concert with ErbB receptors. Cancer Res; 73(14); 4461–73. ©2013 AACR.
- Published
- 2013
45. Gonadal hormones and the control of reactive gliosis
- Author
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Luis M. Garcia-Segura, Iñigo Azcoitia, María Ángeles Arévalo, Estefania Acaz-Fonseca, and María Santos-Galindo
- Subjects
Bioquímica ,Central nervous system ,Neurociencias ,Biology ,Parkin ,Proinflammatory cytokine ,Behavioral Neuroscience ,Endocrinology ,medicine ,Animals ,Humans ,Gliosis ,Neuroinflammation ,Microglia ,Endocrine and Autonomic Systems ,Neurodegeneration ,medicine.disease ,medicine.anatomical_structure ,Neuroprotective Agents ,Brain Injuries ,medicine.symptom ,Neuroscience ,Gonadal Hormones ,Hormone ,Signal Transduction - Abstract
This article is part of a Special Issue >Hormones & Neurotrauma>.Astrocytes and microglia respond to central nervous system (CNS) injury with changes in morphology, proliferation, migration and expression of inflammatory regulators. This phenomenon is known as reactive gliosis. Activation of astrocytes and microglia after acute neural insults, such as stroke or traumatic CNS injury, is considered to be an adaptive response that contributes to minimize neuronal damage. However, reactive gliosis may amplify CNS damage under chronic neurodegenerative conditions. Progesterone, estradiol and testosterone have been shown to control reactive gliosis in different models of CNS injury, modifying the number of reactive astrocytes and reactive microglia and the expression of anti-inflammatory and proinflammatory mediators. The actions of gonadal hormones on reactive gliosis involve different mechanisms, including the modulation of the activity of steroid receptors, such as estrogen receptors α and β, the regulation of nuclear factor-κB mediated transcription of inflammatory molecules and the recruitment of the transcriptional corepressor c-terminal binding protein to proinflammatory promoters. In addition, the Parkinson's disease related gene parkin and the endocannabinoid system also participate in the regulation of reactive gliosis by estradiol. The control exerted by gonadal hormones on reactive gliosis may affect the response of neural tissue to trauma and neurodegeneration and may contribute to sex differences in the manifestation of neurodegenerative diseases. However, the precise functional consequences of the regulation of reactive gliosis by gonadal hormones under acute and chronic neurodegenerative conditions are still not fully clarified. © 2012 Elsevier Inc.
- Published
- 2013
46. Connective integration of hippocampal grafts in excitotoxic hippocampal lesions in adult rats: an anterograde axonal tracing study
- Author
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Susana Aznar, Iñigo Azcoitia, Jens Zimmer, Niels Tønder, and Jens Christian Sørensen
- Subjects
Biotinylated dextran amine ,Pathology ,medicine.medical_specialty ,Hippocampus ,Biology ,Commissure ,Hippocampal formation ,Lesion ,chemistry.chemical_compound ,surgical procedures, operative ,medicine.anatomical_structure ,nervous system ,Developmental Neuroscience ,Neurology ,chemistry ,Biocytin ,medicine ,Fascia dentata ,Neurology (clinical) ,medicine.symptom ,Ibotenic acid - Abstract
Exchange of nerve connections between developing neural grafts and adult recipient brains is enhanced for grafts placed in excitotoxic lesions, which spare recipient brain afferent axons in otherwise neuron-depleted lesion areas. In previous studies of hippocampal grafts placed in such lesions, we have used anterograde axonal degeneration, histochemical Timm staining and acetylcholinesterase to demonstrate host-graft interconnectivity. In this study, we have now used three anterograde axonal tracers, Phaseoulus vulgaris-leukoaglutinin (PHA-L), biocytin and biotinylated dextran amine (BDA), which allow individual fibers to be traced. Adult male rats with 1-week-old axon-sparing ibotenic acid lesions of the dorsal CA3 region or fascia dentata were grafted into the respective lesions with suspensions of fetal (El8-19) CA3 cells or a block of neonatal fascia dentata tissue. One to twelve months later, recipients were injected with Phaseoulus vulgaris-leukoaglutinin or biocytin in the hippocampus contralateral to the graft to trace the possible ingrowth and distribution within the transplants of host commissural axons, or into the transplants with biotinylated dextran amine in order to trace outgrowing graft fibers. In rats with succesfull host Phaseoulus vulgaris-leukoaglutinin or biocytin injections, the CA3 and fascia dentata transplants were innervated by labelled host commissural fibers. In the dentate transplants, most commissural fibers projected as normally to the inner part of the molecular layer, with fewer aberrant fibers extending more superficially into the molecular layer. Following injections into the fascia dentata and CA3 grafts of biotinylated dextran amine, labelled graft fibers were traced into the ipsilateral host dentate hilus, CA3 and CA1. From some CA3 containing grafts, a few labelled fibers were also observed passing through the host fimbria-fornix to the lateral septum on the grafted side. A few fibers were projected as far as to the most septal levels of the contralateral CA1.
- Published
- 1996
47. Brain Aromatase and Neuroprotection in Mammals
- Author
-
Iñigo Azcoitia, María Ángeles Arévalo, and Luis M. Garcia-Segura
- Subjects
biology ,biology.protein ,Aromatase ,Neuroprotection ,Neuroscience - Published
- 2012
48. List of Contributors
- Author
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Greti Aguilera, Deanna M. Arble, Iñigo Azcoitia, Sarah L. Berga, Wah Chin Boon, Pierre M.G. Bouloux, Cyril Y. Bowers, Ellen R. Busby, Rebecca Campbell, Frances A. Champagne, Evangelia Charmandari, Alon Chen, George P. Chrousos, Iain J. Clarke, Georges Copinschi, Virginia L. Crowder, James P. Curley, Wouter W. de Herder, E. Ronald de Kloet, Ines Donangelo, Alison J. Douglas, Dana Erickson, Richard A. Feelders, George Fink, Luis M. Garcia-Segura, Thang S. Han, Leo J. Hofland, Ali Iranmanesh, Marian Joëls, Ilia N. Karatsoreos, Henk Karst, Tomoshige Kino, Joseph R. Kurian, Dik J. Kwekkeboom, Steven W. Lamberts, Lawrence C. Layman, Gareth Leng, Jon E. Levine, Malcolm J. Low, Mike Ludwig, Margaret M. McCarthy, Bruce S. McEwen, Marilyn Y. McGinnis, Shlomo Melmed, Robert P. Millar, Ali Mohamadi, Randy J. Nelson, Claire L. Newton, Donald W. Pfaff, Vincent Prevot, Graeme J. Roch, Ferdinand Roelfsema, Antonia K. Roseweir, David R. Rubinow, Katya B. Rubinow, Randall R. Sakai, Roberto Salvatori, Willis K. Samson, Peter J. Schmidt, Karen A. Scott, Barbara B. Sherwin, Nancy M. Sherwood, Aniket R. Sidhaye, Evan R. Simpson, Jeremy T. Smith, Yolanda R. Smith, Edward M. Stricker, Yehezkel Sztainberg, Kellie L.K. Tamashiro, Ei Terasawa, Brian C. Trainor, Fred W. Turek, Eve Van Cauter, Johannes D. Veldhuis, Joseph G. Verbalis, Martha H. Vitaterna, Alan G. Watts, Fredric E. Wondisford, Susan Wray, Gina L.C. Yosten, and R. Thomas Zoeller
- Published
- 2012
49. Hormones and the Aging Brain
- Author
-
Luis M. Garcia-Segura and Iñigo Azcoitia
- Subjects
Nervous system ,medicine.medical_specialty ,Hippocampus ,Amygdala ,Temporal lobe ,medicine.anatomical_structure ,Endocrinology ,Cerebral cortex ,Internal medicine ,medicine ,Aging brain ,sense organs ,Prefrontal cortex ,Psychology ,Neuroscience ,Hormone - Abstract
Publisher Summary This chapter explains how the immune, endocrine and nervous systems undergo a remarkable adjustment with aging. Changes in immune function, endocrine secretions or endocrine signaling with aging affect the activity of different brain regions involved in cognition and emotions, such as the hippocampus, the amygdala and the frontal cortex. The aging process induces important biochemical and morphological changes in peripheral nerves, and the prevalence of peripheral neuropathy in humans rises from about 2.4% to 8% with aging. Aging is accompanied by remarkable structural remodeling and volume changes of different brain regions. Cognitive processes that rely on the medial temporal lobe and prefrontal cortex, such as learning, memory and executive function, show considerable aging-related impairments. The involution of the thymus with aging is the cause of alterations in cellular and humoral immunity, which affects all tissues and organs, including the nervous system. Aging-associated changes in hormonal levels may involve differences in secretion, metabolism, or both. Stress hormones affect other brain regions, such as the cerebral cortex and the amygdala.
- Published
- 2012
50. Estradiol Meets Notch Signaling in Developing Neurons
- Author
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Iñigo Azcoitia, Estefania Acaz-Fonseca, Isabel Ruiz-Palmero, Julia Simon-Areces, Luis M. Garcia-Segura, and María Ángeles Arévalo
- Subjects
medicine.medical_specialty ,Neurite ,Endocrinology, Diabetes and Metabolism ,Mini Review ,Notch signaling pathway ,G protein-coupled estrogen receptor ,hairy and enhancer of split ,Biology ,lcsh:Diseases of the endocrine glands. Clinical endocrinology ,Endocrinology ,Downregulation and upregulation ,Neurogenein 3 ,Internal medicine ,medicine ,dendritogenesis ,Gliogenesis ,neurogenin 3 ,lcsh:RC648-665 ,Neurogenesis ,G protein-coupled receptor 30 ,estrogen receptors ,Cell biology ,Notch proteins ,Hes3 signaling axis ,GPER ,hormones, hormone substitutes, and hormone antagonists - Abstract
The transmembrane receptor Notch, a master developmental regulator, controls gliogene- sis, neurogenesis, and neurite development in the nervous system. Estradiol, acting as a hormonal signal or as a neurosteroid, also regulates these developmental processes. Here we review recent evidence indicating that estradiol and Notch signaling interact in devel- oping hippocampal neurons by a mechanism involving the putative membrane receptor G protein-coupled receptor 30.This interaction is relevant for the control of neuronal differen- tiation, since the downregulation of Notch signaling by estradiol results in the upregulation of neurogenin 3, which in turn promotes dendritogenesis. © 2011 Arevalo, Ruiz-Palmero, Simon-Areces, Acaz-Fonseca, Azcoitia and Garcia-Segura.
- Published
- 2011
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