Maria Jose Bellini - Academia.edu (original) (raw)

Papers by Maria Jose Bellini

Hormone Molecular Biology and Clinical Investigation, 2010

Estrogen neuroprotection has been shown in pathological conditions damaging the hippocampus, such... more Estrogen neuroprotection has been shown in pathological conditions damaging the hippocampus, such as trauma, aging, neurodegeneration, excitotoxicity, oxidative stress, hypoglycemia, amyloid-b peptide exposure and ischemia. Hypertensive encephalopathy also targets the hippocampus; therefore, hypertension seems an appropriate circumstance to evaluate steroid neuroprotection. Two experimental models of hypertension, spontaneously hypertensive rats (SHR) and deoxycorticosterone (DOCA)-salt hypertensive rats, develop hippocampal abnormalities, which include decreased neurogenesis in the dentate gyrus, astrogliosis, low expression of brain-derived neurotrophic factor (BDNF) and decreased number of neurons in the hilar region, with respect of their normotensive strains Wistar Kyoto (WKY) and Sprague-Dawley rats. After estradiol was given for 2 weeks to SHR and DOCA-treated rats, both hypertensive models normalized their faulty hippocampal parameters. Thus, estradiol treatment positively modulated neurogenesis in the dentate gyrus of the hippocampus, according to bromodeoxyuridine incorporation and doublecortin immunocytochemistry, decreased reactive astrogliosis, increased BDNF mRNA and protein expression in the dentate gyrus and increased neuronal number in the hilar region of the dentate gyrus. A role of local estrogen biosynthesis is suggested in SHR, because basal aromatase mRNA in the hippocampus and immunoreactive aromatase protein in cell processes of the dentate gyrus were highly expressed in these rats. Estradiol further stimulated aromatase-related parameters in SHR but not in WKY. These observations strongly support that a combination of exogenous estrogens to those locally synthesized

European Journal of Neuroscience, Jul 16, 2020

Development of alternative therapies for treating functional deficits after different neurologica... more Development of alternative therapies for treating functional deficits after different neurological damages is a challenge in neuroscience. Insulin‐like growth factor‐1 (IGF‐1) is a potent neurotrophic factor exerting neuroprotective actions in brain and spinal cord. It is used to prevent or treat injuries of the central nervous system using different administration routes in different animal models. In this study, we evaluated whether intracisternal (IC) route for IGF‐1 gene therapy may abrogate or at least reduce the structural and behavioral damages induced by the intraparenchymal injection of kainic acid (KA) into the rat spinal cord. Experimental (Rad‐IGF‐1) and control (Rad‐DsRed‐KA) rats were evaluated using a battery of motor and sensory tests before the injection of the recombinant adenovector (day −3), before KA injection (day 0) and at every post‐injection (pi) time point (days 1, 2, 3 and 7 pi). Histopathological changes and neuronal and glial counting were assessed. Pretreatment using IC delivery of RAd‐IGF‐1 improved animal's general condition and motor and sensory functions as compared to Rad‐DsRed‐KA‐injected rats. Besides, IC Rad‐IGF‐1 therapy abrogated later spinal cord damage and reduced the glial response induced by KA as observed in Rad‐DsRed‐KA rats. We conclude that the IC route for delivering RAd‐IGF‐1 prevents KA‐induced excitotoxicity in the spinal cord.

Neuroscience, May 1, 2010

Progressive dysfunction of hypothalamic tuberoinfundibular dopaminergic (TIDA) neurons during nor... more Progressive dysfunction of hypothalamic tuberoinfundibular dopaminergic (TIDA) neurons during normal aging is associated in the female rat with chronic hyperprolactinemia. We assessed the effectiveness of glial cell line-derived neurotrophic factor (GDNF) gene therapy to restore TIDA neuron function in senile female rats and reverse their chronic hyperprolactinemia. Young (2.5 months) and senile (29 months) rats received a bilateral intrahypothalamic injection (10 10 pfu) of either an adenoviral vector expressing the gene for b-galactosidase; (Y-bgal and S-bgal, respectively) or a vector expressing rat GDNF (Y-GDNF and S-GDNF, respectively). Transgenic GDNF levels in supernatants of GDNF adenovector-transduced N2a neuronal cell cultures were 2564 ng/ml, as determined by bioassay. In the rats, serum prolactin (PRL) was measured at regular intervals. On day 17 animals were sacrificed and neuronal nuclear antigen (NeuN) and tyrosine hydroxylase (TH) immunoreactive cells counted in the arcuate-periventricular hypothalamic region. The S-GDNF but not the S-bgal rats, showed a significant reduction in body weight. The chronic hyperprolactinemia of the senile females was significantly ameliorated in the S-GDNF rats (P<0.05) but not in the S-bgal rats. Neither age nor GDNF induced significant changes in the number of NeuN and TH neurons. We conclude that transgenic GDNF ameliorates chronic hyperprolactinemia in aging female rats, probably by restoring TIDA neuron function.

Tercera Época, Nov 1, 2014

Aging

Aging is the result of the progressive loss of homeostasis and functional body impairment affecti... more Aging is the result of the progressive loss of homeostasis and functional body impairment affecting the whole body, including the central nervous system (CNS). The hypothalamus has been described to be the key brain area responsible for the regulation of whole-body aging processes, by modulating neuro-www.aging-us.com

European Journal of Neuroscience, 2020

It is well‐established that females live longer than males. Paradoxically, women tend to have poo... more It is well‐established that females live longer than males. Paradoxically, women tend to have poorer health, a condition often named sex frailty. The aim of this study was to evaluate possible frailty predictors in older mice in a sex‐specific manner, in order to employ these predictors to follow‐up therapy efficiency. To further evaluate therapy effects, we also investigated the use of neurotrophic insulin‐like growth factor 1 (IGF‐1) gene therapy and its correlation with the expression of this frailty and emotional behaviour. In order to evaluate frailty, we employed two different approaches. We performed a frailty assessment through a 31‐Item Clinical Frailty Index and through a Performance‐Based 8‐Item Frailty Index. Our results show that both indexes are in concordance to evaluate sex differences, but they do not correlate when evaluating IGF‐1 therapy effects. Moreover, in order to reduce test‐to‐test variability for measures of dependent variables, we compared open field results across studies assessing sex and treatment by means of the z‐score normalization. The data show that regular open field parameters submitted to z‐score normalization analysis could be a useful tool to identify sex differences in ageing mice after growth factor therapies. Taking this into account, sex is a factor that influences the incidence and/or nature of all major complex diseases; the main outcome of our investigation is the development of an efficient tool that compares the use of different frailty index calculations. This represents an important strategy in order to identify sex differences and therapy efficiency in ageing models.

Fil: Herrera, Macarena Lorena. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro... more Fil: Herrera, Macarena Lorena. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Cordoba. Instituto de Farmacologia Experimental de Cordoba. Universidad Nacional de Cordoba. Facultad de Ciencias Quimicas. Instituto de Farmacologia Experimental de Cordoba; Argentina

Frontiers in Cellular Neuroscience, 2015

Molecular Neurobiology

Brain aging is characterized by chronic neuroinflammation caused by activation of glial cells, ma... more Brain aging is characterized by chronic neuroinflammation caused by activation of glial cells, mainly microglia, leading to alterations in homeostasis of the central nervous system. Microglial cells are constantly surveying their environment to detect and respond to diverse signals. During aging, microglia undergoes a process of senescence, characterized by loss of ramifications, spheroid formation, and fragmented processes, among other abnormalities. Therefore, the study of changes in microglia during is of great relevance to understand age-related declines in cognitive and motor function. We have targeted the deleterious effects of aging by implementing IGF-1 gene transfer, employing recombinant adenoviral vectors (RAds) as a delivery system. In this study, we performed intracerebroventricular (ICV) RAd-IGF-1 or control injection on aged female rats and evaluated its effect on caudate-putamen unit (CPu) gene expression and inflammatory state. Our results demonstrate that IGF-1 overexpression modified aged microglia of the CPu towards an anti-inflammatory condition increasing the proportion of double immuno-positive Iba1+Arg1+ cells. We also observed that phosphorylation of Akt was increased in animals treated with RAd-IGF-1. Moreover, IGF-1 gene transfer was able to regulate CPu pro-inflammatory environment in female aged rats by down-regulating the expression of genes typically overexpressed during aging. RNA-Seq data analysis identified 97 down-modulated DEG in the IGF-1 group as compared to the DsRed one. Interestingly, 12 of these DEG are commonly overexpressed during aging, and 9 out of 12 are expressed in microglia/macrophages and are involved in different processes that lead to neuroinflammation and/or neuronal loss. Finally, we observed that IGF-1 overexpression led to an improvement in motor functions. Although further studies are necessary, with the present results, we conclude that IGF-1 gene transfer is modifying both the pro-inflammatory environment and activation of microglia/macrophages in CPu. In this regard, IGF-1 gene transfer could counteract the neuroinflammatory effects associated with aging and improve motor functions in senile animals.

En los ítems anteriores se ha establecido claramente la importancia de la vía de síntesis del mev... more En los ítems anteriores se ha establecido claramente la importancia de la vía de síntesis del mevalonato y sus derivados esferoides y no esferoides en el crecimiento y la proliferación celular. Ha quedado claro que la regulación de esta vía se logra principalmente controlando la actividad de la HMG-CoA reductasa a distintos niveles, tanto en su síntesis como en su degradación. También se mencionó que existe una fuerte vinculación entre la colesterogénesis y el metabolismo de ácidos grasos insaturados, dado que las variaciones en el contenido de colesterol celular pueden modificar la expresión de los genes de las distintas desaturasas involucradas en la síntesis de estos ácidos grasos. Considerando el papel relevante que tienen la síntesis de mevalonato y colesterol en la proliferación celular, tanto en células normales como en células neoplásicas, y atendiendo a la estrecha relación que existe entre la vía del mevalonato y el metabolismo de otros lípidos celulares, los objetivos pri...

Theriogenology, 2019

To test the hypothesis that postnatal sexual steroids induce an impairment of domestic male cat r... more To test the hypothesis that postnatal sexual steroids induce an impairment of domestic male cat reproductive function, this study describes the physical, endocrine, steroidogenical and histological effects of a single, high dose of a postnatal sexual steroid in this species. Twenty male kittens were randomly assigned within the first 24 h of birth to: Testosterone enanthate 12.5 mg sc (TE; n = 8), medroxyprogesterone acetate 10 mg sc (MA; n = 6), or Placebo sc (PL; n = 6). The cats were followed until puberty when they were castrated. Kittens achieved puberty without age differences among groups (P > 0.05). Two MA cats presented abnormal testicular descent. Histological evaluation of the MA (P < 0.01), but not of TE testes revealed decreased diameter (P < 0.01) and epithelial height (P < 0.01) of the seminiferous tubules. Leydig cell nuclear area was also reduced in this group. Conversely, tubular/intertubular ratio was increased in TE animals (P < 0.01). Quantitative real-time PCR analysis of mRNA expression of testicular tissue revealed no significant differences among groups for StAR, CYP17A1 and androgen receptors. TE animals showed decreased CYP19A1 mRNA expression (P < 0.05). In the first 4 postnatal weeks, fecal testosterone (T) values were high, basal and intermediate in TE, MA and PL (P < 0.05), respectively. These differences progressively diminished and the three groups presented basal T concentrations from the 7th week on (P > 0.05). It was concluded that the postnatal progestagen initially suppressed the gonadal axis and caused an impairment of spermatogenesis and testicular descent at puberty. Androgen treatment caused downregulation of the final steroidogenic cascade.

Frontiers in Pharmacology, 2018

Perinatal asphyxia (PA) remains as one of the most important causes of shortterm mortality, psych... more Perinatal asphyxia (PA) remains as one of the most important causes of shortterm mortality, psychiatric and neurological disorders in children, without an effective treatment. In previous studies we have observed that the expression of different neurodegenerative markers increases in CA1 hippocampal area of 4-months-old male rats born by cesarean section and exposed for 19 min to PA. We have also shown that a late treatment with 17β estradiol (daily dose of 250 µg/kg for 3 days) was able to revert the brain alterations observed in those animals. Based on these previous results, the main aim of the present study was to explore the mechanism by which the estrogenic treatment is involved in the reversion of the chronic neurodegenerative conditions induced by PA. We demonstrated that estradiol treatment of adult PA exposed animals induced an increase in estrogen receptor (ER) α and insulin-like growth factor receptor (IGF-1R) protein levels, an activation of the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase 3 beta/β-catenin signaling pathway and an increase in Bcl-2/Bax ratio in the hippocampus in comparison to PA exposed animals treated with vehicle. Taking together, our data suggest that the interaction between ERα and IGF-IR, with the subsequent downstream activation, underlies the beneficial effects of estradiol observed in late treatment of PA.

Behavioural Brain Research, 2019

Highlights  Frailty phenotype underlies depressive-like symptoms in aged mice model.

Frontiers in Aging Neuroscience, 2019

Microglial cells become dystrophic with aging; this phenotypic alteration contributes to basal ce... more Microglial cells become dystrophic with aging; this phenotypic alteration contributes to basal central nervous system (CNS) neuroinflammation being a risk factor for age related neurodegenerative diseases. In previous studies we have observed that insulin like growth factor 1 (IGF1) gene therapy is a feasible approach to target brain cells, and that is effective to modify inflammatory response in vitro and to ameliorate cognitive or motor deficits in vivo. Based on these findings, the main aim of the present study is to investigate the effect of IGF1 gene therapy on microglia distribution and morphology in the senile rat. We found that IGF1 therapy leads to a region-specific modification of aged microglia population.

Prostaglandins, Leukotrienes and Essential Fatty Acids, 2003

It is well known that simvastatin affects cholesterol synthesis. Furthermore it inhibits growth a... more It is well known that simvastatin affects cholesterol synthesis. Furthermore it inhibits growth and proliferation and perturbs fatty acid metabolism in some cell lines. We have studied the effects of simvastatin on the uptake and metabolism of exogenous fatty acid in the human lung adenocarcinoma A549 cells. Simvastatin inhibited the proliferation of A549, and caused an increment in phospholipid/cholesterol ratio due to an increment in phospholipid content without affecting cholesterol content. All the fatty acids were uptaken and metabolized in both control and treated cells. The conversion of palmitic, linoleic and dihomo-g-linoleic acids to their metabolites and products/precursor ratios for the desaturation and elongation reactions showed that simvastatin enhanced the D5 desaturation step and altered some elongating steps. The machinery for unsaturated fatty acid synthesis in A549 is quite sensitive to simvastatin and its effects could have important implication taking into account that highly unsaturated fatty acids are involved in the regulation of diverse cellular functions by themselves or through their metabolites.

Journal of Pharmacy & Pharmaceutical Sciences, 2012

Purpose. To evaluate the association between starting early treatment with anti-TNF and effective... more Purpose. To evaluate the association between starting early treatment with anti-TNF and effectiveness as well as the possibility of applying therapeutic spacing in daily practice in patients with rheumatoid arthritis (RA). Methods. Observational, retrospective study conducted in two universitary hospitals in Spain. RA patients who received the first anti-TNF (adalimumab: ADA, etanercept: ETN or infliximab: IFX) during the study period (October 2006-2010) were included. Demographic data, time since diagnosis, disease activity (DAS28-ESR) and anti-TNF dosage were analyzed. Therapeutic objective was defined as DAS28

European Journal of Hospital Pharmacy: Science and Practice, 2013

efficiency. Measuring efficiency in clinical practise is key for optimization and rational use of... more efficiency. Measuring efficiency in clinical practise is key for optimization and rational use of biological medicines.

Frontiers of Hormone Research, 2006

The implementation of experimental gene therapy in animal models of neuroendocrine diseases is an... more The implementation of experimental gene therapy in animal models of neuroendocrine diseases is an area of growing interest. In the hypothalamus, restorative gene therapy has been successfully implemented in Brattleboro rats, an arginine vasopressin (AVP) mutant which suffers from diabetes insipidus, and in Koletsky (fa(k)/fa(k)) and in Zucker (fa/fa) rats which have leptin receptor mutations that render them obese, hyperphagic and hyperinsulinemic. In the above models, viral vectors expressing AVP, leptin receptor b and proopiomelanocortin, respectively, were stereotaxically injected in the relevant hypothalamic regions. In rats, aging brings about a progressive degeneration and loss of hypothalamic tuberoinfundibular dopaminergic (TIDA) neurons, which are involved in the tonic inhibitory control of prolactin secretion and lactotropic cell proliferation. Stereotaxic injection of an adenoviral vector expressing insulin-like growth factor I corrected their chronic hyperprolactinemia and restored TIDA neuron numbers. Spontaneous intermediate lobe pituitary tumors in a retinoblastoma (Rb) gene mutant mouse were corrected by injection of an adenoviral vector expressing the human Rb cDNA and experimental prolactinomas in rats were partially reduced by intrapituitary injection of an adenoviral vector expressing the HSV1-thymidine kinase suicide gene. These results suggest that further implementation of gene therapy strategies in neuroendocrine models may be highly rewarding.