Amalia Molinero - Academia.edu (original) (raw)

Papers by Amalia Molinero

Journal of Neuroscience Research, 2004

Transgenic expression of interleukin-6 (IL-6) in the CNS under the control of the glial fibrillar... more Transgenic expression of interleukin-6 (IL-6) in the CNS under the control of the glial fibrillary acidic protein (GFAP) gene promoter (GFAP-IL6 mice) induces significant inflammation and neurodegeneration but also affords neuroprotection against acute traumatic brain injury. This neuroprotection is likely mediated by the IL-6-induced protective factors metallothioneins-I and -II (MT-I+II). Here we evaluate the neuroprotective roles of IL-6 vs. MT-I+II during 6-aminonicotinamide (6-AN)-induced neurotoxicity, by using GFAP-IL6 mice and transgenic mice overexpressing MT-I (TgMT) as well as GFAP-IL6 mice crossed with TgMT mice (GFAP-IL6 x TgMT). 6-AN caused acute damage of brainstem gray matter areas identified by necrosis of astrocytes, followed by inflammatory responses. After 6-AN-induced toxicity, secondary damage was observed, consisting of oxidative stress, neurodegeneration, and apoptotic cell death. We hereby show that the primary injury caused by 6-AN was comparable in wild-type and GFAP-IL6 mice, but MT-I overexpression could significantly protect the brain tissue. As expected, GFAP-IL6 mice showed increased CNS inflammation with more gliosis, macrophages, and lymphocytes, including increased cytokine expression, relative to the other mice. However, GFAP-IL6 mice showed reduced oxidative stress (judged from nitrotyrosine, malondialdehyde, and 8-oxoguanine stainings), neurodegeneration (accumulation of neurofibrillary tangles), and apoptosis (determined from TUNEL and caspase-3). MT-I+II expression was significantly higher in GFAP-IL6 mice than in wild types, which may contribute to the IL-6-induced neuroprotection. In support of this, overexpression of MT-I in GFAP-IL6 x TgMT as well as TgMT mice protected the brainstem tissue significantly from 6-AN-induced toxicity and secondary brain tissue damage. Overall, the results demonstrate that brain MT-I+II proteins are fundamental neuroprotective factors, which in the future may become therapeutic agents.

Journal of Neurochemistry, 2005

Traumatic injury to the brain is one of the leading causes of injury-related death or disability.... more Traumatic injury to the brain is one of the leading causes of injury-related death or disability. Brain response to injury is orchestrated by cytokines, such as interleukin (IL)-6, but the full repertoire of responses involved is not well known. We here report the results obtained with microarrays in wild-type and IL-6 knockout mice subjected to a cryolesion of the somatosensorial cortex and killed at 0, 1, 4, 8 and 16 days post-lesion. Overall gene expression was analyzed by using Affymetrix genechips/oligonucleotide arrays with 12 400 probe sets corresponding to 10 000 different murine genes (MG_U74Av2). A robust, conventional statistical method (twoway ANOVA) was employed to select the genes significantly affected. An orderly pattern of gene responses was clearly detected, with genes being up-or down-regulated at specific timings consistent with the processes involved in the initial tissue injury and later regeneration of the parenchyma. IL-6 deficiency showed a dramatic effect in the expression of many genes, especially in the 1 day post-lesion timing, which presumably underlies the poor capacity of IL-6 knockout mice to cope with brain damage. The results highlight the importance of IL-6 controlling the response of the brain to injury as well as the suitability of microarrays for identifying specific targets worthy of further study.

Molecular Brain Research, Aug 1, 1997

IL-6 is a pro-inflammatory cytokine that has previously been associated with herpes simplex virus... more IL-6 is a pro-inflammatory cytokine that has previously been associated with herpes simplex virus type 1 reactivation. To further investigate this relationship during acute infection, ocular HSV-1 infection was studied in transgenic mice homozygous or heterozygous expression of IL-6 by astrocytes in the central nervous system. The virus load in both the eye and trigeminal ganglia was significantly reduced at day 6 but not day 3 post infection in the homozygous IL-6 transgenic mice compared to the wild type and heterozygous littermates. IL-6 protein and mRNA levels in the eye coincided with the level of transgene expression in mice acutely infected with virus (i.e.. day 3 post infection). Likewise, IL-6 transcript levels in the TG mirrored the expression of the transgene in the mice throughout the course ofthe infection into latency. The HSV-1 tl lytic phase gene ICP27 was rapidly down-regulated by day 6 post infection in the TG of homozygous IL-6 transgenic mice compared to the wild type and heterozygous littermates. The resistance to acute HSV-1 infection in the homozygous IL-6 transgenic mice correlated with a significant elevation in IFN-ctIP in the eye compared to the wild type or heterozygous IL-6 transgenic animals. Heterozygous and homozygous IL-6 transgenic mice latently infected with HSV-1 showed elevated anti-HSV-1 antibody titers compared to the latently infected wild type controls. Collectively, the results suggest dosedependent IL-6 antagonism of acute HSV-1 infection in vivo.

Journal of Neuroscience Research, 2005

We examined metallothionein (MT)‐induced neuroprotection during kainic acid (KA)‐induced excitoto... more We examined metallothionein (MT)‐induced neuroprotection during kainic acid (KA)‐induced excitotoxicity by studying transgenic mice with MT‐I overexpression (TgMT mice). KA induces epileptic seizures and hippocampal excitotoxicity, followed by inflammation and delayed brain damage. We show for the first time that even though TgMT mice were more susceptible to KA, the cerebral MT‐I overexpression decreases the hippocampal inflammation and delayed neuronal degeneration and cell death as measured 3 days after KA administration. Hence, the proinflammatory responses of microglia/macrophages and lymphocytes and their expression of interleukin (IL)‐1, IL‐6, IL‐12, tumor necrosis factor‐α and matrix metalloproteinases (MMP‐3, MMP‐9) were significantly reduced in hippocampi of TgMT mice relative to wild‐type mice. Also by 3 days after KA, the TgMT mice showed significantly less delayed damage, such as oxidative stress (formation of nitrotyrosine, malondialdehyde, and 8‐oxoguanine), neurodegeneration (neuronal accumulation of abnormal proteins), and apoptotic cell death (judged by TUNEL and activated caspase‐3). This reduced bystander damage in TgMT mice could be due to antiinflammatory and antioxidant actions of MT‐I but also to direct MT‐I effects on the neurons, in that significant extracellular MT presence was detected. Furthermore, MT‐I overexpression stimulated astroglia and increased immunostaining of antiinflammatory IL‐10, growth factors, and neurotrophins (basic fibroblastic growth factor, transforming growth factor‐β, nerve growth factor, brain‐derived neurotrophic factor, glial‐derived neurotrophic factor) in hippocampus. Accordingly, MT‐I has different functions that likely contribute to the increased neuron survival and improved CNS condition of TgMT mice. The data presented here add new insight into MT‐induced neuroprotection and indicate that MT‐I therapy could be used against neurological disorders. © 2004 Wiley‐Liss, Inc.

Neuroscience, Feb 1, 2001

ÐThe role of interleukin-6 in hippocampal tissue damage after injection with kainic acid, a rigid... more ÐThe role of interleukin-6 in hippocampal tissue damage after injection with kainic acid, a rigid glutamate analogue inducing epileptic seizures, has been studied by means of interleukin-6 null mice. At 35 mg/kg, kainic acid induced convulsions in both control (75%) and interleukin-6 null (100%) mice, and caused a signi®cant mortality (62%) only in the latter mice, indicating that interleukin-6 de®ciency increased the susceptibility to kainic acid-induced brain damage. To compare the histopathological damage caused to the brain, control and interleukin-6 null mice were administered 8.75 mg/kg kainic acid and were killed six days later. Morphological damage to the hippocampal ®eld CA1±CA3 was seen after kainic acid treatment. Reactive astrogliosis and microgliosis were prominent in kainic acid-injected normal mice hippocampus, and clear signs of increased oxidative stress were evident. Thus, the immunoreactivity for inducible nitric oxide synthase, peroxynitrite-induced nitration of proteins and byproducts of fatty acid peroxidation were dramatically increased, as was that for metallothionein I 1 II, Mn-superoxide dismutase and Cu/Zn-superoxide dismutase. In accordance, a signi®cant neuronal apoptosis was caused by kainic acid, as revealed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling and interleukin-1b converting enzyme/Caspase-1 stainings. In kainic acid-injected interleukin-6 null mice, reactive astrogliosis and microgliosis were reduced, while morphological hippocampal damage, oxidative stress and apoptotic neuronal death were increased. Since metallothionein-I 1 II levels were lower, and those of inducible nitric oxide synthase higher, these concomitant changes are likely to contribute to the observed increased oxidative stress and neuronal death in the interleukin-6 null mice. The present results demonstrate that interleukin-6 de®ciency increases neuronal injury and impairs the in¯ammatory response after kainic acid-induced seizures.

Springer eBooks, Nov 21, 2008

Glia, Feb 15, 1999

Injury to the central nervous system (CNS) elicits an inflammatory response involving activation ... more Injury to the central nervous system (CNS) elicits an inflammatory response involving activation of microglia, brain macrophages, and astrocytes, processes likely mediated by the release of proinflammatory cytokines. In order to determine the role of interleukin-6 (IL-6) during the inflammatory response in the brain following disruption of the blood-brain barrier (BBB), we examined the effects of a focal cryo injury to the fronto-parietal cortex in interleukin-6-deficient (IL-6-/-) and normal (IL-6+/+) mice. In IL-6+/+ mice, brain injury resulted in the appearance of brain macrophages and reactive astrocytes surrounding the lesion site. In addition, expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) and metallothionein-I+II (MT-I+II) were increased in these cells, while the brain-specific MT-III was only moderately upregulated. In IL-6-/- mice, however, the response of brain macrophages and reactive astrocytes was markedly depressed and the number of NSE positive neurons was reduced. Brain damage-induced GM-CSF and MT-I+II expression were also markedly depressed compared to IL-6+/+ mice. In contrast, MT-III immunoreactivity was markedly increased in brain macrophages and astrocytes. In situ hybridization analysis indicates that MT-I+II but not MT-III immunoreactivity reflect changes in the messenger levels. The number of cell divisions was similar in IL-6+/+ and IL-6-/- mice. The present results demonstrate that IL-6 is crucial for the recruitment of myelo-monocytes and activation of glial cells following brain injury with disrupted BBB. Furthermore, our results suggest IL-6 is important for neuroprotection and the induction of GM-CSF and MT expression. The opposing effect of IL-6 on MT-I+II and MT-III levels in the damaged brain suggests MT isoform-specific functions.

Experimental Neurology, 2002

We have evaluated the physiological relevance of metallothionein-1؉2 (MT-1؉2) in the CNS followin... more We have evaluated the physiological relevance of metallothionein-1؉2 (MT-1؉2) in the CNS following damage caused by a focal cryolesion onto the cortex. In comparison to normal mice, transgenic mice overexpressing the MT-1 isoform (TgMTI* mice) showed a significant decrease of the number of activated microglia/macrophage and of CD3؉ T lymphocytes in the area surrounding the lesion, while astrocytosis was increased. The TgMTI* mice showed a diminished peripheral macrophage but not CD3 T cell response to the cryolesion. This altered inflammatory response produced a decreased expression of the proinflammatory cytokines IL-1␤, IL-6, and TNF-␣ and an increased expression of the growth factors bFGF, TGF␤1, and VEGF in the TgMTI* mice relative to control mice, which might be related to the increased angiogenesis and regeneration of the parenchyma of the former mice. The overexpression of MT-1 dramatically reduced the cryolesion-induced oxidative stress and neuronal apoptosis. Remarkably, these effects were also obtained by the intraperitoneal administration of MT-2 to both normal and MT-1؉2 knockout mice. These results fully support the notion that MT-1؉2 are essential in the CNS for coping with focal brain injury and suggest a potential therapeutic use of these proteins.

Cytokine, Jul 1, 2015

Previous studies demonstrate associations of low 25-hydroxyvitamin D (25(OH)D) concentrations wit... more Previous studies demonstrate associations of low 25-hydroxyvitamin D (25(OH)D) concentrations with low bone mineral density (BMD) and fractures, motivating widespread use of vitamin D supplements for bone health. However, previous studies have been limited to predominantly White populations despite differences in the distribution and metabolism of 25(OH)D by race/ethnicity. We determined associations of serum 25(OH)D, 24,25dihydroxyvitamin D (24,25(OH 2)D 3), and parathyroid hormone (PTH) with BMD among 1773 adult participants in the Multi-Ethnic Study of Atherosclerosis (MESA) in a staggered cross-sectional study design. Vitamin D metabolites were measured using liquid chromatography-mass spectroscopy and PTH using a 2-site immunoassay from serum collected in 2000-2002. Volumetric trabecular lumbar BMD was measured from computed tomography scans performed in 2002-2005 expressed as g/cm 3. We used linear regression and graphical methods to compare associations of vitamin D metabolite and PTH concentrations with BMD as the outcomes measure among White (n = 714), Black (n = 353), Chinese (n = 249), and Hispanic (n = 457) participants. Serum 25(OH)D and 24,25(OH 2)D 3 concentrations were highest among Whites and lowest among Blacks. BMD was greatest among Black participants. Higher serum 25(OH)D was only associated with higher BMD among Whites and Chinese participants (P-for-interaction = 0.054). Comparing the lowest category of 25(OH)D (b 20 ng/ml) to the highest (≥30 ng/ml), the adjusted mean difference in BMD was-8.1 g/cm 3 (95% CI −14.8, −1.4) for Whites; − 10.2 g/cm 3 (− 20.4, 0.0) for Chinese vs. 8.8 g/cm 3 (− 2.8, 20.5) for Black and − 1.1 g/cm 3 (− 8.3, 6.2) for Hispanic. Similar results were observed for serum 24,25(OH 2)D 3. Serum PTH was not associated with BMD. In a multi-ethnic population, associations of 25(OH)D with BMD were strongest among White and Chinese participants and null among Black and Hispanic participants. Further studies are needed to determine optimal biomarkers for bone health for multiple ethnic groups.

Journal of Morphology, May 14, 2017

Marine Biology, Oct 1, 1991

The common sole Solea solea Linnaeus, 1758 was collected from the Ebro Estuary each month (Januar... more The common sole Solea solea Linnaeus, 1758 was collected from the Ebro Estuary each month (January-December) throughout 1987. The compostion of its natural diet was examined, and the possible influence of sex and age on prey selection. The contents of 461 stomachs were analyzed by means of frequency of occurrence, numerical abundance and Simpson's prey-dominance index in order to determine the dominant, occasional or accidental prey categories; 43 different families of prey were classified. Crustaceans comprised 54.9%, polychaetes 34.1% and molluscs (10.9%) of its diet. Significant differences in the basic diet were observed as a function of sex and age. Examination of the contents of the alimentary tracts revealed that males and females have different diets even when sharing the same habitat. The age-class groups also have different diets, smaller prey being replaced by increasingly larger food items with increasing age (size).

Experimental Biology and Medicine, Oct 1, 2006

In recent years It has become Increasingly clear that the metallothloneln (MT) family of proteins... more In recent years It has become Increasingly clear that the metallothloneln (MT) family of proteins Is Important In neurobiology. MT•I and MT•II are normally dramatically up-regulated by neurolnflammatlon. Results for MT-III are less clear. MTs could also be relevant In human neuropathology. In Alzheimer disease (AD), a major neurodegeneratlve disease, clear signs of Inflammation and oxidative stress were detected associated with amyloid plaques. Furthermore, the number of cells expressing apoptotlc markers was also significantly increased in these plaques. As expected, MT•I and MT-lIlmmunostslnlng was dramatically Increased In cells surrounding the plaques, consistent with astrocytosls and microgllosls, as well as the Increased oxidative stress elicited by the amyloid deposits. MT• III, in contrast, remained essentially unaltered, which agrees with some but not all studies, of AD. In situ hybridization results in a transgenic mouse model of AD amyloid deposits, the Supportby the Minislerio de Ciencia y Tecnologfa and Feder(SAP2002-D1268) and Minislerio de Educaci6n y Ciencia and Feder SAF2005-00671 (l.II.) is fully acknowledged.

Journal of Neurotrauma, Nov 1, 1999

Metallothionein (MT)-III: Generation of Polyclonal Antibodies, Comparison With MT-I + II in the F... more Metallothionein (MT)-III: Generation of Polyclonal Antibodies, Comparison With MT-I + II in the Freeze Lesioned Rat Brain and in a Bioassay With Astrocytes, and Analysis of Alzheimer' s Disease B rains

Abstract Alzheimer's disease (AD) is the most prevalent form of dementia, in which signs of n... more Abstract Alzheimer's disease (AD) is the most prevalent form of dementia, in which signs of neuroinflammation, oxidative stress, and neuronal death are important. Transition metals such as Zn, Fe, and Cu have also been shown to be altered in AD. The heavy metal–binding proteins, metallothioneins (MTs), have been shown to be influenced by AD and to have significant antioxidant, antiinflammatory, and antiapoptotic properties. A number of mouse models of AD have been created, and in some of them, such as the Tg2576 mice, the regulation of the MT family of proteins has been studied. The MT1+2 isoforms are typically upregulated by AD-like pathology, whereas the results for MT3 are less clear-cut. MTs had different effects on survival, depending on the isoform and the sex and age of the mouse (perinatal/weaning or later). MTs in general promote the formation of amyloid plaques (dense core and diffuse) in the hippocampus and, to a lesser extent, in the cortex, particularly in females. MT1+2 had an inhibitory effect on glial cells in young but not old mice, in which amyloid-β plaques are prominent. The absence of MT3 decreased the CA1 hippocampal layer, suggesting an important role in neuronal survival.

European Neuropsychopharmacology, 2019

Comparative Biochemistry and Physiology Part A: Physiology, Aug 1, 1994

Neurochemistry International, May 1, 2000

Zinc is an essential heavy metal for the normal function of the central nervous system (CNS), but... more Zinc is an essential heavy metal for the normal function of the central nervous system (CNS), but the knowledge of its metabolism and functions is scarce. In this report we have studied the eect of a zinc de®cient diet on the regulation of brain metallothioneins (MTs). In situ hybridization analysis revealed that brain MT-I induction by restraint stress was signi®cantly blunted in some but not all brain areas in the mice fed the zinc de®cient diet compared to normally fed mice. In contrast, brain MT-I induction by the administration of bacterial lipopolysaccharide (LPS) was not signi®cantly lower in the mice fed the zinc de®cient diet. In contrast to MT-I, MT-III mRNA levels were minimally aected by either stress or LPS. Yet, signi®cant decreasing eects of the zinc de®cient diet were observed in areas such as the neocortex, CA1±CA3 neuronal layer and dentate gyrus of the hippocampus, and the Purkinje neuronal layer of the cerebellum. These results demonstrate that dietary zinc de®ciency impairs the response of brain MTs during both stress and LPS-elicited in¯ammatory response in a highly speci®c manner.

Neuroimmunomodulation, 2007

Traumatic brain injury is one of the leading causes of incapacity and death among young people. I... more Traumatic brain injury is one of the leading causes of incapacity and death among young people. Injury to the brain elicits a potent inflammatory response, comprising recruitment of inflammatory cells, reactive astrogliosis and activation of brain macrophages. Under the influence of presumably several cytokines and growth factors, a cascade of events is activated that result ultimately in increased oxidative stress and tissue damage, but also in activation of counterregulatory factors and tissue regeneration. The complexity of this response is being unraveled by high-throughput methodologies such as microarrays. The combination of these modern techniques with the comparison of normal and genetically modified mice boosts the significance of the results obtained. With this approach, we have demonstrated that a cytokine such as interleukin-6 is one of the key players in the response of the brain to injury.

Glia, 2019

Traumatic brain injury (TBI) is a major health problem with high rates of mortality and morbidity... more Traumatic brain injury (TBI) is a major health problem with high rates of mortality and morbidity worldwide. The response of the brain to TBI is orchestrated by a number of cytokines, including interleukin‐6 (IL‐6). IL‐6 is a major cytokine in the central nervous system and it is produced by different cells, such as neurons, glial cells, and endothelial cells. Since glial cells are one of the most important sources and targets of IL‐6, we have examined the role of microglia‐derived IL‐6 in normal conditions and following a model of TBI, cryolesion of the somatosensorial cortex. To this end, tamoxifen‐inducible microglial IL‐6‐deficient (Il6ΔMic, using Cx3cr1 CreER model) mice and control (Il6lox/lox) mice were used. In normal conditions, microglial IL‐6 deficiency reduced deambulation and exploratory behavior and decreased anxiety in a sex‐dependent manner. The transcriptome profile following cryolesion was dramatically altered 1 day post‐lesion in Il6ΔMic compared with Il6lox/lox m...

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