We explored sex-biased effects of the primary stress glucocorticoid hormone corticosterone on the... more We explored sex-biased effects of the primary stress glucocorticoid hormone corticosterone on the miRNA expression profile in the rat hippocampus. Adult adrenalectomized (ADX) female and male rats received a single corticosterone (10 mg/kg) or vehicle injection, and after 6 h, hippocampi were collected for miRNA, mRNA, and Western blot analyses. miRNA profiling microarrays showed a basal sex-biased miRNA profile in ADX rat hippocampi. Additionally, acute corticosterone administration triggered a sex-biased differential expression of miRNAs derived from genes located in several chromosomes and clusters on the X and 6 chromosomes. Putative promoter analysis unveiled that most corticosterone-responsive miRNA genes contained motifs for either direct or indirect glucocorticoid actions in both sexes. The evaluation of transcription factors indicated that almost 50% of miRNA genes sensitive to corticosterone in both sexes was under glucocorticoid receptor regulation. Transcription factor-m...
ABSTRACT Major depressive disorder is a serious mental disorder with high prevalence and recurren... more ABSTRACT Major depressive disorder is a serious mental disorder with high prevalence and recurrence rate. Once depression is diagnosed, effective pharmacological treatments must be rapidly initiated. Depression etiology and responsiveness to antidepressants have been related to the activity of the hypothalamic-pituitary-adrenal (HPA) axis. Depressed subjects do not respond equally to the same drug. This variability could be explained by interindividual genetic differences related to HPA axis, including CRHR1 receptor.Objectives To associate the salivary cortisol levels, prior to antidepressant treatment, and the CRHR1 rs242939 polymorphism with the response to therapy with fluoxetine.Methods We performed a pharmacogenetic prospective longitudinal study including clinic follow-up, endocrine and genetic evaluations. After diagnosis, patients started the pharmacotherapy. The severity of the disease and clinical response were evaluated by the Hamilton Depression Rating Scale (HAM-D). Rapid and slow responses were considered as reductions in the HAM-D scores of at least 50% at the third and eight weeks respectively.Results157 patients were recruited. Salivary cortisol levels at 8:00AM were lower in rapid responders than in not responders (p-value = 0.0122). No differences were observed after eight weeks of treatment. The rs242939 polymorphism was in Hardy Weinberg equilibrium (p = 0,24) and was significantly associated with early response (p = 0.019). There was no association after two month of therapy.Discussion and conclusionsAlterations in the CRHR1 receptor may significantly impact the regulation of stress response. The association observed in this study may be related with some refractoriness in the regulation of CRHR1 gene in non responders.SupportedBy Fondecyt 1090219.
Depressive disorder involves emotional, cognitive, autonomic and endocrine alterations and also e... more Depressive disorder involves emotional, cognitive, autonomic and endocrine alterations and also evidences support the role of stress in the development of this disorder. Because the hypothalamic-pituitary-adrenal axis is involved in the stress response with a concomitant rise in plasma corticoids, the present study compares the antidepressant effects of sertraline (10 mg/kg, i.p.) on behavioral changes elicited by (i) restraint stress (2.5 h/day for 13 days) and (ii) corticosterone injections (30 mg/kg, s.c., for 13 days). Stressed animals, but not corticosterone-treated animals displayed anxiety behavior and a reduction in the acquisition of a conditioned avoidance response to 25% of control levels (8.0 ± 2.2 vs. 31.7 ± 3.2), being this effect partly sensitive to sertraline. Stressed, but not corticosterone-treated, animals displayed an increased escape failure compared with the control group (24.6% ± 3.5 vs. 1.6 ± 0.7), an effect partly prevented by sertraline treatment (7.3% ± 2.0). Both stressed rats and corticosterone-treated rats showed an increase in immobility in the forced swim test, an effect prevented by sertraline. These results suggest that the altered behaviors elicited by stress and corticosterone can be explained by neural modifications that are sensitive to the sertraline antidepressant.
Autism spectrum disorder (ASD) is a neurodevelopmental alteration characterized by social/communi... more Autism spectrum disorder (ASD) is a neurodevelopmental alteration characterized by social/communicative deficits, repetitive/stereotyped movements, and restricted/obsessive interests. However, there is not much information about whether movement alterations in ASD comprise modifications at the basic kinematic level, such as trajectory and velocity, which may contribute to the higher level of processing that allows the perception and interpretation of actions performed by others, and hence, impact social interaction. In order to further explore possible motor alterations in ASD, we analyzed movement parameters in the Valproate (VPA) animal model of autism. We found that VPA-treated rats displayed greater movement acceleration, reduced distance between stops, spent more time in the corner of the open-field arena, and executed a number of particular behaviors; for example, supported rearing and circling, with no major changes in distance and velocity. However, in the social interaction...
Autism is a neurodevelopmental disorder characterized by a deep deficit in language and social in... more Autism is a neurodevelopmental disorder characterized by a deep deficit in language and social interaction, accompanied by restricted, stereotyped and repetitive behaviors. The use of genetic autism animal models has revealed that the alteration of the mechanisms controlling the formation and maturation of neural circuits are points of convergence for the physiopathological pathways in several types of autism. Brain Derived Neurotrophic Factor (BDNF), a key multifunctional regulator of brain development, has been related to autism in several ways. However, its precise role is still elusive, in part, due to its extremely complex posttranscriptional regulation. In order to contribute to this topic, we treated prenatal rats with Valproate, a well-validated model of autism, to analyze BDNF levels in the hippocampus of juvenile rats. Valproate-treated rats exhibited an autism-like behavioral profile, characterized by a deficit in social interaction, anxiety-like behavior and repetitive behavior. In situ hybridization (ISH) experiments revealed that Valproate reduced BDNF mRNA, especially long-3 UTR-containing transcripts, in specific areas of the dentate gyrus (DG) and CA3 regions. At the same time, Valproate reduced BDNF immunoreactivity in the suprapyramidal and lucidum layers of CA3, but improved hippocampus-dependent spatial learning. The molecular changes reported here may help to explain the cognitive and behavioral signs of autism and reinforce BDNF as a potential molecular target for this neurodevelopmental disorder.
Oral bioavailability of loperamide is restricted by its limited absorption in the gastrointestina... more Oral bioavailability of loperamide is restricted by its limited absorption in the gastrointestinal tract due to its poor aqueous solubility and its P-glycoprotein (Pgp) substrate characteristic. In addition, ammonium methacrylate copolymers have shown to have mucoadhesive properties, whereas poloxamer 188, has been suggested as a Pgp inhibitor. Thus, in this work, we evaluate conditions that affect physicochemical parameters of ammonium methacrylate/poloxamer 188-based nanocarriers loaded with loperamide hydrochloride. Nanocarriers were synthesized by nanoprecipitation, enhancing loperamide encapsulation efficiency by modifying the aqueous phase to basic pH. The isolation of the non-encapsulated drug fraction from the nanocarriers-incorporated fraction was conducted by centrifugation, ultrafiltration, vacuum filtration and diafiltration. The last method was effective in providing a deeper understanding of drug-nanocarrier loading and interactions by means of modeling the data obtained by it. Through diafiltration, it was determined an encapsulation efficiency of about 93%, from which a 38% ±6 was shown to be reversibly (thermodynamic interaction) and a 62% ±6 irreversibly (kinetic interaction) bound. Finally, release profiles were assessed through empirical and semi-empirical modeling, showing a biphasic release behavior (burst effect 11.34% and total release at 6 h = 33% ±1). Thus, encapsulation efficiency and release profile were shown to have a strong mathematical modeling-based correlation, providing the mechanistic approach presented in this article a solid support for future translational investigations.
A single stress exposure facilitates memory formation through neuroplastic processes that reshape... more A single stress exposure facilitates memory formation through neuroplastic processes that reshape excitatory synapses in the hippocampus, probably requiring changes in extracellular matrix components. We tested the hypothesis that matrix metalloproteinase 9 (MMP-9), an enzyme that degrades components of extracellular matrix and synaptic proteins such as β-dystroglycan (β-DG), changes their activity and distribution in rat hippocampus during the acute stress response. After 2.5 h of restraint stress, we found (i) increased MMP-9 levels and potential activity in whole hippocampal extracts, accompanied by β-DG cleavage, and (ii) a significant enhancement of MMP-9 immunoreactivity in dendritic fields such as stratum radiatum and the molecular layer of hippocampus. After 24 h of stress, we found that (i) MMP-9 net activity rises at somatic field, i.e., stratum pyramidale and granule cell layers, and also at synaptic field, mainly stratum radiatum and the molecular layer of hippocampus, a...
Studies conducted in rodents subjected to chronic stress and some observations in humans after ps... more Studies conducted in rodents subjected to chronic stress and some observations in humans after psychosocial stress, have allowed to establish a link between stress and the susceptibility to many complex diseases, including mood disorders. The studies in rodents have revealed that chronic exposure to stress negatively affects synaptic plasticity by triggering changes in the production of trophic factors, subunit levels of glutamate ionotropic receptors, neuron morphology, and neurogenesis in the adult hippocampus. These modifications may account for the impairment in learning and memory processes observed in chronically stressed animals. It is plausible then, that stress modifies the interplay between signal transduction cascades and gene expression regulation in the hippocampus, therefore leading to altered neuroplasticity and functioning of neural circuits. Considering that miRNAs play an important role in post-transcriptional-regulation of gene expression and participate in severa...
Previous studies in rats have demonstrated that chronic restraint stress triggers anhedonia, depr... more Previous studies in rats have demonstrated that chronic restraint stress triggers anhedonia, depressive-like behaviors, anxiety and a reduction in dendritic spine density in hippocampal neurons. In this study, we compared the effect of repeated stress on the expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor subunits in dorsal and ventral hippocampus (VH). Adult male Sprague-Dawley rats were randomly divided into control and stressed groups, and were daily restrained in their motion (2.5 h/day) during 14 days. We found that chronic stress promotes an increase in c-Fos mRNA levels in both hippocampal areas, although it was observed a reduction in the immunoreactivity at pyramidal cell layer. Furthermore, Arc mRNAs levels were increased in both dorsal and VH, accompanied by an increase in Arc immunoreactivity in dendritic hippocampal layers. Furthermore, stress triggered a reduction in PSD-95 and NR1 protein levels in who...
Biochemical and biophysical research communications, Aug 26, 2017
Myelin basic protein (MBP) is a key component of myelin, the specialized lipid membrane that enca... more Myelin basic protein (MBP) is a key component of myelin, the specialized lipid membrane that encases the axons of all neurons. Both plasminogen (Pg) and tissue-type plasminogen activator (t-PA) bind to MBP with high affinity. We investigated the kinetics and mechanisms involved in this process using immobilized MBP and found that Pg activation by t-PA is significantly stimulated by MBP. This mechanism involves the binding of t-PA via a lysine-dependent mechanism to the Lys(91) residue of the MBP NH2-terminal region Asp(82) -Pro(99), and the binding of Pg via a lysine-dependent mechanism to the Lys(122) residue of the MBP COOH-terminal region Leu(109)-Gly(126). In this context, MBP mimics fibrin and because MBP is a plasmin substrate, our results suggest direct participation of the Pg activation system on MBP physiology.
Serotonin (5-HT) is a neurotransmitter that plays an important role in neuronal plasticity. Varia... more Serotonin (5-HT) is a neurotransmitter that plays an important role in neuronal plasticity. Variations in the levels of 5-HT at the synaptic cleft, expression or dysfunction of 5-HT receptors may alter brain development and predispose to various mental diseases. Here, we review the transduction pathways described in various cell types transfected with recombinant 5-HT1A receptor (5-HT1AR), specially contrasting with those findings obtained in neuronal cells. The 5-HT1AR is detected in early stages of neural development and is located in the soma, dendrites and spines of hippocampal neurons. The 5-HT1AR differs from other 5-HT receptors because it is coupled to different pathways, depending on the targeted cell. The signaling pathway associated with this receptor is determined by Gα isoforms and some cascades involve βγ signaling. The activity of 5-HT1AR usually promotes a reduction in neuronal excitability and firing, provokes a variation in cAMP and Ca(2+), levels which may be link...
Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder characterized by de... more Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder characterized by deficits in social communication and social interaction, and repetitive and stereotypical patterns of behavior. Previously, a common physiopathological pathway, involving the control of synaptic protein synthesis, was proposed as a convergence point in ASD. In particular, a role for local mRNA translation activated by class I metabotropic glutamate receptor type 5 (mGluR5) was suggested in genetic syndromes with autistic signs and in the prenatal exposition to the valproate model of autism. However, the role of the other members of class I metabotropic glutamate receptors, including mGluR1, has been poorly studied. The present study analyzed the immunoreactivity for mGluR1a in the hippocampus of rats prenatally treated with valproate. Pregnant dams (embryonic day 12.5) were injected with valproate (450 mg/kg) and subsequently, the behavior and mGluR1a were evaluated at postnatal day 30. Experimental rats exhibited social deficit, repetitive conduct and anxious behaviors compared with that of the control animals. Additionally, the present study observed an increased level of mGluR1a-immunoreactivity in the hilus of dentate gyrus and in the CA1 alveus region of the hippocampus. These results suggested an over-functioning of mGluR1a signaling in the hippocampus, induced in the valproate model of autism, which may serve a role in cognitive and behavioral signs of ASD.
Journal of Receptors and Signal Transduction, 1986
The specific binding of L-[3H]-glutamic acid (GLU) was investigated in synaptic membranes from ra... more The specific binding of L-[3H]-glutamic acid (GLU) was investigated in synaptic membranes from rat substantia nigra. L-[3H]-GLU binding to the membrane preparations occurred in a reversible and saturable way. The specific binding was stimulated by the presence of CaCl2 and was reduced by freezing and thawing the membranes. Scatchard analysis of the saturation isotherms yielded a non-linear plot suggesting that the binding reaction does not occur through a simple bimolecular association. Assuming non-interacting binding sites, a high (KD1, 139 nM; Bmax1, 3.5 pmoles/mg protein) and a low (KD2, 667 nM; Bmax2, 15.1 pmoles/mg protein) affinity L-[3H]-GLU binding site were obtained. The kinetics of dissociation of bound L-[3H]-GLU was biphasic; the respective dissociation rate constant (k-1) being 0.20 min-1 and 0.013 min-1. A series of amino acid receptor agonists and antagonists were tested as inhibitors of L-[3H]-GLU specific binding. Quisqualic acid, L-GLU and D-alpha-aminoadipate (D-alpha-AA) were the most potent inhibitors. DL-2-amino-4-phosphonobutyrate (APB), N-Methyl-D-aspartate (NMDA) and D-GLU were moderate inhibitors, whereas diaminopimelic acid (DAPA) and glutamate diethyl ester (GDEE) exhibited the lowest relative potency. Kainic acid (KA), gamma-aminobutyric acid (GABA) and bicuculline were not able to modify at any concentration used the specific binding of L-[3H]-GLU. These data demonstrate the presence of specific GLU binding sites in synaptic structures at substantia nigra level and support the idea that excitatory amino acids may play a role in synaptic transmission in this brain region.
Journal of Cardiovascular Pharmacology, Sep 1, 2005
Administration of the beta-adrenergic agonist isoproterenol results in cardiac apoptosis. The eff... more Administration of the beta-adrenergic agonist isoproterenol results in cardiac apoptosis. The effect of short-term beta-adrenergic stimulation by isoproterenol on the activity of plasma, lung, and left ventricular (LV) angiotensin I-converting enzyme (ACE) activity and its association with the development of cardiac apoptosis was investigated. beta-Adrenergic stimulation for 24 hours produced an early increase only in the proapoptotic proteins bax and bcl-XS without changes in the levels of the antiapoptotic protein bcl-XL. The ratio between these bcl family proteins was indicative of apoptosis and correlated with an early and significant increase (300%) in DNA laddering. However, after 5 days of the beta-adrenergic stimulation, the ratio changed in favor of antiapoptotic proteins and correlated with the absence of DNA fragmentation. In addition, LV and plasma ACE activities increased markedly with isoproterenol over the study period up to 5 days. ACE activity also regulated expression of the antiapoptotic gene bcl-XL. The administration of perindopril (an ACE inhibitor) prevented the observed increase in bax and bcl-XS levels and attenuated (50% decrease, P<0.05) the effect of isoproterenol on DNA fragmentation. Thus, early and transient cardiac apoptosis triggered by the beta-adrenergic agonist isoproterenol is reversed in the presence of perindopril.
We explored sex-biased effects of the primary stress glucocorticoid hormone corticosterone on the... more We explored sex-biased effects of the primary stress glucocorticoid hormone corticosterone on the miRNA expression profile in the rat hippocampus. Adult adrenalectomized (ADX) female and male rats received a single corticosterone (10 mg/kg) or vehicle injection, and after 6 h, hippocampi were collected for miRNA, mRNA, and Western blot analyses. miRNA profiling microarrays showed a basal sex-biased miRNA profile in ADX rat hippocampi. Additionally, acute corticosterone administration triggered a sex-biased differential expression of miRNAs derived from genes located in several chromosomes and clusters on the X and 6 chromosomes. Putative promoter analysis unveiled that most corticosterone-responsive miRNA genes contained motifs for either direct or indirect glucocorticoid actions in both sexes. The evaluation of transcription factors indicated that almost 50% of miRNA genes sensitive to corticosterone in both sexes was under glucocorticoid receptor regulation. Transcription factor-m...
ABSTRACT Major depressive disorder is a serious mental disorder with high prevalence and recurren... more ABSTRACT Major depressive disorder is a serious mental disorder with high prevalence and recurrence rate. Once depression is diagnosed, effective pharmacological treatments must be rapidly initiated. Depression etiology and responsiveness to antidepressants have been related to the activity of the hypothalamic-pituitary-adrenal (HPA) axis. Depressed subjects do not respond equally to the same drug. This variability could be explained by interindividual genetic differences related to HPA axis, including CRHR1 receptor.Objectives To associate the salivary cortisol levels, prior to antidepressant treatment, and the CRHR1 rs242939 polymorphism with the response to therapy with fluoxetine.Methods We performed a pharmacogenetic prospective longitudinal study including clinic follow-up, endocrine and genetic evaluations. After diagnosis, patients started the pharmacotherapy. The severity of the disease and clinical response were evaluated by the Hamilton Depression Rating Scale (HAM-D). Rapid and slow responses were considered as reductions in the HAM-D scores of at least 50% at the third and eight weeks respectively.Results157 patients were recruited. Salivary cortisol levels at 8:00AM were lower in rapid responders than in not responders (p-value = 0.0122). No differences were observed after eight weeks of treatment. The rs242939 polymorphism was in Hardy Weinberg equilibrium (p = 0,24) and was significantly associated with early response (p = 0.019). There was no association after two month of therapy.Discussion and conclusionsAlterations in the CRHR1 receptor may significantly impact the regulation of stress response. The association observed in this study may be related with some refractoriness in the regulation of CRHR1 gene in non responders.SupportedBy Fondecyt 1090219.
Depressive disorder involves emotional, cognitive, autonomic and endocrine alterations and also e... more Depressive disorder involves emotional, cognitive, autonomic and endocrine alterations and also evidences support the role of stress in the development of this disorder. Because the hypothalamic-pituitary-adrenal axis is involved in the stress response with a concomitant rise in plasma corticoids, the present study compares the antidepressant effects of sertraline (10 mg/kg, i.p.) on behavioral changes elicited by (i) restraint stress (2.5 h/day for 13 days) and (ii) corticosterone injections (30 mg/kg, s.c., for 13 days). Stressed animals, but not corticosterone-treated animals displayed anxiety behavior and a reduction in the acquisition of a conditioned avoidance response to 25% of control levels (8.0 ± 2.2 vs. 31.7 ± 3.2), being this effect partly sensitive to sertraline. Stressed, but not corticosterone-treated, animals displayed an increased escape failure compared with the control group (24.6% ± 3.5 vs. 1.6 ± 0.7), an effect partly prevented by sertraline treatment (7.3% ± 2.0). Both stressed rats and corticosterone-treated rats showed an increase in immobility in the forced swim test, an effect prevented by sertraline. These results suggest that the altered behaviors elicited by stress and corticosterone can be explained by neural modifications that are sensitive to the sertraline antidepressant.
Autism spectrum disorder (ASD) is a neurodevelopmental alteration characterized by social/communi... more Autism spectrum disorder (ASD) is a neurodevelopmental alteration characterized by social/communicative deficits, repetitive/stereotyped movements, and restricted/obsessive interests. However, there is not much information about whether movement alterations in ASD comprise modifications at the basic kinematic level, such as trajectory and velocity, which may contribute to the higher level of processing that allows the perception and interpretation of actions performed by others, and hence, impact social interaction. In order to further explore possible motor alterations in ASD, we analyzed movement parameters in the Valproate (VPA) animal model of autism. We found that VPA-treated rats displayed greater movement acceleration, reduced distance between stops, spent more time in the corner of the open-field arena, and executed a number of particular behaviors; for example, supported rearing and circling, with no major changes in distance and velocity. However, in the social interaction...
Autism is a neurodevelopmental disorder characterized by a deep deficit in language and social in... more Autism is a neurodevelopmental disorder characterized by a deep deficit in language and social interaction, accompanied by restricted, stereotyped and repetitive behaviors. The use of genetic autism animal models has revealed that the alteration of the mechanisms controlling the formation and maturation of neural circuits are points of convergence for the physiopathological pathways in several types of autism. Brain Derived Neurotrophic Factor (BDNF), a key multifunctional regulator of brain development, has been related to autism in several ways. However, its precise role is still elusive, in part, due to its extremely complex posttranscriptional regulation. In order to contribute to this topic, we treated prenatal rats with Valproate, a well-validated model of autism, to analyze BDNF levels in the hippocampus of juvenile rats. Valproate-treated rats exhibited an autism-like behavioral profile, characterized by a deficit in social interaction, anxiety-like behavior and repetitive behavior. In situ hybridization (ISH) experiments revealed that Valproate reduced BDNF mRNA, especially long-3 UTR-containing transcripts, in specific areas of the dentate gyrus (DG) and CA3 regions. At the same time, Valproate reduced BDNF immunoreactivity in the suprapyramidal and lucidum layers of CA3, but improved hippocampus-dependent spatial learning. The molecular changes reported here may help to explain the cognitive and behavioral signs of autism and reinforce BDNF as a potential molecular target for this neurodevelopmental disorder.
Oral bioavailability of loperamide is restricted by its limited absorption in the gastrointestina... more Oral bioavailability of loperamide is restricted by its limited absorption in the gastrointestinal tract due to its poor aqueous solubility and its P-glycoprotein (Pgp) substrate characteristic. In addition, ammonium methacrylate copolymers have shown to have mucoadhesive properties, whereas poloxamer 188, has been suggested as a Pgp inhibitor. Thus, in this work, we evaluate conditions that affect physicochemical parameters of ammonium methacrylate/poloxamer 188-based nanocarriers loaded with loperamide hydrochloride. Nanocarriers were synthesized by nanoprecipitation, enhancing loperamide encapsulation efficiency by modifying the aqueous phase to basic pH. The isolation of the non-encapsulated drug fraction from the nanocarriers-incorporated fraction was conducted by centrifugation, ultrafiltration, vacuum filtration and diafiltration. The last method was effective in providing a deeper understanding of drug-nanocarrier loading and interactions by means of modeling the data obtained by it. Through diafiltration, it was determined an encapsulation efficiency of about 93%, from which a 38% ±6 was shown to be reversibly (thermodynamic interaction) and a 62% ±6 irreversibly (kinetic interaction) bound. Finally, release profiles were assessed through empirical and semi-empirical modeling, showing a biphasic release behavior (burst effect 11.34% and total release at 6 h = 33% ±1). Thus, encapsulation efficiency and release profile were shown to have a strong mathematical modeling-based correlation, providing the mechanistic approach presented in this article a solid support for future translational investigations.
A single stress exposure facilitates memory formation through neuroplastic processes that reshape... more A single stress exposure facilitates memory formation through neuroplastic processes that reshape excitatory synapses in the hippocampus, probably requiring changes in extracellular matrix components. We tested the hypothesis that matrix metalloproteinase 9 (MMP-9), an enzyme that degrades components of extracellular matrix and synaptic proteins such as β-dystroglycan (β-DG), changes their activity and distribution in rat hippocampus during the acute stress response. After 2.5 h of restraint stress, we found (i) increased MMP-9 levels and potential activity in whole hippocampal extracts, accompanied by β-DG cleavage, and (ii) a significant enhancement of MMP-9 immunoreactivity in dendritic fields such as stratum radiatum and the molecular layer of hippocampus. After 24 h of stress, we found that (i) MMP-9 net activity rises at somatic field, i.e., stratum pyramidale and granule cell layers, and also at synaptic field, mainly stratum radiatum and the molecular layer of hippocampus, a...
Studies conducted in rodents subjected to chronic stress and some observations in humans after ps... more Studies conducted in rodents subjected to chronic stress and some observations in humans after psychosocial stress, have allowed to establish a link between stress and the susceptibility to many complex diseases, including mood disorders. The studies in rodents have revealed that chronic exposure to stress negatively affects synaptic plasticity by triggering changes in the production of trophic factors, subunit levels of glutamate ionotropic receptors, neuron morphology, and neurogenesis in the adult hippocampus. These modifications may account for the impairment in learning and memory processes observed in chronically stressed animals. It is plausible then, that stress modifies the interplay between signal transduction cascades and gene expression regulation in the hippocampus, therefore leading to altered neuroplasticity and functioning of neural circuits. Considering that miRNAs play an important role in post-transcriptional-regulation of gene expression and participate in severa...
Previous studies in rats have demonstrated that chronic restraint stress triggers anhedonia, depr... more Previous studies in rats have demonstrated that chronic restraint stress triggers anhedonia, depressive-like behaviors, anxiety and a reduction in dendritic spine density in hippocampal neurons. In this study, we compared the effect of repeated stress on the expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor subunits in dorsal and ventral hippocampus (VH). Adult male Sprague-Dawley rats were randomly divided into control and stressed groups, and were daily restrained in their motion (2.5 h/day) during 14 days. We found that chronic stress promotes an increase in c-Fos mRNA levels in both hippocampal areas, although it was observed a reduction in the immunoreactivity at pyramidal cell layer. Furthermore, Arc mRNAs levels were increased in both dorsal and VH, accompanied by an increase in Arc immunoreactivity in dendritic hippocampal layers. Furthermore, stress triggered a reduction in PSD-95 and NR1 protein levels in who...
Biochemical and biophysical research communications, Aug 26, 2017
Myelin basic protein (MBP) is a key component of myelin, the specialized lipid membrane that enca... more Myelin basic protein (MBP) is a key component of myelin, the specialized lipid membrane that encases the axons of all neurons. Both plasminogen (Pg) and tissue-type plasminogen activator (t-PA) bind to MBP with high affinity. We investigated the kinetics and mechanisms involved in this process using immobilized MBP and found that Pg activation by t-PA is significantly stimulated by MBP. This mechanism involves the binding of t-PA via a lysine-dependent mechanism to the Lys(91) residue of the MBP NH2-terminal region Asp(82) -Pro(99), and the binding of Pg via a lysine-dependent mechanism to the Lys(122) residue of the MBP COOH-terminal region Leu(109)-Gly(126). In this context, MBP mimics fibrin and because MBP is a plasmin substrate, our results suggest direct participation of the Pg activation system on MBP physiology.
Serotonin (5-HT) is a neurotransmitter that plays an important role in neuronal plasticity. Varia... more Serotonin (5-HT) is a neurotransmitter that plays an important role in neuronal plasticity. Variations in the levels of 5-HT at the synaptic cleft, expression or dysfunction of 5-HT receptors may alter brain development and predispose to various mental diseases. Here, we review the transduction pathways described in various cell types transfected with recombinant 5-HT1A receptor (5-HT1AR), specially contrasting with those findings obtained in neuronal cells. The 5-HT1AR is detected in early stages of neural development and is located in the soma, dendrites and spines of hippocampal neurons. The 5-HT1AR differs from other 5-HT receptors because it is coupled to different pathways, depending on the targeted cell. The signaling pathway associated with this receptor is determined by Gα isoforms and some cascades involve βγ signaling. The activity of 5-HT1AR usually promotes a reduction in neuronal excitability and firing, provokes a variation in cAMP and Ca(2+), levels which may be link...
Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder characterized by de... more Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder characterized by deficits in social communication and social interaction, and repetitive and stereotypical patterns of behavior. Previously, a common physiopathological pathway, involving the control of synaptic protein synthesis, was proposed as a convergence point in ASD. In particular, a role for local mRNA translation activated by class I metabotropic glutamate receptor type 5 (mGluR5) was suggested in genetic syndromes with autistic signs and in the prenatal exposition to the valproate model of autism. However, the role of the other members of class I metabotropic glutamate receptors, including mGluR1, has been poorly studied. The present study analyzed the immunoreactivity for mGluR1a in the hippocampus of rats prenatally treated with valproate. Pregnant dams (embryonic day 12.5) were injected with valproate (450 mg/kg) and subsequently, the behavior and mGluR1a were evaluated at postnatal day 30. Experimental rats exhibited social deficit, repetitive conduct and anxious behaviors compared with that of the control animals. Additionally, the present study observed an increased level of mGluR1a-immunoreactivity in the hilus of dentate gyrus and in the CA1 alveus region of the hippocampus. These results suggested an over-functioning of mGluR1a signaling in the hippocampus, induced in the valproate model of autism, which may serve a role in cognitive and behavioral signs of ASD.
Journal of Receptors and Signal Transduction, 1986
The specific binding of L-[3H]-glutamic acid (GLU) was investigated in synaptic membranes from ra... more The specific binding of L-[3H]-glutamic acid (GLU) was investigated in synaptic membranes from rat substantia nigra. L-[3H]-GLU binding to the membrane preparations occurred in a reversible and saturable way. The specific binding was stimulated by the presence of CaCl2 and was reduced by freezing and thawing the membranes. Scatchard analysis of the saturation isotherms yielded a non-linear plot suggesting that the binding reaction does not occur through a simple bimolecular association. Assuming non-interacting binding sites, a high (KD1, 139 nM; Bmax1, 3.5 pmoles/mg protein) and a low (KD2, 667 nM; Bmax2, 15.1 pmoles/mg protein) affinity L-[3H]-GLU binding site were obtained. The kinetics of dissociation of bound L-[3H]-GLU was biphasic; the respective dissociation rate constant (k-1) being 0.20 min-1 and 0.013 min-1. A series of amino acid receptor agonists and antagonists were tested as inhibitors of L-[3H]-GLU specific binding. Quisqualic acid, L-GLU and D-alpha-aminoadipate (D-alpha-AA) were the most potent inhibitors. DL-2-amino-4-phosphonobutyrate (APB), N-Methyl-D-aspartate (NMDA) and D-GLU were moderate inhibitors, whereas diaminopimelic acid (DAPA) and glutamate diethyl ester (GDEE) exhibited the lowest relative potency. Kainic acid (KA), gamma-aminobutyric acid (GABA) and bicuculline were not able to modify at any concentration used the specific binding of L-[3H]-GLU. These data demonstrate the presence of specific GLU binding sites in synaptic structures at substantia nigra level and support the idea that excitatory amino acids may play a role in synaptic transmission in this brain region.
Journal of Cardiovascular Pharmacology, Sep 1, 2005
Administration of the beta-adrenergic agonist isoproterenol results in cardiac apoptosis. The eff... more Administration of the beta-adrenergic agonist isoproterenol results in cardiac apoptosis. The effect of short-term beta-adrenergic stimulation by isoproterenol on the activity of plasma, lung, and left ventricular (LV) angiotensin I-converting enzyme (ACE) activity and its association with the development of cardiac apoptosis was investigated. beta-Adrenergic stimulation for 24 hours produced an early increase only in the proapoptotic proteins bax and bcl-XS without changes in the levels of the antiapoptotic protein bcl-XL. The ratio between these bcl family proteins was indicative of apoptosis and correlated with an early and significant increase (300%) in DNA laddering. However, after 5 days of the beta-adrenergic stimulation, the ratio changed in favor of antiapoptotic proteins and correlated with the absence of DNA fragmentation. In addition, LV and plasma ACE activities increased markedly with isoproterenol over the study period up to 5 days. ACE activity also regulated expression of the antiapoptotic gene bcl-XL. The administration of perindopril (an ACE inhibitor) prevented the observed increase in bax and bcl-XS levels and attenuated (50% decrease, P<0.05) the effect of isoproterenol on DNA fragmentation. Thus, early and transient cardiac apoptosis triggered by the beta-adrenergic agonist isoproterenol is reversed in the presence of perindopril.
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Papers by Jenny Fiedler