Biomedical subjects

C R Oliveira

Publications and source records attributed to C R Oliveira.

At least 19 recordsLinked to original sources

PubMed2006

Increased density and synapto-protective effect of adenosine A2A receptors upon sub-chronic restraint stress.

Stress initially causes adaptive changes in the brain and can lead to neurodegeneration if continuously present. Noxious brain conditions trigger the release of adenosine that can control brain function and neurodegeneration through inhibitory A(1) and facilitatory A(2A) receptors. We tested the effect of restraint stress on the density of adenosine receptors and their effect on the outcome of stress, focusing in a known affected region, the hippocampus. Sub-chronic restraint stress (6 h/day for 7 days) caused a parallel decrease of the density of A(1) receptors (15-20%) and an increase (near 250%) of A(2A) receptor density in rat hippocampal nerve terminals. This indicates that sub-chronic stress unbalances adenosine receptors, up-regulating A(2A) and down-regulating A(1) receptors. Sub-chronic stress did not cause hippocampal neurodegeneration but decreased the immunoreactivity (immunohistochemistry and Western blot) of a synaptic marker, synaptophysin. The blockade of A(2A) receptors with 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine (0.05 mg/kg, daily i.p. injection) attenuated the loss of synaptophysin immunoreactivity observed in the hippocampus of rats subjected to sub-chronic restraint stress. This ability of A(2A) receptor antagonists to prevent the earliest stress-induced synaptic modifications provides a neurochemical and morphological correlate for the interest of A(2A) receptor antagonists to attenuate the burden of chronic stress.

Analysis of Variance↗

PubMed2006

Cytotoxicity of materials used in perforation repair tested using the V79 fibroblast cell line and the granulocyte-macrophage progenitor cells.

AIM: To compare the cytotoxicity of materials used to repair perforations using permanent V79 fibroblasts and murine granulocyte-macrophage progenitor cells (CFU-GM). METHODOLOGY: Set specimens from amalgam, glass-ionomer, SuperEBA, N-Rickert, MTA and gutta-percha were eluted with culture medium for 72 h and their cytotoxicities were assessed by incubating the extracts with V79 and bone marrow-derived progenitors for 24 h and 7 days, respectively. Cytotoxicity on V79 cells was judged using the total nucleic acid content (NAC), neutral red uptake (NRU) and reduction of the tetrazolium salt (MTT). The number of bone marrow CFU-GM colonies determined in clonal cultures stimulated with recombinant murine granulocyte-macrophage colony-stimulating factor was used to assess cytotoxicity to progenitor cells. Statistical analyses were conducted using the one-way analysis of variance and Tukey's test where appropriate. RESULTS: All materials were cytotoxic in both cell systems; however, CFU-GM was more sensitive to the extracts than V79 cells. A similar rank order of toxicity was observed in V79 cells using the NAC and the MTT assays: glass-ionomer > N-Rickert congruent with SuperEBA > gutta-percha > amalgam congruent with MTA (P < 0.05). In contrast, the NRU test exhibited a lower sensitivity to MTA, gutta-percha and amalgam extracts. In the clonal culture assay, the toxicity was less pronounced in the presence of gutta-percha, SuperEBA and MTA. Similar cellular responses were found by placing the set specimens directly in the clonal culture dishes. CONCLUSIONS: The sensitivity of toxicity depended on the choice of the endpoint and the cell-culture system. Nevertheless, MTA was ranked as the least cytotoxic cement in both cell systems.

Acrylic Resins↗

PubMed2006

Insulin attenuates diabetes-related mitochondrial alterations: a comparative study.

This study evaluated and compared the effect of insulin treatment on the status of brain, heart and kidney mitochondria isolated from 12-week streptozotocin (STZ)-induced diabetic rats versus STZ-diabetic animals treated with insulin during a period of 4 weeks. Mitochondria isolated from 12-week citrate (vehicle)-treated rats were used as control. Several mitochondrial parameters were evaluated: respiratory indexes (state 3 and 4 of respiration, respiratory control and ADP/O ratios), transmembrane potential, depolarization and repolarization levels, ATP, glutathione and coenzyme Q contents, production of hydrogen peroxide, superoxide dismutase, glutathione peroxidase and glutathione reductase activities and the ability of mitochondria to accumulate calcium. We observed that diabetes promoted a significant decrease in kidney and brain mitochondrial coenzyme Q9 content while this parameter was increased in heart mitochondria. Furthermore, diabetes induced a significant increase in hydrogen peroxide production in kidney mitochondria this effect being accompanied by a significant increase in glutathione peroxidase and reductase activities. Furthermore, brain mitochondria isolated from diabetic animals presented a lower ATP content and ability to accumulate calcium. In contrast, heart and kidney mitochondria presented a slight higher capacity to accumulate calcium. Insulin treatment normalized the levels of coenzyme Q9 and glutathione peroxidase and reductase activities and increased ATP content and the ability to accumulate calcium. Altogether these results suggest that insulin treatment attenuates diabetes-induced mitochondrial alterations protecting against the increase in oxidative stress and improving oxidative phosphorylation efficiency. In this line, insulin therapy, besides its well-known importance in the maintenance of glycemic control, may help to protect against mitochondrial dysfunction associated to several age-related disorders such as diabetes.

Animals↗

PubMed2006

The key role of mitochondria in Alzheimer's disease.

Mitochondria are uniquely poised to play a pivotal role in neuronal cell survival or death because they are regulators of both energy metabolism and apoptotic pathways. This review is mainly focused in the discussion of evidence suggesting a clear association between amyloid-beta toxicity, mitochondrial dysfunction, oxidative stress and neuronal damage/death in Alzheimer's disease pathophysiology. The knowledge that mitochondrial dysfunction has a preponderant role in Alzheimer's disease opened a window for new therapeutic strategies aimed to preserve/ameliorate mitochondrial function. Based on recent developments in mitochondrial research, increased pharmacological and pharmaceutical efforts have lead to the emergence of 'Mitochondrial Medicine' as a whole new field of biomedical research being this topic discussed in the last section of this review.

Alzheimer Disease↗

PubMed2005

Protective effect of zinc on amyloid-beta 25-35 and 1-40 mediated toxicity.

Amyloid beta-peptide (Abeta) is widely held to be associated with Alzheimer's disease, the insoluble aggregates of the peptide being the major constituents of senile plaques. In this study, we evaluated the effect of Zn(2+) (5, 50 and 200 microM) on Abeta induced toxicity using the human teratocarcinome (NT2) cell line. Our results proved that 50 and 200 microM Zn(2+) protected NT2 cells from Abeta 25-35 toxicity. Zinc was also shown to be effective by preventing the loss of mitochondrial membrane potential (DeltaPsi(m)) induced by Abeta 25-35, not allowing cytochrome c release from mitochondria, and subsequently, caspase 3 activation. However, when the cells were treated with Abeta 1-40, only Zn(2+) 5 microM had a protective effect. We have further observed that 5 microM Zn(2+) prevented Abeta 1-40 aggregation into a beta-sheet structure. Considering the results presented, we argue that Zn(2+) has a concentration-dependent protective effect.

Amyloid beta-Peptides↗

PubMed2005

Bystander effect in synergy to anergy in oral tolerance of Blomia tropicalis/ovalbumin murine co-immunization model.

Oral tolerance is an important approach in allergic diseases and murine model can provide useful information to improve its understanding and therapeutic measures. To address the influence of non-related allergen sensitization in immunized mice with the mite Blomia tropicalis (Bt) or ovalbumin (OVA) or with both Bt/OVA allergens. Furthermore, we sought to verify oral tolerance effect in the Bt/OVA co-immunization model. Mice sensitized with Bt and then exposed to OVA developed an enhanced IgE response to both allergens; contrariwise, this effect was not observed when OVA-sensitization was prior to Bt-sensitization. Co-injection of Bt and OVA led to a dominant IgE response towards OVA over Bt, which was not observed when co-immunization was performed with a 240-fold less amount of OVA. Induction of oral tolerance with OVA, prior to co-immunization, suppressed IgE response to both allergens, probably as a consequence of the increased levels of IFN-gamma found in these animals. The results evidenced that, depending on allergenic potential, new allergen exposure may exert an adjuvant effect to the first allergen used in the sensitization. The bystander suppression to non-related allergens through oral tolerance should be a useful mechanism to control sensitization to new allergens.

Administration, Oral↗

PubMed2005

Presynaptic kainate receptors are localized close to release sites in rat hippocampal synapses.

The subsynaptic distribution of kainate receptors is still a matter of much debate given its importance to understand the way they influence neuronal communication. Here, we show that, in synapses of the rat hippocampus, presynaptic kainate receptors are localized within the presynaptic active zone close to neurotransmitter release sites. The activation of these receptors with low concentrations of agonists induces the release of [(3)H]glutamate in the absence of a depolarizing stimulus. Furthermore, this modulation of [(3)H]glutamate release by kainate is more efficient when compared with a KCl-evoked depolarization that causes a more than two-fold increase in the intra-terminal calcium concentration but no apparent release of [(3)H]glutamate, suggesting a direct receptor-mediated process. Using a selective synaptic fractionation technique that allows for a highly efficient separation of presynaptic, postsynaptic and non-synaptic proteins we confirmed that, presynaptically, kainate receptors are mainly localized within the active zone of hippocampal synapses where they are expected to be in a privileged position to modulate synaptic phenomena.

Animals↗

PubMed2005

Different synaptic and subsynaptic localization of adenosine A2A receptors in the hippocampus and striatum of the rat.

Adenosine A(2A) receptors are most abundant in the striatum where they control the striatopallidal pathway thus controlling locomotion. Extra-striatal A(2A) receptors are considerably less abundant but their blockade confers robust neuroprotection. We now have investigated if striatal and extra-striatal A(2A) receptors have a different neuronal location to understand their different functions. The binding density of the A(2A) antagonist, [(3)H]-7-(2-phenylethyl)-5-amino-2-(2-furyl)pyrazolo[4,3e][1,2,4]triazolo[1,5-c]pyrimidine ([(3)H]SCH 58261), was enriched in nerve terminals membranes (B(max)=103+/-12 fmol/mg protein) compared with total membranes (B(max)=29+/-4 fmol/mg protein) from the hippocampus, the same occurring with A(2A) receptor immunoreactivity. In contrast, there was no enrichment of [(3)H]SCH 58261 binding or A(2A) receptor immunoreactivity in synaptosomal compared with total membranes from the striatum. Further subcellular fractionation of hippocampal nerve terminals revealed that A(2A) receptor immunoreactivity was enriched in the active zone of presynaptic nerve terminals, whereas it was predominantly located in the postsynaptic density in the striatum, although a minority of striatal A(2A) receptors were located in the presynaptic active zone. These results indicate that A(2A) receptors in the striatum are not enriched in synapses in agreement with the preponderant role of A(2A) receptors in signal processing in striatopallidal neurons. In contrast, hippocampal A(2A) receptors are enriched in synapses, mainly in the active zone, in accordance with their role in controlling neurotransmitter release. This regional variation in the neuronal distribution of A(2A) receptors reinforces the care required to extrapolate our knowledge from striatal A(2A) receptors to other brain preparations.

Animals↗

PubMed2005

Adenosine A1 and A2A receptors are co-expressed in pyramidal neurons and co-localized in glutamatergic nerve terminals of the rat hippocampus.

Adenosine is a neuromodulator that controls neurotransmitter release through inhibitory A1 and facilitatory A2A receptors. Although both adenosine receptor-mediated inhibition and facilitation of glutamate release have been observed, it is not clear whether both A1 and A2A receptors are located in the same glutamatergic nerve terminal or whether they are located on different populations of these terminals. Thus, we have tested if single pyramidal glutamatergic neurons from the hippocampus simultaneously expressed A1 and A2A receptor mRNA and if A1 and A2A receptors were co-localized in hippocampal glutamatergic nerve terminals. Single cell PCR analysis of visually identified pyramidal neurons revealed the simultaneous presence of A1 and A2A receptor mRNA in four out 16 pyramidal cells possessing glutamatergic markers but not GABAergic or astrocytic markers. Also, A1 and A2A receptor immunoreactivities were co-localized in 26 +/- 4% of nerve terminals labeled with antibodies against vesicular glutamate transporters type 1 or 2, i.e. glutamatergic nerve terminals. This indicates that glutamatergic neurons in the hippocampus co-express A1 and A2A receptors and that these two receptors are co-localized in a subset of glutamatergic nerve terminals.

Animals↗

PubMed2005

Mitochondrial dysfunction in autism spectrum disorders: a population-based study.

A minority of cases of autism has been associated with several different organic conditions, including bioenergetic metabolism deficiency. In a population-based study, we screened associated medical conditions in a group of 120 children with autism (current age range 11y 5mo to 14y 4mo, mean age 12y 11mo [SD 9.6mo], male:female ratio 2.9:1). Children were diagnosed using Diagnostic and Statistical Manual of Mental Disorders criteria, the Autism Diagnostic Interview--Revised, and the Childhood Autism Rating Scale; 76% were diagnosed with typical autism and 24% with atypical autism. Cognitive functional level was assessed with the Griffiths scale and the Wechsler Intelligence Scale for Children and was in the normal range in 17%. Epilepsy was present in 19 patients. Plasma lactate levels were measured in 69 patients, and in 14 we found hyperlactacidemia. Five of 11 patients studied were classified with definite mitochondrial respiratory chain disorder, suggesting that this might be one of the most common disorders associated with autism (5 of 69; 7.2%) and warranting further investigation.

Adolescent↗

PubMed2005

Neurodegenerative pathways in Parkinson's disease: therapeutic strategies.

Parkinson's disease (PD), considered one of the major neurological disorders, is characterized by the loss of dopaminergic neurons in the pars compacta of the substantia nigra and by the presence of intraneuronal cytoplasmic inclusions called Lewy bodies. The causes for degeneration of PD neurons remain unclear, however, recent findings contributed to clarify this issue. This review will discuss the current understanding of the mechanisms underlying Parkinson's disease pathogenesis, focusing on the current and potential therapeutic strategies for human treatment.

Animals↗

PubMed2005

Alzheimer's disease-associated neurotoxic mechanisms and neuroprotective strategies.

The characteristic hallmarks of Alzheimer's disease (AD), the most common form of dementia in the elderly, include senile plaques, mainly composed of beta-amyloid (Abeta) peptide, neurofibrillary tangles and selective synaptic and neuronal loss in brain regions involved in learning and memory. Genetic studies, together with the demonstration of Abeta neurotoxicity, led to the development of the amyloid cascade hypothesis to explain the AD-associated neurodegenerative process. However, a modified version of this hypothesis has emerged, the Abeta cascade hypothesis, which takes into account the fact that soluble oligomeric forms and protofibrils of Abeta and its intraneuronal accumulation also play a key role in the pathogenesis of the disease. Recent evidence posit that synaptic dysfunction triggered by non fibrillar Abeta species is an early event involved in memory decline in AD. The current understanding of the molecular mechanisms responsible for impaired synaptic function and cognitive deficits is outlined in this review, focusing on oxidative stress and disturbed metal ion homeostasis, Ca(2+) dysregulation, mitochondria and endoplasmic reticulum dysfunction, cholesterol dyshomeostasis and impaired neurotransmission. The activation of apoptotic cell death as a mechanism of neuronal loss in AD, and the prominent role of neuroinflammation in this neurodegenerative disorder, are also reviewed herein. Furthermore, we will focus on the more relevant therapeutical strategies currently used, namely those involving antioxidants, drugs for neurotransmission improvement, hormonal replacement, gamma- and beta- secretase inhibitors, Abeta clearance agents (Abeta immunization, disruption of Abeta fibrils, modulation of the cholesterol-mediated Abeta transport), non-steroidal anti-inflammatory drugs (NSAIDs), microtubules stabilizing drugs and kinase inhibitors.

Alzheimer Disease↗

PubMed2004

IgA response in serum and gut secretion in sensitized mice fed with the dust mite Dermatophagoides pteronyssinus extract.

Induced oral tolerance to mucosal-exposed antigens in immunized animals is of particular interest for the development of immunotherapeutic approaches to human allergic diseases. This is a unique feature of mucosal surfaces which represent the main contact interface with the external environment. However, the influence of oral tolerance on specific and natural polyreactive IgA antibodies, the major defense mechanism of the mucosa, is unknown. We have shown that oral administration of an extract of the dust mite Dermatophagoides pteronyssinus (Dp) to primed mice caused down-regulation of IgE responses and an increase in tumor growth factor-beta secretion. In the present study, we observed that primed inbred female A/Sn mice (8 to 10 weeks old) fed by gavage a total weight of 1.0-mg Dp extract on the 6th, 7th and 8th days post-immunization presented normal secretion of IL-4 and IL-10 in gut-associated lymphoid tissue and a decreased production of interferon gamma induced by Dp in the draining lymph nodes (13,340 +/- 3,519 vs 29,280 +/- 2,971 pg/ml). Mice fed the Dp extract also showed higher levels of serum anti-Dp IgA antibodies and an increase of IgA-secreting cells in mesenteric lymph nodes (N = 10), reflecting an increase in total fecal IgA antibodies (N = 10). The levels of secretory anti-Dp IgA antibodies increased after re-immunization regardless of Dp extract feeding. Oral tolerance did not interfere with serum or secretory IgA antibody reactivity related to self and non-self antigens. These results suggest that induction of oral tolerance to a Dp extract in sensitized mice triggered different regulatory mechanisms which inhibited the IgE response and stimulated systemic and secretory IgA responses, preserving the natural polyreactive IgA antibody production.

Administration, Oral↗

PubMed2004

Blomia tropicalis and Dermatophagoides pteronyssinus mites evoke distinct patterns of airway cellular influx in type I hypersensitivity murine model.

Murine models of hypersensitivity to allergens are useful tools for the evaluation of strategies to downmodulate IgE response. We sought to compare allergen inflammatory pulmonary response in previously sensitized mice orally administered with dust mites Blomia tropicalis (Bt) or Dermatophagoides pteronyssinus (Dp). Sensitized A/Sn mice fed with Bt or Dp showed a significant decrease in the IgE response compared to control-immunized mice. Bt-immunized mice demonstrated an accumulation of neutrophils in the bronchoalveolar lavage fluid, while Dp-immunized mice revealed an intense influx of eosinophils in the airway. Bt oral administration did not attenuate cell influx in the airway and Dp-fed mice showed a significant decrease of neutrophils and lymphocytes in the bronchoalveolar lavage fluid. These findings demonstrated that oral tolerance induction to Bt and Dp extract in sensitized mice decrease IgE response, but does not interfere in local inflammatory pulmonary response. The distinct profile of airway cellular infiltration between mites immunization suggest an interesting model to study allergic inflammation.

Animals↗

PubMed2004

Effect of streptozotocin-induced diabetes on rat brain mitochondria.

This study evaluated several parameters related to mitochondrial function and oxidative stress in streptozotocin (STZ)-treated rats, a model of type 1 diabetes. For this purpose, the respiratory indexes (RCR and ADP/O ratio), mitochondrial transmembrane potential (DeltaPsim), repolarization lag phase, repolarization level, mitochondrial enzymatic activities, ATP and malondialdehyde (MDA) levels, reduced glutathione (GSH), vitamin E and cardiolipin contents were determined in rat brain mitochondria isolated after 4 and 9 weeks after STZ treatment. Brain mitochondria isolated from citrate (vehicle)-treated Wistar rats were used as control. We observed that STZ-induced diabetes did not substantially affect brain mitochondrial function. Instead, 4-week diabetic rats presented higher mitochondrial respiratory chain enzymatic activities, especially succinate-cytochrome C reductase activity, compared to 4-week control rats. In 9-week diabetic rats, only a significant decrease in cardiolipin content was observed; however, a significant increase in mitochondrial GSH content occurred. All other parameters analysed remained statistically unchanged. From these results, we conclude that STZ-induced diabetes did not promote brain mitochondrial dysfunction, suggesting that oxidative stress associated with type 1 diabetes is not directly related to mitochondrial dysfunction, but probably is related to extramitochondrial factor(s).

Animals↗

PubMed2003

Aluminium-induced impairment of Ca2+ modulatory action on GABA transport in brain cortex nerve terminals.

The gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in vertebrate CNS. At GABAergic synapses, a high-affinity transporter exists, which is responsible for GABA reuptake and release during neurotransmission. GABA transporter activity depends on the phosphorylation/dephosphorylation state, being modulated by Ca(2+)/calmodulin-dependent protein phosphatase 2B (calcineurin). Aluminium is known to interfere with the Ca(2+)/calmodulin signalling pathway. In this work, we investigate the action of aluminium on GABA translocation mediated by the high-affinity transporter, using synaptic plasma membrane (SPM) vesicles and synaptosomes isolated from brain cortex. Aluminium completely relieved Ca(2+) downregulation of GABA transporter, when mediating uptake or release. Accordingly, aluminium inhibited Ca(2+)/calmodulin-dependent calcineurin activity present in SPM, in a concentration-dependent manner. The deleterious action of aluminium on the modulation of GABA transport was ascertained by comparative analysis of the aluminium effect on GABA uptake and release, under conditions favouring SPM dephosphorylation (presence of intracellular micromolar Ca(2+)) or phosphorylation (absence of Ca(2+) and/or presence of W-7, a selective calmodulin antagonist). In conclusion, aluminium-induced relief of Ca(2+) modulatory action on GABA transporter may contribute significantly to modify GABAergic signalling during neurotoxic events in response to aluminium exposure.

Aluminum↗

PubMed2003

Drugs of abuse induce apoptotic features in PC12 cells.

Drugs of abuse induce the release of dopamine in the central nervous system, particularly in the mesolimbic-mesocortical pathway. As dopamine may act as a neurotoxin, in this study, we analyzed the effects of the drugs of abuse, cocaine, heroin, and amphetamine, on the neurodegeneration of PC12 cells, a dopaminergic cell line, by evaluating the activity of caspase-3 and mitochondrial cytochrome c release. All the drugs were shown to induce caspase-3 activation, similarly to staurosporine, a classical inducer of apoptotic cell death. Furthermore, like staurosporine, the drugs of abuse induced a decrease in mitochondrial cytochrome c content, suggesting the involvement of the mitochondrial apoptotic pathway.

Amphetamine↗

PubMed2003

Inhibition of NF-kB renders cells more vulnerable to apoptosis induced by amyloid beta peptides.

One of the mechanisms leading to neurodegeneration during Alzheimer's disease (AD) is amyloid beta peptide neurotoxicity. In response to a variety of stress insults, namely oxidative stress, the transcription factor NF-kB can be activated. We have previously shown that amyloid beta peptides 25-35 and 1-40 (A beta 25-35 and A beta 1-40) induces cell death. In response to A beta 25-35 or 1-40 treatment, we observed an increase in superoxide dismutase (SOD) activity in NT2 cells. Amyloid beta peptides also induced an increase in SOD expression levels. This could result from NF-kB activation, as determined by the expression of p65. We observed that the NF-kB inhibitor, PDTC, prevented SOD overexpression after A beta treatment. Previously we have shown that A beta peptides could activate caspases-mediated apoptotic cell death. In this study, we analyzed if NF-kB activation prevented cells from caspases-activation and we also observed that inhibition of NF-kB by PDTC induced an increase in caspase-3 and caspase-6 activation. Taken together, these data suggest that pharmacological induction of NF-kB can be a potential target in Alzheimer's disease treatment.

Alzheimer Disease↗