[Show abstract][Hide abstract] ABSTRACT: Background
Hydrogen peroxide (H2O2) is a toxic agent that induces oxidative stress and cell death. Silicon (Si) is a biological element involved in limiting aluminium (Al) absorption with possible preventive effects in Alzheimer’s disease. However, Si has not yet been associated with other neuroprotective mechanisms.
The present experiments evaluated in the SH-SY5Y human neuroblastoma cell line the possible role of different Si G5 (50-1000 ng/mL) concentrations in preventing cellular death induced by H2O2 (400 μM, 24 hours).
Our findings showed that H2O2 promoted cell death in the human SH-SY5Y cell cultures and this could be prevented by Si treatment. The loss in cell viability mediated by H2O2 was due to an apoptotic and necrotic process. Apoptotic death was incurred by regulating caspase-8 activity in the extrinsic pathway. The apoptotic and necrotic cell death induced by H2O2 was almost totally reversed by Si (50-500 ng/mL), indicating that it down-regulates both processes in H2O2 treated cells.
According to our data, Si is able to increase SH-SY5Y cell survival throughout partially blocking cellular damage related to oxidative stress through a mechanism that would affect H2O2/ROS elimination.
BMC Complementary and Alternative Medicine 10/2014; 14(1):384. DOI:10.1186/1472-6882-14-384 · 1.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The discovery that nitric oxide (NO) functions as a signalling molecule in the nervous system has radically changed the concept of neuronal communication. NO induces the release of amino acid neurotransmitters but the underlying mechanisms remain to be elucidated.
The aim of this work was to study the effect of NO on amino acid neurotransmitter release (Asp, Glu, Gly and GABA) in cortical neurons as well as the mechanism underlying the release of these neurotransmitters. Cortical neurons were stimulated with SNAP, a NO donor, and the release of different amino acid neurotransmitters was measured by HPLC. The involvement of voltage dependent Na+ and Ca2+ channels as well as cGMP in its mechanism of action was evaluated.
Our results indicate that NO induces release of aspartate, glutamate, glycine and GABA in cortical neurons and that this release is inhibited by ODQ, an inhibitor of soluble guanylate cyclase. Thus, the NO effect on amino acid neurotransmission could be mediated by cGMP formation in cortical neurons. Our data also demonstrate that the Na+ and Ca2+ voltage- dependent calcium channels are involved in the NO effects on cortical neurons.
PLoS ONE 03/2014; 9(3):e90703. DOI:10.1371/journal.pone.0090703 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In the present work, we have studied whether cell death could be induced in cortical neurons from rats subjected to different period of O2 deprivation and low glucose (ODLG). This "in vitro" model is designed to emulate the penumbra area under ischemia. In these conditions, cortical neurons displayed loss of mitochondrial respiratory ability however, nor necrosis neither apoptosis occurred despite ROS production. The absence of cellular death could be a consequence of increased antioxidant responses such as superoxide dismutase-1 (SOD1) and GPX3. In addition, the levels of reduced glutathione were augmented and HIF-1/3α overexpressed. After long periods of ODLG (12-24 h) cortical neurons showed cellular and mitochondrial membrane alterations and did not recuperate cellular viability during reperfusion. This could mean that therapies directed toward prevention of cellular and mitochondrial membrane imbalance or cell death through mechanisms other than necrosis or apoptosis, like authophagy, may be a way to prevent ODLG damage.
International Journal of Molecular Sciences 02/2014; 15(2):2475-93. DOI:10.3390/ijms15022475 · 2.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Brain ischaemia and reperfusion produce alterations in the microenvironment of the parenchyma, including ATP depletion, ionic homeostasis alterations, inflammation, release of multiple cytokines and abnormal release of neurotransmitters. As a consequence, the induction of proliferation and migration of neural stem cells is redirected towards the peri-infarct region. The success of new neurorestorative treatments for damaged brain implies the need to describe with greater accuracy the mechanisms in charge of regulating adult neurogenesis, both under physiological and pathological conditions. Recent evidence demonstrates that many neurotransmitters, glutamate in particular, control the subventricular zone (SVZ), thus being part of the complex signal network that exerts a remarkable influence on the production of new neurons. Neurotransmitters provide a link between brain activity and SVZ neurogenesis. Therefore, a deeper knowledge of the role of neurotransmitters systems, such as glutamate and its transporters, in adult neurogenesis, may prove a valuable tool to be utilised as a neurorestorative therapy in this pathology.
[Show abstract][Hide abstract] ABSTRACT: INTRODUCTION. Brain ischemia and reperfusion produce alterations in the microenvironment of the parenchyma, including ATP depletion, ionic homeostasis alterations, inflammation, release of multiple cytokines and abnormal release of neurotransmitters. As a consequence, the induction of proliferation and migration of neural stem cells towards the peri-infarct region occurs. DEVELOPMENT. The success of new neurorestorative treatments for damaged brain implies the need to know, with greater accuracy, the mechanisms in charge of regulating adult neurogenesis, both under physiological and pathological conditions. Recent evidence demonstrates that many neurotransmitters, glutamate in particular, control the subventricular zone, thus being part of the complex signalling network that influences the production of new neurons. CONCLUSION. Neurotransmitters provide a link between brain activity and subventricular zone neurogenesis. Therefore, a deeper knowledge of the role of neurotransmitters systems, such as glutamate and its transporters, in adult neurogenesis, may provide a valuable tool to be used as a neurorestorative therapy in this pathology.
Revista de neurologia 11/2012; 55(9):533-42. · 0.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To identify the upstream signals of neuronal apoptosis in patients with medically intractable temporal lobe epilepsy (TLE), we evaluated by immunohistochemistry and confocal microscopy brain tissues of 13 TLE patients and 5 control patients regarding expression of chemokines and cell-cycle proteins. The chemokine RANTES (CCR5) and other CC-chemokines and apoptotic markers (caspase-3, -8, -9) were expressed in lateral temporal cortical and hippocampal neurons of TLE patients, but not in neurons of control cases. The chemokine RANTES is usually found in cytoplasmic and extracellular locations. However, in TLE neurons, RANTES was displayed in an unusual location, the neuronal nuclei. In addition, the cell-cycle regulatory transcription factor E2F1 was found in an abnormal location in neuronal cytoplasm. The pro-inflammatory enzyme cyclooxygenase-2 and cytokine interleukin-1β were expressed both in neurons of patients suffering from temporal lobe epilepsy and from cerebral trauma. The vessels showed fibrin leakage, perivascular macrophages and expression of IL-6 on endothelial cells. In conclusion, the cytoplasmic effects of E2F1 and nuclear effects of RANTES might have novel roles in neuronal apoptosis of TLE neurons and indicate a need to develop new medical and/or surgical neuroprotective strategies against apoptotic signaling by these molecules. Both RANTES and E2F1 signaling are upstream from caspase activation, thus the antagonists of RANTES and/or E2F1 blockade might be neuroprotective for patients with medically intractable temporal lobe epilepsy. The results have implications for the development of new medical and surgical therapies based on inhibition of chemotactic and mitogenic stimuli of neuronal apoptosis in patients with medically intractable temporal lobe epilepsy.
[Show abstract][Hide abstract] ABSTRACT: Hematic administration of bone marrow-derived mesenchymal stem cells (MSCs) in acute ischemic stroke may not only be an effective reparative treatment but also a brain protective therapy that improves neurological recovery. Our purpose was to study whether either i.v. or intracarotid (i.c.) administration of allogenic MSCs during the acute phase were effective in improving neurological recovery and decreasing brain damage in an experimental rat model. In a model of permanent middle cerebral artery occlusion (pMCAO), we analyzed: neurological evaluation; MSCs migration and implantation; interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels; lesion volume; cell death; cellular proliferation; vascular endothelial growth factor (VEGF) expression and blood vessel number. Regardless of the administration route, treated groups showed better neurological recovery, without significant differences between the two groups. Migration and implantation of MSCs in the lesion area was observed in animals receiving i.c. but not i.v. treatment. The highest cytokine values were observed in the i.v. MSCs and i.c. control groups, and these levels were significantly different from the corresponding i.v. control and i.c. MSCs groups, respectively. In addition, there were significant differences between the i.v. MSCs and i.c. MSCs groups in IL-6 levels. Neither treatment reduced infarction volume. However, cell death, measured as TUNEL+ cells was decreased with significant differences between control groups. BrdU+ cells were also significantly increased in the peri-infarct zone at 14 days. VEGF expression was significantly higher in the i.c. MSCs group than in the i.c. control group and blood vessel number was significantly higher in treated groups than control groups with significant differences in the peri-infarct zone at 14 days. We conclude that allogenic MSCs administration shows therapeutic efficacy in our acute ischemic stroke model. Both routes demonstrably improved neurological recovery and provided brain protection.
[Show abstract][Hide abstract] ABSTRACT: Growth hormone (GH) and intestinal trefoil factor (ITF) have been involved in intestinal protection and repair. This study investigates the effects of GH administration on ITF expression and histological changes associated with tissue injury in an intestinal rat model of radiation. Adult male rats were divided into four groups: control, GH, radiation and radiation + GH (GHyRAD). Ileum samples were obtained at 2 or 72 h after radiation and processed to determine ITF levels (mRNA and protein) by quantitative polymerase chain reaction, Western blot and immunohistochemistry. In addition, goblet ITF-positive cells were identified by immunohistochemistry at 72 h. Our results showed an upregulation of mRNA and protein production of ITF in ileum samples after GH and radiation + GH compared with control and irradiated samples. Irradiation alone affected ITF protein expression. However, irradiation after GH pretreatment produced the highest ITF mRNA and protein levels at both the tested time points. ITF-producing goblet cells were identified in intestinal villi (apical location). GH treatment increased the number of ITF-producing goblet cells, and radiation after GH treatment displayed further increase in the number of ITF-positive goblet cells. GH upregulates ITF in normal intestinal tissue. This upregulation is higher when radiation is given after GH treatment. Nevertheless, the mechanism by which GH regulates ITF expression remains unclear and is still under investigation. These results could open up new avenues in the therapeutic reparative and protective effects of GH during radiotherapy and chemotherapy.
Experimental Biology and Medicine 02/2011; 236(2):205-11. DOI:10.1258/ebm.2010.009358 · 2.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Neuroinflammation is a key process in the neuropathogenesis of AIDS virus since as a result of the aberrant activation of the chemokine receptors (CXCR4, CX3CR1 and CR5) produces proinflammatory cytokine release by infected cells, increases microglial neurotoxicity and generates lipoperoxides and reactive oxygen species (ROS) that eventually damage the neuron. Moreover, the neurotoxin Tat produces dendritic loss by interacting with the low-density lipoprotein receptor (LRP) and also overstimulates N-methyl D-aspartate receptors (NMDA). Furthermore, the aberrant interaction of glycoprotein gp120 with the CXCR4 chemokine receptor causes caspase-3-dependent apoptosis (ceramide is also released) activating apoptotic proteins (p53 and retinoblastoma), which are part of the neurotoxic mechanisms associated to neuronal dysfunction in neuroAIDS. Similarly, gliosis/microglial activation and the release of neurotoxic factors by infected monocytes with elevated amounts of certain chemokines in the cerebrospinal fluid (MCP-1 and fractalkine, among others) contribute to the neuropathogenesis of HIV-1. Alpha-synuclein and beta amyloid deposits have also been detected in post mortem brains of seropositives patients. In addition, there are studies have detected several systemic markers related with the degenerative effects of the virus and its neurotoxins on the central nervous system; such as osteopontin, CD163 and fractalkine, among others. Lastly, clinical trials have been conducted using protective strategies related that attempt to inhibit apoptotic proteins (GSK-3 beta), microglial activation inhibitors (minocycline), antioxidants (selegiline) or trophic factors (IGF-1, growth hormone or erythropoietin). These trials have shown that their treatments are beneficial and complementary to treat complications of HIV/AIDS.
Revista de neurologia 01/2011; 52(2):101-11. · 0.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Among available treatments in the acute ischemic stroke, only intravenous thrombolysis has been demonstrated to be efficacious. Although the majority of pharmacological neuroprotectants have been efficacious in experimental studies, they have failed in clinical trials. Hence, we need to consider integrated cerebral protection which includes the concept of cerebral repair by supporting cerebral plasticity. We provide a nonsystematic review of the studies published on cerebral protection and repair treatments of cerebral ischemia considering the possibilities of stimulating brain plasticity by trophic factors and cell therapy. The majority of the neuroprotective drugs have failed in clinical trials. Citicoline shows a benefit in meta-analysis and it is currently being explored in a new trial (ICTUS). Neuroprotective drugs combined with reperfusion offer favorable results in experimental animals, but data from clinical studies are not enough. Repair therapies using cerebral plasticity stimulation (trophic factors) and cell therapy have shown certain efficacy in experimental and clinical studies and they are a developing route with clinical therapeutic perspectives.