Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 10 de 10
Filter
Add more filters










Publication year range
1.
Mol Neurobiol ; 57(10): 4187-4201, 2020 Oct.
Article in English | MEDLINE | ID: mdl-32683653

ABSTRACT

Amyloid-ß (Aß) peptides play a significant role in the pathogenesis of Alzheimer's disease (AD). Neurotoxic effects promoted by Aß peptides involve glutamate transmission impairment, decrease of neurotrophic factors, mitochondrial dysfunction, oxidative stress, synaptotoxicity, and neuronal degeneration. Here, we assessed the early events evoked by Aß1-40 on the hippocampus. Additionally, we sought to unravel the molecular mechanisms of atorvastatin preventive effect on Aß-induced hippocampal damage. Mice were treated orally (p.o.) with atorvastatin 10 mg/kg/day during 7 consecutive days before the intracerebroventricular (i.c.v.) infusion of Aß1-40 (400 pmol/site). Twenty-four hours after Aß1-40 infusion, a reduced content of mature BDNF/proBDNF ratio was observed in Aß-treated mice. However, there is no alteration in synaptophysin, PSD-95, and doublecortin immunocontent in the hippocampus. Aß1-40 promoted an increase in reactive oxygen species (ROS) and nitric oxide (NO) generation in hippocampal slices, and atorvastatin prevented this oxidative burst. Mitochondrial OXPHOS was measured by high-resolution respirometry. At this time point, Aß1-40 did not alter the O2 consumption rates (OCR) related to phosphorylating state associated with complexes I and II, and the maximal OCR. However, atorvastatin increased OCR of phosphorylating state associated with complex I and complexes I and II, maximal OCR of complexes I and II, and OCR associated with mitochondrial spare capacity. Atorvastatin treatment improved mitochondrial function in the rodent hippocampus, even after Aß infusion, pointing to a promising effect of improving brain mitochondria bioenergetics. Therefore, atorvastatin could act as an adjuvant in battling the symptoms of AD to preventing or delaying the disease progression.


Subject(s)
Amyloid beta-Peptides/administration & dosage , Atorvastatin/pharmacology , Hippocampus/pathology , Mitochondria/metabolism , Oxidative Stress/drug effects , Animals , Brain-Derived Neurotrophic Factor/metabolism , Electron Transport/drug effects , Humans , Injections, Intraventricular , Male , Membrane Potential, Mitochondrial/drug effects , Mice , Mitochondria/drug effects , Nerve Tissue Proteins/metabolism , Nitric Oxide/metabolism , Nitric Oxide Synthase Type II/metabolism , Oxidative Phosphorylation/drug effects , Oxygen Consumption/drug effects , Reactive Oxygen Species/metabolism
2.
Mol Neurobiol ; 54(8): 6163-6173, 2017 Oct.
Article in English | MEDLINE | ID: mdl-27709490

ABSTRACT

Intracerebroventricular (icv) amyloid-beta (Aß)1-40 infusion to mice has been demonstrated to cause neurotoxicty and depressive-like behavior and it can be used to evaluate antidepressant and neuroprotective effect of drugs. Atorvastatin is a widely used statin that has demonstrated antidepressant-like effect in predictable animal behavioral models and neuroprotective effect against Aß1-40 infusion. The purpose of this study was to determine the effect of in vivo atorvastatin treatment against Aß1-40-induced changes in mood-related behaviors and biochemical parameters in ex vivo hippocampal slices from mice. Atorvastatin treatment (10 mg/kg, p.o., once a day for seven consecutive days) abolished depressive-like and anhedonic-like behaviors induced by Aß1-40 (400 pmol/site, icv) infusion. Aß1-40-induced hippocampal cell damage was reversed by atorvastatin treatment. Aß1-40 infusion decreased glutamate uptake in hippocampal slices, and atorvastatin did not altered it. Glutamine synthetase activity was not altered by any treatment. Atorvastatin also increased hippocampal mature brain-derived neurotrophic factor (mBDNF)/precursor BDNF (proBDNF) ratio, suggesting an increase of proBDNF to mBDNF cleavage. Accordingly, increased tissue-type plasminogen activator (tPA) and p11 genic expression were observed in hippocampus of atorvastatin-treated mice. Atorvastatin displays antidepressant-like and neuroprotective effects against Aß1-40-induced toxicity, and these effects may involve tPA- and p11-mediated cleavage of proBDNF to mBDNF.


Subject(s)
Amyloid beta-Peptides/pharmacology , Atorvastatin/therapeutic use , Behavior, Animal/drug effects , Brain-Derived Neurotrophic Factor/metabolism , Cell Death/drug effects , Depression/prevention & control , Neuroprotective Agents/therapeutic use , Peptide Fragments/pharmacology , Protein Precursors/metabolism , Animals , Antidepressive Agents/pharmacology , Antidepressive Agents/therapeutic use , Atorvastatin/pharmacology , Depression/metabolism , Glutamate-Ammonia Ligase/metabolism , Hippocampus/drug effects , Hippocampus/metabolism , Male , Mice , Motor Activity/drug effects , Neurons/drug effects , Neurons/metabolism , Neuroprotective Agents/pharmacology
3.
Purinergic Signal ; 12(4): 707-718, 2016 12.
Article in English | MEDLINE | ID: mdl-27613537

ABSTRACT

Guanosine, the endogenous guanine nucleoside, prevents cellular death induced by ischemic events and is a promising neuroprotective agent. During an ischemic event, nitric oxide has been reported to either cause or prevent cell death. Our aim was to evaluate the neuroprotective effects of guanosine against oxidative damage in hippocampal slices subjected to an in vitro ischemia model, the oxygen/glucose deprivation (OGD) protocol. We also assessed the participation of nitric oxide synthase (NOS) enzymes activity on the neuroprotection promoted by guanosine. Here, we showed that guanosine prevented the increase in ROS, nitric oxide, and peroxynitrite production induced by OGD. Moreover, guanosine prevented the loss of mitochondrial membrane potential in hippocampal slices subjected to OGD. Guanosine did not present an antioxidant effect per se. The protective effects of guanosine were mimicked by inhibition of neuronal NOS, but not of inducible NOS. The neuroprotective effect of guanosine may involve activation of cellular mechanisms that prevent the increase in nitric oxide production, possibly via neuronal NOS.


Subject(s)
Guanosine/pharmacology , Hippocampus/drug effects , Hypoxia/metabolism , Membrane Potential, Mitochondrial/drug effects , Neuroprotective Agents/pharmacology , Oxidative Stress/drug effects , Reactive Oxygen Species/metabolism , Animals , Cell Death/drug effects , Glucose/metabolism , Hippocampus/metabolism , Male , Nitric Oxide Synthase/metabolism , Rats , Rats, Wistar
4.
Neurotox Res ; 29(4): 460-8, 2016 May.
Article in English | MEDLINE | ID: mdl-26858177

ABSTRACT

Guanosine (GUO) has been shown to act as a neuroprotective agent against glutamatergic excitotoxicity by increasing glutamate uptake and decreasing its release. In this study, a putative effect of GUO action on glutamate transporters activity modulation was assessed in hippocampal slices subjected to oxygen and glucose deprivation (OGD), an in vitro model of brain ischemia. Slices subjected to OGD showed increased excitatory amino acids release (measured by D-[(3)H]aspartate release) that was prevented in the presence of GUO (100 µM). The glutamate transporter blockers, DL-TBOA (10 µM), DHK (100 µM, selective inhibitor of GLT-1), and sulfasalazine (SAS, 250 µM, Xc(-) system inhibitor) decreased OGD-induced D-aspartate release. Interestingly, DHK or DL-TBOA blocked the decrease in glutamate release induced by GUO, whereas SAS did not modify the GUO effect. GUO protected hippocampal slices from cellular damage by modulation of glutamate transporters, however selective blockade of GLT-1 or Xc- system only did not affect this protective action of GUO. OGD decreased hippocampal glutamine synthetase (GS) activity and GUO recovered GS activity to control levels without altering the kinetic parameters of GS activity, thus suggesting GUO does not directly interact with GS. Additionally, the pharmacological inhibition of GS activity with methionine sulfoximine abolished the effect of GUO in reducing D-aspartate release and cellular damage evoked by OGD. Altogether, results in hippocampal slices subjected to OGD show that GUO counteracts the release of excitatory amino acids, stimulates the activity of GS, and decreases the cellular damage by modulation of glutamate transporters activity.


Subject(s)
Amino Acid Transport System X-AG/metabolism , Glucose/deficiency , Glutamate-Ammonia Ligase/metabolism , Guanosine/pharmacology , Hippocampus/drug effects , Hypoxia/pathology , Analysis of Variance , Animals , Aspartic Acid/pharmacokinetics , Dose-Response Relationship, Drug , Enzyme Inhibitors/pharmacology , Gene Expression Regulation/drug effects , Glutamine/pharmacology , In Vitro Techniques , Male , Rats , Rats, Wistar , Tritium/pharmacokinetics
5.
Neurotox Res ; 28(1): 32-42, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25827781

ABSTRACT

Deposition of amyloid-ß (Aß) peptides into specific encephalic structures has been pointed as an important event related to Alzheimer's disease pathogenesis and associated with activation of glial cells, neuroinflammation, oxidative responses, and cognitive deficits. Aß-induced pro-oxidative damage may regulate the activity of glutamate transporters, leading to reduced glutamate uptake and, as a consequence, excitotoxic events. Herein, we evaluated the effects of the pretreatment of atorvastatin, a HMG-CoA reductase inhibitor, on behavioral and biochemical alterations induced by a single intracerebroventricular (i.c.v.) injection of aggregated Aß1-40 in mice. Atorvastatin (10 mg/kg/day, p.o.) was administered through seven consecutive days before Aß1-40 administration. Aß1-40 caused significant cognitive impairment in the object-place recognition task (2 weeks after the i.c.v. injection) and this phenomenon was abolished by atorvastatin pretreatment. Ex vivo evaluation of glutamate uptake into hippocampal and cerebral cortices slices showed atorvastatin, and Aß1-40 decreased hippocampal and cortical Na(+)-dependent glutamate uptake. However, Aß1-40 increased Na(+)-independent glutamate uptake and it was prevented by atorvastatin in prefrontal cortex slices. Moreover, Aß1-40 treatment significantly increased the cerebrocortical activities of glutathione reductase and glutathione peroxidase and these events were blunted by atorvastatin pretreatment. Reduced or oxidized glutathione levels were not altered by Aß1-40 and/or atorvastatin treatment. These results extend the notion of the protective action of atorvastatin against neuronal toxicity induced by Aß1-40 demonstrating that a pretreatment with atorvastatin prevents the spatial learning and memory deficits induced by Aß in rodents and promotes changes in glutamatergic and antioxidant systems mainly in prefrontal cortex.


Subject(s)
Amyloid beta-Peptides/toxicity , Atorvastatin/administration & dosage , Cognition Disorders/chemically induced , Cognition Disorders/prevention & control , Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage , Peptide Fragments/toxicity , Acetylcholinesterase/metabolism , Animals , Glutamic Acid/metabolism , Hippocampus/drug effects , Hippocampus/metabolism , Infusions, Intraventricular , Male , Mice , Oxidative Stress , Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , Recognition, Psychology/drug effects , Spatial Learning/drug effects , Spatial Memory/drug effects
6.
J Pharm Pharmacol ; 66(9): 1294-302, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24707860

ABSTRACT

OBJECTIVES: Aloysia gratissima aqueous extract (AE) was investigated as a putative protective agent against quinolinic acid (QA)-induced seizures in mice and hippocampal cell damage. Additionally, AE and ferulic acid (FA), the major compound of AE, were tested against neurotoxicity evoked by glutamate or its N-methyl-D-aspartate receptor (NMDAR) agonist, QA on hippocampal slices, in vitro. METHODS: Mice were treated with AE before QA infusion (36.8 nmol/site) and seizures were analysed. Cellular viability and modulation of excitatory amino acid transport were verified in hippocampal slices. In-vitro AE or FA was tested against neurotoxicity induced by glutamate or QA. KEY FINDINGS: AE did not prevent QA-induced seizures; however, it prevented cellular death and disruption of excitatory amino acid transport. In-vitro AE (0.1 or 1.0 mg/ml) or FA (1 or 10 µm), improved cell viability against citotoxicity exerted by glutamate or QA, respectively. Both AE and FA have protective effects depending on activation of the phosphatidylinositol-3 kinase (PI3K) signalling pathway. CONCLUSIONS: AE attenuated QA-induced cell damage possibly involving the glutamate transport modulation through NMDAR interaction. FA shows a similar profile of neuroprotection promoted by AE. Therefore, AE treatment might be a useful strategy in preventing brain damage caused by exacerbation of glutamatergic toxicity in nervous system disorders.


Subject(s)
Glutamic Acid/adverse effects , Hippocampus/drug effects , Neurotoxicity Syndromes/drug therapy , Phytotherapy , Plant Extracts/therapeutic use , Quinolinic Acid/adverse effects , Verbenaceae/chemistry , Animals , Biological Transport , Cell Death/drug effects , Cell Survival/drug effects , Coumaric Acids/pharmacology , Coumaric Acids/therapeutic use , Excitatory Amino Acid Agonists/adverse effects , Excitatory Amino Acids/metabolism , Hippocampus/metabolism , Hippocampus/pathology , Male , Mice, Inbred Strains , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Neurotoxicity Syndromes/metabolism , Neurotoxicity Syndromes/pathology , Phosphatidylinositol 3-Kinase/metabolism , Plant Extracts/pharmacology , Receptors, N-Methyl-D-Aspartate/agonists , Seizures/chemically induced , Seizures/metabolism
7.
J Neurochem ; 126(4): 437-50, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23713463

ABSTRACT

Guanosine (GUO) is an endogenous modulator of glutamatergic excitotoxicity and has been shown to promote neuroprotection in in vivo and in vitro models of neurotoxicity. This study was designed to understand the neuroprotective mechanism of GUO against oxidative damage promoted by oxygen/glucose deprivation and reoxygenation (OGD). GUO (100 µM) reduced reactive oxygen species production and prevented mitochondrial membrane depolarization induced by OGD. GUO also exhibited anti-inflammatory actions as inhibition of nuclear factor kappa B activation and reduction of inducible nitric oxide synthase induction induced by OGD. These GUO neuroprotective effects were mediated by adenosine A1 receptor, phosphatidylinositol-3 kinase and MAPK/ERK. Furthermore, GUO recovered the impairment of glutamate uptake caused by OGD, an effect that occurred via a Pertussis toxin-sensitive G-protein-coupled signaling, blockade of adenosine A2A receptors (A2A R), but not via A1 receptor. The modulation of glutamate uptake by GUO also involved MAPK/ERK activation. In conclusion, GUO, by modulating adenosine receptor function and activating MAPK/ERK, affords neuroprotection of hippocampal slices subjected to OGD by a mechanism that implicates the following: (i) prevention of mitochondrial membrane depolarization, (ii) reduction of oxidative stress, (iii) regulation of inflammation by inhibition of nuclear factor kappa B and inducible nitric oxide synthase, and (iv) promoting glutamate uptake.


Subject(s)
Encephalitis , Guanosine/metabolism , Hippocampus/immunology , Hippocampus/metabolism , Hypoxia, Brain , Animals , Cell Survival/drug effects , Cell Survival/physiology , Encephalitis/drug therapy , Encephalitis/immunology , Encephalitis/metabolism , GTP-Binding Protein alpha Subunits, Gi-Go/metabolism , Glucose/pharmacology , Glutamic Acid/pharmacokinetics , Guanosine/pharmacology , Hippocampus/cytology , Hypoxia, Brain/drug therapy , Hypoxia, Brain/immunology , Hypoxia, Brain/metabolism , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/immunology , Male , Membrane Potential, Mitochondrial/physiology , NF-kappa B/metabolism , Nerve Tissue Proteins/metabolism , Neuroprotective Agents/pharmacology , Nitric Oxide Synthase Type II/metabolism , Organ Culture Techniques , Oxidative Stress/drug effects , Oxidative Stress/physiology , Oxygen/pharmacology , Phosphatidylinositol 3-Kinases/metabolism , Rats , Rats, Wistar , Reactive Oxygen Species/metabolism , Receptor, Adenosine A1/metabolism , Synaptotagmins , Tritium
8.
Neurochem Int ; 62(7): 948-55, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23500607

ABSTRACT

Oxygen-glucose deprivation (OGD) in brain cells increases extracellular glutamate concentration leading to excitotoxicity. Glutamate uptake from the synaptic cleft is carried out by glutamate transporters, which are likely to be modulated by oxidative stress. Therefore, oxidative stress is associated with reduced activity of glutamate transporters and glutamine synthetase, thus increasing extracellular glutamate levels that may aggravate damage to brain cells. Atorvastatin, a cholesterol-lowering agent, has been shown to exert neuroprotective effects. The aim of this study was to investigate if in vivo atorvastatin treatment would have protective effects against hippocampal slices subjected to OGD, ex vivo. Atorvastatin pretreatment promoted increased cell viability after OGD and reoxygenation of hippocampal slices. Atorvastatin-induced neuroprotection may be related to diminished oxidative stress, since it prevented OGD-induced decrement of non-proteic thiols (NPSH) levels and increase in the production of reactive oxygen species (ROS). Atorvastatin pretreatment also prevented the OGD-induced decrease in glutamate uptake and glutamine synthetase activity, although it had no effect on OGD-induced excitatory aminoacids release. Addition of cholesterol before OGD and reoxygenation, abolished the protective effect of atorvastatin on cellular viability as well as on glutamate uptake and glutamine synthetase activity. Therefore, atorvastatin is capable of preventing OGD-induced cell death, an effect achieved due to modulation of glutamate uptake and glutamine synthetase activity, and associated with diminished oxidative stress. Additionally, atorvastatin effects were dependent on its action on cholesterol synthesis inhibition. Thus, atorvastatin might be a useful strategy in the prevention of glutamate exitotoxicity involved in brain injuries such as vascular disorders.


Subject(s)
Glutamate-Ammonia Ligase/metabolism , Glutamic Acid/metabolism , Heptanoic Acids/pharmacology , Hippocampus/drug effects , Oxidative Stress/drug effects , Pyrroles/pharmacology , Animals , Atorvastatin , Cell Death/drug effects , Glucose/metabolism , Glutamic Acid/drug effects , Male , Mice , Neurons/drug effects , Neurons/metabolism , Neuroprotective Agents/pharmacology , Oxygen/metabolism , Reactive Oxygen Species/metabolism
9.
Neurotox Res ; 16(2): 106-15, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19526287

ABSTRACT

Statins are cholesterol-lowering agents due to the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Recent studies have shown statins possess pleiotropic effects, which appear to be independent from its cholesterol-lowering action. In this study, we investigated whether atorvastatin would have protective effects against hippocampal cell death promoted by quinolinic acid (QA)-induced seizures in mice. Mice were pretreated with Atorvastatin (1 or 10 mg/kg) or vehicle (saline, 0.9%), orally, once a day for 7 days before the intracerebroventricular (i.c.v.) QA infusion (36.8 nmol/site). Atorvastatin treatment with 1 mg/kg/day did not significantly prevent QA-induced seizures (13.34%). However, administration of atorvastatin 10 mg/kg/day prevented the clonic and/or tonic seizures induced by QA in 29.41% of the mice. Additionally, administration of atorvastatin 10 mg/kg/day significantly prevented QA-induced cell death in the hippocampus. Atorvastatin treatment promoted an increased Akt phosphorylation, which was sustained after QA infusion in both convulsed and non-convulsed mice. Moreover, atorvastatin pretreatment prevented the reduction in glutamate uptake into hippocampal slices induced by QA i.c.v. infusion. These results show that atorvastatin attenuated QA-induced hippocampal cellular death involving the Akt pathway and glutamate transport modulation. Therefore, atorvastatin treatment might be a useful strategy in the prevention of brain injury caused by the exacerbation of glutamatergic toxicity in neurological diseases such as epilepsy.


Subject(s)
Heptanoic Acids/therapeutic use , Hippocampus/drug effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Oncogene Protein v-akt/metabolism , Pyrroles/therapeutic use , Quinolinic Acid , Seizures , Analysis of Variance , Animals , Atorvastatin , Cell Death/drug effects , Complex Mixtures/metabolism , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Administration Schedule , Heptanoic Acids/pharmacology , Hippocampus/pathology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , In Vitro Techniques , Male , Mice , Phosphorylation/drug effects , Pyrroles/pharmacology , Seizures/chemically induced , Seizures/pathology , Seizures/prevention & control , Tetrazolium Salts , Thiazoles , Tritium/metabolism
10.
Neurochem Int ; 52(3): 411-8, 2008 Feb.
Article in English | MEDLINE | ID: mdl-17822807

ABSTRACT

Guanine derivates have been implicated in many relevant extracellular roles, such as modulation of glutamate transmission, protecting neurons against excitotoxic damage. Guanine derivatives are spontaneously released to the extracellular space from cultured astrocytes during oxygen-glucose deprivation (OGD) and may act as trophic factors, glutamate receptors blockers or glutamate transport modulators, thus promoting neuroprotection. The aim of this study was to evaluate the mechanisms involved in the neuroprotective role of the nucleoside guanosine in rat hippocampal slices submitted to OGD, identifying a putative extracellular binding site and the intracellular signaling pathways related to guanosine-induced neuroprotection. Cell damage to hippocampal slices submitted to 15 min of OGD followed by 2 h of reperfusion was decreased by the addition of guanosine (100 microM) or guanosine-5'-monophosphate (GMP, 100 microM). The neuroprotective effect of guanosine was not altered by the addition of adenosine receptor antagonists, nucleosides transport inhibitor, glutamate receptor antagonists, glutamate transport inhibitors, and a non-selective Na(+) and Ca(2+) channel blocker. However, in a Ca(2+)-free medium (by adding EGTA), guanosine was ineffective. Nifedipine (a Ca(2+) channel blocker) increased the neuroprotective effect of guanosine and 4-aminopyridine, a K(+) channel blocker, reversed the neuroprotective effect of guanosine. Evaluation of the intracellular signaling pathways associated with guanosine-induced neuroprotection showed the involvement of PKA, PKC, MEK and PI-3 K pathways, but not CaMKII. Therefore, this study shows guanosine is acting via K(+) channels activation, depending on extracellular Ca(2+) levels and via modulation of the PKA, PKC, MEK and/or PI-3 K pathways.


Subject(s)
Cytoprotection/physiology , Guanosine/metabolism , Hippocampus/metabolism , Hypoxia-Ischemia, Brain/metabolism , Neuroprotective Agents/metabolism , Animals , Binding Sites/drug effects , Binding Sites/physiology , Calcium Channel Blockers/pharmacology , Calcium Channels/drug effects , Calcium Channels/metabolism , Cytoprotection/drug effects , Guanosine/pharmacology , Guanosine Monophosphate/metabolism , Guanosine Monophosphate/pharmacology , Hippocampus/drug effects , Hypoxia-Ischemia, Brain/drug therapy , Hypoxia-Ischemia, Brain/physiopathology , Male , Neuroprotective Agents/pharmacology , Organ Culture Techniques , Potassium Channel Blockers/pharmacology , Potassium Channels/drug effects , Potassium Channels/metabolism , Protein Kinases/drug effects , Protein Kinases/metabolism , Rats , Rats, Wistar , Reperfusion Injury/drug therapy , Reperfusion Injury/metabolism , Reperfusion Injury/physiopathology , Signal Transduction/drug effects , Signal Transduction/physiology
SELECTION OF CITATIONS
SEARCH DETAIL
...