Antidepressant-Like Effects of Chronic Guanosine in the Olfactory Bulbectomy Mouse Model.

Major depressive disorder (MDD) leads to pervasive changes in the health of afflicted patients. Despite advances in the understanding of MDD and its treatment, profound innovation is needed to develop fast-onset antidepressants with higher effectiveness. When acutely administered, the endogenous nucleoside guanosine (GUO) shows fast-onset antidepressant-like effects in several mouse models, including the olfactory bulbectomy (OBX) rodent model.

Effects of intranasal guanosine administration on brain function in a rat model of ischemic stroke.

Ischemic stroke is a major cause of morbidity and mortality worldwide and only few affected patients are able to receive treatment, especially in developing countries. Detailed pathophysiology of brain ischemia has been extensively studied in order to discover new treatments with a broad therapeutic window and that are accessible to patients worldwide. The nucleoside guanosine (Guo) has been shown to have neuroprotective effects in animal models of brain diseases, including ischemic stroke.

Effect of Proline on Cell Death, Cell Cycle, and Oxidative Stress in C6 Glioma Cell Line.

Since proline metabolism has been implicated to play an underlying role in apoptotic signaling and cancer, and hyperprolinemic patients present susceptibility to tumors development, this study investigated the effect of proline on cell death, cell cycle, antioxidant enzymes activities, and immunocontent/activity of proteins involved in cell death/survival signaling pathways in C6 glioma cells. C6 cells were incubated with proline (0-5 mM) for 1 h, 24 h, 48 h, 72 h, or 7 days. Proline in high concentrations slightly decreased LDH release, and no cytotoxic effect was seen by Annexin-PI staining.

Impairment of GABAergic system contributes to epileptogenesis in glutaric acidemia type I.

Objectives: Glutaric acidemia type I (GA-I) is an inherited neurometabolic disorder caused by deficiency of glutaryl-CoA dehydrogenase (GCDH) and characterized by increased levels of glutaric, 3-OH-glutaric, and glutaconic acids in the brain parenchyma. The increment of these organic acids inhibits glutamate decarboxylase (GAD) and consequently lowers the γ-aminobutyric acid (GABA) synthesis. Untreated patients exhibit severe neurologic deficits during development, including epilepsy, especially following an acute encephalopathy outbreak.

α-Ketoadipic Acid and α-Aminoadipic Acid Cause Disturbance of Glutamatergic Neurotransmission and Induction of Oxidative Stress In Vitro in Brain of Adolescent Rats.

Tissue accumulation of α-ketoadipic (KAA) and α-aminoadipic (AAA) acids is the biochemical hallmark of α-ketoadipic aciduria. This inborn error of metabolism is currently considered a biochemical phenotype with uncertain clinical significance. Considering that KAA and AAA are structurally similar to α-ketoglutarate and glutamate, respectively, we investigated the in vitro effects of these compounds on glutamatergic neurotransmission in the brain of adolescent rats.

Olfactory bulbectomy in mice triggers transient and long-lasting behavioral impairments and biochemical hippocampal disturbances.

Major depressive disorder (MDD) is a neuropsychiatric disease that is associated with profound disturbances in affected individuals. Elucidating the pathophysiology of MDD has been frustratingly slow, especially concerning the neurochemical events and brain regions associated with disease progression. Thus, we evaluated the time-course (up to 8weeks) behavioral and biochemical effects in mice that underwent to a bilateral olfactory bulbectomy (OBX), which is used to modeling depressive-like behavior in rodents.

Calcium signaling mechanisms disrupt the cytoskeleton of primary astrocytes and neurons exposed to diphenylditelluride.

Background: Diphenylditelluride (PhTe)2 is a potent neurotoxin disrupting the homeostasis of the cytoskeleton.

Methods: Cultured astrocytes and neurons were incubated with (PhTe)2, receptor antagonists and enzyme inhibitors followed by measurement of the incorporation of [32P]orthophosphate into intermediate filaments (IFs).

Results: (PhTe)2 caused hyperphosphorylation of glial fibrillary acidic protein (GFAP), vimentin and neurofilament subunits (NFL, NFM and NFH) from primary astrocytes and neurons, respectively.

Guanosine Anxiolytic-Like Effect Involves Adenosinergic and Glutamatergic Neurotransmitter Systems.

Accumulating evidences indicate that endogenous modulators of excitatory synapses in the mammalian brain are potential targets for treating neuropsychiatric disorders. Indeed, glutamatergic and adenosinergic neurotransmissions were recently highlighted as potential targets for developing innovative anxiolytic drugs. Accordingly, it has been shown that guanine-based purines are able to modulate both adenosinergic and glutamatergic systems in mammalian central nervous system.

Intranasal guanosine administration presents a wide therapeutic time window to reduce brain damage induced by permanent ischemia in rats.

In addition to its intracellular roles, the nucleoside guanosine (GUO) also has extracellular effects that identify it as a putative neuromodulator signaling molecule in the central nervous system. Indeed, GUO can modulate glutamatergic neurotransmission, and it can promote neuroprotective effects in animal models involving glutamate neurotoxicity, which is the case in brain ischemia. In the present study, we aimed to investigate a new in vivo GUO administration route (intranasal, IN) to determine putative improvement of GUO neuroprotective effects against an experimental model of permanent focal cerebral ischemia.

Severe Hyperhomocysteinemia Decreases Respiratory Enzyme and Na(+)-K(+) ATPase Activities, and Leads to Mitochondrial Alterations in Rat Amygdala.

Severe hyperhomocysteinemia is caused by increased plasma levels of homocysteine (Hcy), a methionine derivative, and is associated with cerebral disorders. Creatine supplementation has emerged as an adjuvant to protect against neurodegenerative diseases, due to its potential antioxidant role. Here, we examined the effects of severe hyperhomocysteinemia on brain metabolism, and evaluated a possible neuroprotective role of creatine in hyperhomocysteinemia, by concomitant treatment with Hcy and creatine (50 mg/Kg body weight).

High postnatal susceptibility of hippocampal cytoskeleton in response to ethanol exposure during pregnancy and lactation.

Ethanol exposure to offspring during pregnancy and lactation leads to developmental disorders, including central nervous system dysfunction. In the present work, we have studied the effect of chronic ethanol exposure during pregnancy and lactation on the phosphorylating system associated with the astrocytic and neuronal intermediate filament (IF) proteins: glial fibrillary acidic protein (GFAP), and neurofilament (NF) subunits of low, medium, and high molecular weight (NFL, NFM, and NFH, respectively) in 9- and 21-day-old pups. Female rats were fed with 20% ethanol in their drinking water during pregnancy and lactation.

Crosstalk Among Disrupted Glutamatergic and Cholinergic Homeostasis and Inflammatory Response in Mechanisms Elicited by Proline in Astrocytes.

Hyperprolinemias are inherited disorder of proline (Pro) metabolism. Patients affected may present neurological manifestations, but the mechanisms of neural excitotoxicity elicited by hyperprolinemia are far from being understood. Considering that the astrocytes are important players in neurological disorders, the aim of the present work was to study the effects 1 mM Pro on glutamatergic and inflammatory parameters in cultured astrocytes from cerebral cortex of rats, exploring some molecular mechanisms underlying the disrupted homeostasis of astrocytes exposed to this toxic Pro concentration.

Experimental Lung Injury Promotes Changes in Oxidative/Nitrative Status and Inflammatory Markers in Cerebral Cortex of Rats.

In the present study, we investigate the effect of lung injury on parameters of oxidative/nitrative stress [reactive oxygen species production, nitrite levels, thiobarbituric acid-reactive substances (TBARS), carbonyl content, sulfhydryl content, activities of antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase), total radical-trapping antioxidant potential, glutathione content, and glucose-6-phosphate dehydrogenase], as well as on inflammation mediators [immunocontent of nuclear factor-kappaB (NF-κB) total (p65), NF-κB phosphorylated (pp65) subunit (cytosolic and nuclear), TNF-α, IL-1β, IL-6, and IL-10] in the cerebral cortex. Cytokine levels in serum were also evaluated. Adult Wistar rats were submitted to lung injury induced by intratracheal instillation of lipopolysaccharide in a dose of 100 μg/100 g body weight.

Mild hyperhomocysteinemia increases brain acetylcholinesterase and proinflammatory cytokine levels in different tissues.

Mild hyperhomocysteinemia is considered to be a risk factor for cerebral and cardiovascular disorders and can be modeled in experimental rats. Inflammation has been implicated in the toxic effects of homocysteine. Cholinergic signaling controls cytokine production and inflammation through the "cholinergic anti-inflammatory pathway," and brain acetylcholinesterase activity plays a role in this regulation.

Experimental lung injury promotes alterations in energy metabolism and respiratory mechanics in the lungs of rats: prevention by exercise.

In the present study we investigated the effects of lung injury on energy metabolism (succinate dehydrogenase, complex II, cytochrome c oxidase, and ATP levels), respiratory mechanics (dynamic and static compliance, elastance and respiratory system resistance) in the lungs of rats, as well as on phospholipids in bronchoalveolar lavage fluid. The protective effect of physical exercise on the alterations caused by lung injury, including lung edema was also evaluated. Wistar rats were submitted to 2 months of physical exercise.

Mild hyperhomocysteinemia reduces the activity and immunocontent, but does not alter the gene expression, of catalytic α subunits of cerebral Na+,K+-ATPase.

Na(+),K(+)-ATPase is a membrane protein which plays a key role in the maintenance of ion homeostasis that is necessary to neuronal excitability, secondary transport and neurotransmitter uptake. Mild hyperhomocysteinemia leads to several clinical manifestations and particularly cerebral diseases; however, little is known about the mechanisms of homocysteine on cerebral Na(+),K(+)-ATPase. In the present study, we investigated the effect of mild hyperhomocysteinemia on the activity, the immunocontent of catalytic subunits (α1, α2, and α3) and the gene expression of this enzyme.

Methylglyoxal-induced cytotoxicity in neonatal rat brain: a role for oxidative stress and MAP kinases.

Carbonyl compounds such as methylglyoxal (MGO) seem to play an important role in complications resulting from diabetes mellitus, in aging and neurodegenerative disorders. In this study, we are showing, that MGO is able to suppress cell viability and induce apoptosis in the cerebral cortex and hippocampus of neonatal rats ex-vivo. These effects are partially related with ROS production, evaluated by DCFH-DA assay.

Disrupted cytoskeletal homeostasis, astrogliosis and apoptotic cell death in the cerebellum of preweaning rats injected with diphenyl ditelluride.

In the present report 15 day-old rats were injected with 0.3μmol of diphenyl ditelluride (PhTe)(2)/kg body weight and parameters of neurodegeneration were analyzed in slices from cerebellum 3 and 6 days afterwards. The earlier responses, at day 3 after injection, included hyperphosphorylation of intermediate filament (IF) proteins from astrocyte (glial fibrillary acidic protein - GFAP - and vimentin) and neuron (low-, medium- and high molecular weight neurofilament subunits: NF-L, NF-M and NF-H); increased mitogen-activated protein kinase (MAPK) (Erk and p38MAPK) and cAMP-dependent protein kinase (PKA) activities.

Cytoskeleton of cortical astrocytes as a target to proline through oxidative stress mechanisms.

Hyperprolinemia is an inherited disorder of proline (Pro) metabolism and patients affected by this disease may present neurological manifestations. However, the mechanisms of neural excitotoxicity elicited by hyperprolinemia are far from being understood. Considering the pivotal role of cytoskeletal remodeling in several neurodegenerative pathologies and the potential links between cytoskeleton, reactive oxygen species production and cell death, the aim of the present work was to study the effects of Pro on astrocyte and neuron cytoskeletal remodeling and the possible oxidative stress involvement.

In vivo treatment with diphenyl ditelluride induces neurodegeneration in striatum of young rats: implications of MAPK and Akt pathways.

In the present report 15day-old Wistar rats were injected with 0.3μmol of diphenyl ditelluride (PhTe)(2)/kg body weight and parameters of neurodegeneration were analyzed in slices from striatum 6days afterwards. We found hyperphosphorylation of intermediate filament (IF) proteins from astrocyte (glial fibrillary acidic protein-GFAP and vimentin) and from neuron (low-, medium- and high molecular weight neurofilament subunits: NF-L, NF-M and NF-H, respectively) and increased MAPK (Erk, JNK and p38MAPK) as well as PKA activities.

Exposure of young rats to diphenyl ditelluride during lactation affects the homeostasis of the cytoskeleton in neural cells from striatum and cerebellum.

In the present report we examined the effect of maternal exposure to diphenyl ditelluride (PhTe)(2) (0.01 mg/kg body weight) during the first 14 days of lactational period on the activity of some protein kinases targeting the cytoskeleton of striatum and cerebellum of their offspring. We analyzed the phosphorylating system associated with glial fibrillary acidic protein (GFAP), and neurofilament of low, medium and high molecular weight (NF-L, NF-M and NF-H, respectively) of pups on PND 15, 21, 30 and 45.

Dual action of chronic ethanol treatment on LPS-induced response in C6 glioma cells.

In this study we investigated the anti-inflammatory effects of chronic ethanol (EtOH) treatment on lipopolysaccharide (LPS)-stimulated C6 glioma cells. The cells were chronically treated with 200mM EtOH; coincubation with LPS and EtOH was obtained upon addition of 2μg/ml LPS to the incubation medium in the last 24h of EtOH exposure. We found that EtOH prevented the LPS-induced production of tumor necrosis factor α (TNFα) without decreasing cell viability.

Evidence that AKT and GSK-3β pathway are involved in acute hyperhomocysteinemia.

Homocysteine is a neurotoxic amino acid that accumulates in several disorders including homocystinuria, neurodegenerative and neuroinflammatory diseases. In the present study we evaluated the effect of acute and chronic hyperhomocysteinemia on Akt, NF-κB/p65, GSK-3β, as well as Tau protein in hippocampus of rats. For acute treatment, rats received a single injection of homocysteine (0.

Chronic hyperhomocysteinemia increases inflammatory markers in hippocampus and serum of rats.

This study investigated the effects of chronic homocysteine administration on some parameters of inflammation, such as cytokines (TNF-α, IL-1β and IL-6), chemokine CCL(2) (MCP-1), nitrite and prostaglandin E(2) levels, as well as on immunocontent of NF-κB/p65 subunit in hippocampus and/or serum of rats. Since acetylcholinesterase has been associated with inflammation, we also evaluated the effect of homocysteine on this enzyme activity in hippocampus of rats. Wistar rats received daily subcutaneous injections of homocysteine (0.

Alterations of PI3K and Akt signaling pathways in the hippocampus and hypothalamus of Wistar rats treated with highly palatable food.

Background/objectives: Highly palatable food (HPF), which is enriched in simple sugars and saturated fat, contributes to obesity and insulin resistance in humans. These metabolic changes are associated with serious complications of the central nervous system, including an elevated risk of cognitive dysfunction. We, herein, treated rats with HPF and then examined the insulin-signaling pathway, in particular, the levels of phosphatidylinositol-3 kinase (PI3K), Akt, and insulin receptor substrate-1 (IRS-1) in the hippocampus and hypothalamus.