16 research outputs found
Effects of IFN-β1a and IFN-β1b treatment on the expression of cytokines, inducible NOS (NOS type II), and myelin proteins in animal model of multiple sclerosis
Effects of IFN-β1a and IFN-β1b treatment on the expression of cytokines, inducible NOS (NOS type II), and myelin proteins in animal model of multiple sclerosis
Endoplasmic Reticulum Stress Underlies Nanosilver-Induced Neurotoxicity in Immature Rat Brain
The growing production of silver nanoparticles (AgNPs), and their widespread use in medical and consumer products, poses a potential threat to the environment and raises questions about biosafety. Immature organisms are particularly susceptible to various insults during development. The biological characteristics of immature organisms are different from those of adults, and dictate the consequences of exposure to various toxic substances, including AgNPs. Nanoparticles are highly reactive and can easily cross the blood–brain barrier (BBB) to accumulate in brain tissues. It is therefore important to investigate the molecular mechanisms of AgNP-induced neurotoxicity in the developing brain. Immature 2-week-old rats were exposed to a low dose of AgNPs (0.2 mg/kg b.w.) over a long period. Subsequently, brain tissues of the animals were subjected to ultrastructural and molecular analyses to determine endoplasmic reticulum (ER) stress. Ultrastructural markers of ER stress, such as pathological alterations in the ER and elongated forms of mitochondria accompanied by autophagy structures, were confirmed to be present in AgNP-exposed rat brain. Evidence for induction of ER stress in neurons was also provided by molecular markers. Upregulation of genes related to the ER-stress-induced unfolded protein response (UPR) pathway, such as GRP78, PERK, and CHOP ATF-6, was observed at the transcriptional and translational levels. The results show that prolonged exposure of immature rats to a low dose of AgNPs during the developmental period leads to induction of ER stress in the neurons of the developing brain. Simultaneously, in response to AgNP-induced ER stress, neurons promote protective mechanisms that partially compensate for ER stress by regulating the biodynamic processes of mitochondria and autophagy
Memantine Modulates Oxidative Stress in the Rat Brain following Experimental Autoimmune Encephalomyelitis
Experimental autoimmune encephalomyelitis (EAE) is an animal model most commonly used in research on the pathomechanisms of multiple sclerosis (MS). The inflammatory processes, glutamate excitotoxicity, and oxidative stress have been proposed as determinants accompanying demyelination and neuronal degeneration during the course of MS/EAE. The aim of the current study was to characterize the role of NMDA receptors in the induction of oxidative stress during the course of EAE. The effect of memantine, the uncompetitive NMDA receptor antagonist, on modulation of neurological deficits and oxidative stress in EAE rats was analyzed using several experimental approaches. We demonstrated that the expression of antioxidative enzymes (superoxide dismutases SOD1 and SOD2) were elevated in EAE rat brains. Under the same experimental conditions, we observed alterations in oxidative stress markers such as increased levels of malondialdehyde (MDA) and decreased levels of sulfhydryl (-SH) groups, both protein and non-protein (indicating protein damage), and a decline in reduced glutathione. Importantly, pharmacological inhibition of ionotropic NMDA glutamate receptors by their antagonist memantine improved the physical activity of EAE rats, alleviated neurological deficits such as paralysis of tail and hind limbs, and modulated oxidative stress parameters (MDA, -SH groups, SOD’s). Furthermore, the current therapy aiming to suppress NMDAR-induced oxidative stress was partially effective when NMDAR’s antagonist was administered at an early (asymptomatic) stage of EAE
Early and Delayed Impact of Nanosilver on the Glutamatergic NMDA Receptor Complex in Immature Rat Brain
Silver nanoparticles (AgNPs) are the one of the most extensively used nanomaterials. The strong antimicrobial properties of AgNPs have led to their use in a wide range of medical and consumer products. Although the neurotoxicity of AgNPs has been confirmed, the molecular mechanisms have not been extensively studied, particularly in immature organisms. Based on information gained from previous in vitro studies, in the present work, we examine whether ionotropic NMDA glutamate receptors contribute to AgNP-induced neurotoxicity in an animal model of exposure. In brains of immature rats subjected to a low dose of AgNPs, we identified ultrastructural and molecular alterations in the postsynaptic region of synapses where NMDA receptors are localized as a multiprotein complex. We revealed decreased expression of several NMDA receptor complex-related proteins, such as GluN1 and GluN2B subunits, scaffolding proteins PSD95 and SynGAP, as well as neuronal nitric oxide synthase (nNOS). Elucidating the changes in NMDA receptor-mediated molecular mechanisms induced by AgNPs, we also identified downregulation of the GluN2B-PSD95-nNOS-cGMP signaling pathway which maintains LTP/LTD processes underlying learning and memory formation during development. This observation is accompanied by decreased density of NMDA receptors, as assessed by a radioligand binding assay. The observed effects are reversible over the post-exposure time. This investigation reveals that NMDA receptors in immature rats are a target of AgNPs, thereby indicating the potential health hazard for children and infants resulting from the extensive use of products containing AgNPs
Glutamate release from synaptosomes (A) and GPV fraction (B) obtained from control, EAE, EAE+amantadine, EAE+memantine, EAE+LY367385, and EAE+MPEP rat brains during the acute phase of the disease (12 d.p.i.).
<p>Bars present total radioactivity in pellet (KCl no added), radioactivity remaining in pellet after depolarization by KCl (pellet radioactivity), and released of [<sup>3</sup>H] glutamate radioactivity from pellet after depolarization by KCl. Membranes were depolarized with 50 mM KCl at a maximum of the uptake curves (6 min), and radioactivity was assayed after 6 min. Results represent the means ± SD from five separate experiments performed in triplicate; * P<0.05 significantly different from the spontaneous release control group; # P<0.05 vs. EAE rats not subjected to therapy (Student's t-test).</p
Na+-dependent [<sup>3</sup>H] glutamate uptake into synaptosomes (A) and the GPV fraction (B) obtained from the control, EAE, EAE+amantadine, EAE+memantine, EAE+LY367385, and EAE+MPEP rat brains during the acute phase of the disease (12 d.p.i.).
<p>Results represent the mean values ± SD from five separate experiments performed in duplicate; * P<0.05, ** P<0.01, significantly different compared with the control group; # P<0.05 vs. EAE rats not subjected to therapy (Student's t-test).</p
Representative electron micrographs of synapses in the forebrain specimens obtained from the control rats (A), EAE rats at 12 d.p.i. (B), EAE+amantadine-treated rats at 12 d.p.i. (C), and EAE+LY 367385-treated rats at 12 d.p.i. (D).
<p>M - mitochondria, S - synaptic vesicles, # - synaptic vesicles accumulation in the extra-synaptic space.</p