Network-Driven Activity and Neuronal Excitability in Hippocampus of Neonatal Rats with Prenatal Hyperhomocysteinemia

Yakovlev, A. V.; Kurmashova, E.; Захаров, А. В.; Ситдикова, Г. Ф.

doi:10.1007/s12668-017-0450-y

Cited by 13 publications

(6 citation statements)

References 24 publications

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“…Moreover, homocysteine accumulation during the prenatal period in different brain region including cerebellum, hippocampus, striatum induces excitotoxicity followed by apoptosis [ 31 , 79 , 80 ] and may impair neuronal network maturation during a critical period of development. This suggestion was supported by results obtained in hippocampal slices of neonatal rats with prenatal hHcy where an increase of neuronal excitability along with a decrease of giant depolarizing potentials important for the establishment of interneuronal connections were observed [ 81 ].…”

Section: Discussionsupporting

confidence: 55%

Hydrogen Sulfide Alleviates Anxiety, Motor, and Cognitive Dysfunctions in Rats with Maternal Hyperhomocysteinemia via Mitigation of Oxidative Stress

et al. 2020

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Hydrogen sulfide (H2S) is endogenously produced from sulfur containing amino acids, including homocysteine and exerts neuroprotective effects. An increase of homocysteine during pregnancy impairs fetal growth and development of the offspring due to severe oxidative stress. We analyzed the effects of the H2S donor—sodium hydrosulfide (NaHS) administered to female rats with hyperhomocysteinemia (hHcy) on behavioral impairments and levels of oxidative stress of their offspring. Rats born from females fed with control or high methionine diet, with or without H2S donor injections were investigated. Rats with maternal hHcy exhibit increased levels of total locomotor activity and anxiety, decreased muscle endurance and motor coordination, abnormalities of fine motor control, as well as reduced spatial memory and learning. Oxidative stress in brain tissues measured by activity of glutathione peroxidases and the level of malondialdehyde was higher in rats with maternal hHcy. Concentrations of H2S and the activity and expression of the H2S generating enzyme—cystathionine-beta synthase—were lower compared to the control group. Administration of the H2S donor to females with hHcy during pregnancy prevented behavioral alterations and oxidative stress of their offspring. The acquisition of behavioral together with biochemical studies will add to our knowledge about homocysteine neurotoxicity and proposes H2S as a potential agent for therapy of hHcy associated disorders.

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Section: Discussionsupporting

confidence: 55%

Hydrogen Sulfide Alleviates Anxiety, Motor, and Cognitive Dysfunctions in Rats with Maternal Hyperhomocysteinemia via Mitigation of Oxidative Stress

et al. 2020

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“…The latter ones are widely expressed in extrasynaptic regions of the plasma membrane and are thought to provide a major contribution to neurodegeneration [19]. Since rat cortical neurons express GluN2A and GluN2B (for a review see [48]), the HCY effects are likely determined preferentially by the activation of GluN2A-containing NMDARs [12,16,20]. In contrast, Glu also activates GluN2B-containing NMDARs, producing more Ca 2+ to be accumulated in the cytoplasm and a pronounced drop of the mitochondrial inner membrane potential, which is usually associated with mitochondrial swelling and neuronal cell death [49].…”

Section: Necrosis At Short-term Excitotoxic Stressmentioning

confidence: 99%

“…The Ca 2+ influx through Ca 2+ -permeable AMPA receptors and synaptic GluN2A-and extrasynaptic GluN2B-containing NMDARs with subsequent ERK MAPK and caspase-3 activation play a role in the glutamate-induced neurotoxicity [17][18][19]. In contrast, HCY activates synaptic GluN2A-containing NMDARs and desensitized extrasynaptic NMDARs, causing excitatory transmission hyperactivity [20,21]. Therefore, the HCY-induced neurotoxicity differs from that of glutamate in many aspects, most likely including intracellular signaling cascades as well.…”

Section: Introductionmentioning

confidence: 99%

Calcium Export from Neurons and Multi-Kinase Signaling Cascades Contribute to Ouabain Neuroprotection in Hyperhomocysteinemia

et al. 2020

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Pathological homocysteine (HCY) accumulation in the human plasma, known as hyperhomocysteinemia, exacerbates neurodegenerative diseases because, in the brain, this amino acid acts as a persistent N-methyl-d-aspartate receptor agonist. We studied the effects of 0.1–1 nM ouabain on intracellular Ca2+ signaling, mitochondrial inner membrane voltage (φmit), and cell viability in primary cultures of rat cortical neurons in glutamate and HCY neurotoxic insults. In addition, apoptosis-related protein expression and the involvement of some kinases in ouabain-mediated effects were evaluated. In short insults, HCY was less potent than glutamate as a neurotoxic agent and induced a 20% loss of φmit, whereas glutamate caused a 70% decrease of this value. Subnanomolar ouabain exhibited immediate and postponed neuroprotective effects on neurons. (1) Ouabain rapidly reduced the Ca2+ overload of neurons and loss of φmit evoked by glutamate and HCY that rescued neurons in short insults. (2) In prolonged 24 h excitotoxic insults, ouabain prevented neuronal apoptosis, triggering proteinkinase A and proteinkinase C dependent intracellular neuroprotective cascades for HCY, but not for glutamate. We, therefore, demonstrated here the role of PKC and PKA involving pathways in neuronal survival caused by ouabain in hyperhomocysteinemia, which suggests existence of different appropriate pharmacological treatment for hyperhomocysteinemia and glutamate excitotoxicity.

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“…The Ca 2+ in ux through Ca 2+ -permeable AMPA receptors and synaptic GluN2A-and extrasynaptic GluN2B-containing NMDARs with subsequent ERK MAPK and Caspase-3 activation play a role in the glutamate-induced neurotoxicity [17][18][19]. In contrast, HCY activates synaptic GluN2A-containing NMDARs and desensitized extrasynaptic NMDARs, causing excitatory transmission hyperactivity [20,21]. Therefore, the HCY-induced neurotoxicity differs from the glutamate one in many aspects, most likely, including intracellular signaling cascades as well.…”

Section: Introductionmentioning

confidence: 99%

Calcium export from neurons and multi-kinase signaling cascades contribute to ouabain neuroprotection in hyperhomocysteinemia

Ivanova

Kokorina

Timofeeva

et al. 2020

Preprint

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Background: Subnanomolar ouabain binding to the Na,K-ATPase triggers intracellular signaling, prevents an overload of neurons with Ca2+, and their apoptosis caused by glutamate receptor agonists. Elevated plasma homocysteine (HCY), known as hyperhomocysteinemia, represents a risk factor for stroke and can exacerbate many neuronal disorders. HCY acts as a persistent N-methyl-D-aspartate receptor (NMDAR) agonist, which, in contrast to glutamate, desensitizes NMDARs containing GluN2B subunits. Mechanisms of HCY neurotoxicity remain not clearly understood since GluN2B-containing NMDARs provide a major contribution to excitotoxicity among glutamate receptors.Methods: Using fluorescent tools combined with the confocal microscopy, we compared 0.1 - 1 nM ouabain effects on the intracellular Ca2+ signaling, on the mitochondrial inner membrane voltage and the cell viability in primary cultures of rat cortical neurons in glutamate and HCY neurotoxic insults. We also studied an apoptosis-related protein expression and the involvement of some kinases in ouabain mediated effects.Results: In short insults HCY was less potent than glutamate as a neurotoxic agent. This amino acid induced the voltage loss (∆φmit) of 0.2 of the total mitochondrial inner membrane voltage (φmit) instead of ∆φmit = 0.7 for glutamate. We have found that subnanomolar ouabain exhibited rapid and postponed neuroprotective effects on neurons and (1) rapidly reduced the Ca2+ overload of neurons and the voltage loss of inner mitochondrial membranes evoked by glutamate and HCY, and (2) prevented neuronal apoptosis during 24 h treatments with glutamate or HCY. Using a set of specific kinase inhibitors such as PKA inhibitor, chelerythrine, and KN93, we demonstrated the role of multi-kinase signaling pathways involving PKC and PKA in neuronal survival caused by ouabain in hyperhomocysteinemia. Conclusions: Subnanomolar ouabain prevents neurodegeneration caused by glutamate and HCY. For both amino acids, ouabain evokes an acceleration of Ca2+ export by sodium-calcium exchangers from neurons preventing the voltage loss by mitochondrial inner membranes that rescue neurons in short insults. In prolonged insults, ouabain triggers intracellular neuroprotective cascades, including activation of PKA and PKC for HCY, but not for glutamate. This suggests that different appropriate pharmacology for hyperhomocysteinemia and glutamate excitotoxicity could be applied for clinical treatments.

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Network-Driven Activity and Neuronal Excitability in Hippocampus of Neonatal Rats with Prenatal Hyperhomocysteinemia

Cited by 13 publications

References 24 publications

Hydrogen Sulfide Alleviates Anxiety, Motor, and Cognitive Dysfunctions in Rats with Maternal Hyperhomocysteinemia via Mitigation of Oxidative Stress

Hydrogen Sulfide Alleviates Anxiety, Motor, and Cognitive Dysfunctions in Rats with Maternal Hyperhomocysteinemia via Mitigation of Oxidative Stress

Calcium Export from Neurons and Multi-Kinase Signaling Cascades Contribute to Ouabain Neuroprotection in Hyperhomocysteinemia

Calcium export from neurons and multi-kinase signaling cascades contribute to ouabain neuroprotection in hyperhomocysteinemia

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