Dicholine salt of succinic acid, a neuronal insulin sensitizer, ameliorates cognitive deficits in rodent models of normal aging, chronic cerebral hypoperfusion, and beta-amyloid peptide-(25–35)-induced amnesia

Сторожева, З. И.; Proshin, A. T.; Шерстнев, В. В.; Storozhevykh, T. P.; Senilova, Yana E; Persiyantseva, Nadezhda A; Pinelis, V. G.; Семенова, Н. А.; Захарова, Е. И.; Помыткин, И. А.

doi:10.1186/1471-2210-8-1

Cited by 27 publications

(36 citation statements)

References 67 publications

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“…Previously reported effects of DS on increased levels of hippocampal IGF-2, brain N-acetylaspartate/creatine, choline acetyltransferase activity (Storozheva et al, 2008; Cline et al, 2012) can attest for the here observed memory preserving effects of DS. Interestingly, choline acetyltransferase activity in the brain was shown to be regulated by neuronal insulin receptor-mediated mechanisms (Hoyer, 2003).…”

Section: Discussionsupporting

confidence: 73%

Dicholine succinate, the neuronal insulin sensitizer, normalizes behavior, REM sleep, hippocampal pGSK3 beta and mRNAs of NMDA receptor subunits in mouse models of depression

Cline

Costa-Nunes

Cespuglio

et al. 2015

Front. Behav. Neurosci.

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Central insulin receptor-mediated signaling is attracting the growing attention of researchers because of rapidly accumulating evidence implicating it in the mechanisms of plasticity, stress response, and neuropsychiatric disorders including depression. Dicholine succinate (DS), a mitochondrial complex II substrate, was shown to enhance insulin-receptor mediated signaling in neurons and is regarded as a sensitizer of the neuronal insulin receptor. Compounds enhancing neuronal insulin receptor-mediated transmission exert an antidepressant-like effect in several pre-clinical paradigms of depression; similarly, such properties for DS were found with a stress-induced anhedonia model. Here, we additionally studied the effects of DS on several variables which were ameliorated by other insulin receptor sensitizers in mice. Pre-treatment with DS of chronically stressed C57BL6 mice rescued normal contextual fear conditioning, hippocampal gene expression of NMDA receptor subunit NR2A, the NR2A/NR2B ratio and increased REM sleep rebound after acute predation. In 18-month-old C57BL6 mice, a model of elderly depression, DS restored normal sucrose preference and activated the expression of neural plasticity factors in the hippocampus as shown by Illumina microarray. Finally, young naïve DS-treated C57BL6 mice had reduced depressive- and anxiety-like behaviors and, similarly to imipramine-treated mice, preserved hippocampal levels of the phosphorylated (inactive) form of GSK3 beta that was lowered by forced swimming in pharmacologically naïve animals. Thus, DS can ameliorate behavioral and molecular outcomes under a variety of stress- and depression-related conditions. This further highlights neuronal insulin signaling as a new factor of pathogenesis and a potential pharmacotherapy of affective pathologies.

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Section: Discussionsupporting

confidence: 73%

Dicholine succinate, the neuronal insulin sensitizer, normalizes behavior, REM sleep, hippocampal pGSK3 beta and mRNAs of NMDA receptor subunits in mouse models of depression

Cline

Costa-Nunes

Cespuglio

et al. 2015

Front. Behav. Neurosci.

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“…Although both ligands are endogenous to the brain, they are common metabolites and it is presently unclear whether they could serve a physiological role, acting at native mGlu1 receptors. Consistent with the current findings on the cytoprotective properties of succinate, it was shown previously to ameliorate cognitive defects in a rat model of Alzheimer's disease (Storozheva et al, 2008). These compounds may now be used as lead structures in the design of new biased agonists, and especially antagonists, with the ability to affect mGlu1 receptor-mediated protective signaling without disturbing classic G protein-mediated signal transduction.…”

Section: Downloaded Fromsupporting

confidence: 71%

Ligand Bias at Metabotropic Glutamate 1a Receptors: Molecular Determinants That Distinguish β-Arrestin-Mediated from G Protein-Mediated Signaling

Emery¹,

DiRaddo²,

Miller³

et al. 2012

Mol Pharmacol

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The metabotropic glutamate 1a (mGlu1a) receptor is a G protein-coupled receptor linked with phosphoinositide (PI) hydrolysis and with ␤-arrestin-1-mediated sustained extracellular signal-regulated kinase (ERK) phosphorylation and cytoprotective signaling. Previously, we reported the existence of ligand bias at this receptor, inasmuch as glutamate induced both effects, whereas quisqualate induced only PI hydrolysis. In the current study, we showed that mGlu1 receptor agonists such as glutamate, aspartate, and L-cysteate were unbiased and activated both signaling pathways, whereas quisqualate and (S)-3,5-dihydroxyphenylglycine stimulated only PI hydrolysis. Competitive antagonists inhibited only PI hydrolysis and not the ␤-arrestin-dependent pathway, whereas a noncompetitive mGlu1 receptor antagonist blocked both pathways. Mutational analysis of the ligand binding domain of the mGlu1a receptor revealed that Thr188 residues were essential for PI hydrolysis but not for protective signaling, whereas Arg323 and Lys409 residues were required for ␤-arrestin-1-mediated sustained ERK phosphorylation and cytoprotective signaling but not for PI hydrolysis. Therefore, the mechanism of ligand bias appears to involve different modes of agonist interactions with the receptor ligand binding domain. Although some mGlu1a receptor agonists are biased toward PI hydrolysis, we identified two endogenous compounds, glutaric acid and succinic acid, as new mGlu1 receptor agonists that are fully biased toward ␤-arrestinmediated protective signaling. Pharmacological studies indicated that, in producing the two effects, glutamate interacted in two distinct ways with mGlu1 receptors, inasmuch as competitive mGlu1 receptor antagonists that blocked PI hydrolysis did not inhibit cytoprotective signaling. Quisqualate, which is biased toward PI hydrolysis, failed to inhibit glutamate-induced protection, and glutaric acid, which is biased toward protection, did not interfere with glutamate-induced PI hydrolysis. Taken together, these data indicate that ligand bias at mGlu1 receptors is attributable to different modes of receptor-glutamate interactions, which are differentially coupled to PI hydrolysis and ␤-arrestin-mediated cytoprotective signaling, and they reveal the existence of new endogenous agonists acting at mGlu1 receptors.

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“…In the studies reported here cell viability was quantified using calcein AM/EthD-1 double staining (Figure 1A). Using the MTT assay, an indicator of mitochondrial activity, we confirmed that ceramide treatment of HCSF caused mitochondrial dysfunction, a likely cause of the loss of cell viability (Figure 1B) [23], [24].…”

Section: Resultsmentioning

confidence: 88%

Mitochondrial Dysfunction Links Ceramide Activated HRK Expression and Cell Death

et al. 2011

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PurposeCell death is an essential process in normal development and homeostasis. In eyes, corneal epithelial injury leads to the death of cells in underlying stroma, an event believed to initiate corneal wound healing. The molecular basis of wound induced corneal stromal cell death is not understood in detail. Studies of others have indicated that ceramide may play significant role in stromal cell death following LASIK surgery. We have undertaken the present study to investigate the mechanism of death induced by C6 ceramide in cultures of human corneal stromal (HCSF) fibroblasts.MethodsCultures of HCSF were established from freshly excised corneas. Cell death was induced in low passage (p<4) cultures of HCSF by treating the cells with C6 ceramide or C6 dihydroceramide as a control. Cell death was assessed by Live/Dead cell staining with calcein AM and ethidium homodimer-1 as well as Annexin V staining, caspase activation and TUNEL staining Mitochondrial dysfunction was assessed by Mito Sox Red, JC-1 and cytochrome C release Gene expression was examined by qPCR and western blotting.ResultsOur data demonstrate ceramide caused mitochondrial dysfunction as evident from reduced MTT staining, cyto c release from mitochondria, enhanced generation of ROS, and loss in mitochondrial membrane potential (ΔΨm). Cell death was evident from Live -Dead Cell staining and the inability to reestablish cultures from detached cells. Ceramide induced the expression of the harikari gene(HRK) and up-regulated JNK phosphorylation. In ceramide treated cells HRK was translocated to mitochondria, where it was found to interact with mitochondrial protein p32. The data also demonstrated HRK, p32 and BAD interaction. Ceramide-induced expression of HRK, mitochondrial dysfunction and cell death were reduced by HRK knockdown with HRK siRNA.ConclusionOur data document that ceramide is capable of inducing death of corneal stromal fibroblasts through the induction of HRK mediated mitochondria dysfunction.

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Dicholine salt of succinic acid, a neuronal insulin sensitizer, ameliorates cognitive deficits in rodent models of normal aging, chronic cerebral hypoperfusion, and beta-amyloid peptide-(25–35)-induced amnesia

Cited by 27 publications

References 67 publications

Dicholine succinate, the neuronal insulin sensitizer, normalizes behavior, REM sleep, hippocampal pGSK3 beta and mRNAs of NMDA receptor subunits in mouse models of depression

Dicholine succinate, the neuronal insulin sensitizer, normalizes behavior, REM sleep, hippocampal pGSK3 beta and mRNAs of NMDA receptor subunits in mouse models of depression

Ligand Bias at Metabotropic Glutamate 1a Receptors: Molecular Determinants That Distinguish β-Arrestin-Mediated from G Protein-Mediated Signaling

Mitochondrial Dysfunction Links Ceramide Activated HRK Expression and Cell Death

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