Protective effects of NMDA receptor antagonist, memantine, against senescence of PC12 cells: A possible role of nNOS and combined effects with donepezil

Ota, Hidetaka; Ogawa, Sumito; Ouchi, Yasuyoshi; Akishita, Masahiro

doi:10.1016/j.exger.2015.09.016

Cited by 16 publications

(12 citation statements)

References 41 publications

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“…Our data are in agreement with other pharmacological studies in rodent’s models or in AD patients, showing the benefits of combinations of donepezil with drugs acting on other neurotransmission systems such as histaminergic neurotransmission (Cho et al 2011 ) or NMDA receptors (Ota et al 2015 ; Atri et al 2015 ). However, these studies (at the exception of Sors et al 2017 ) demonstrated additive effects of the combinations of the drugs (which means that the effect of two compounds is equal to the sum of the effect of the two compounds taken separately) rather than a synergistic interaction, as this is the case of our present study.…”

Section: Discussionsupporting

confidence: 91%

Synergistic enhancing-memory effect of donepezil and S 47445, an AMPA positive allosteric modulator, in middle-aged and aged mice

et al. 2017

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Positive allosteric modulators of AMPA receptors (AMPA-PAMs) are described to facilitate cognitive processes in different memory-based models. Among them, S 47445 is a novel potent and selective AMPA-PAM. In order to assess its efficacy after repeated administration, S 47445 effect was evaluated in two aging-induced memory dysfunction tasks in old mice, one short-term working memory model evaluated in a radial maze task and one assessing contextual memory performance. S 47445 was shown to improve cognition in both models sensitive to aging. In fact, administration of S 47445 at 0.3 mg/kg (s.c.) reversed the age-induced deficits of the working memory model whatever the retention interval. Moreover, in the contextual task, S 47445 also reversed the age-induced deficit at all tested doses (from 0.03 to 0.3 mg/kg, p.o.). Since donepezil, an acetylcholinesterase inhibitor, induces only moderate symptomatic effects on memory in Alzheimer’s disease patients, an alternative strategy for treatment of cognitive symptoms could be to act simultaneously on both glutamatergic AMPA receptors and cholinergic pathways by combining pharmacological treatments. The present study further examined such effects by assessing combinations of S 47445 and donepezil given orally during 9 days in aged C57/Bl6J mice using contextual memory task (CSD) and the working memory model of serial alternation task (AT). Interestingly, a significant synergistic memory-enhancing effect was observed with the combination of donepezil at 0.1 mg/kg with S 47445 at 0.1 mg/kg p.o. in the CSD or with S 47445 at 0.1 and 0.3 mg/kg in AT in comparison to compounds given alone and without any pharmacokinetic interaction.Electronic supplementary materialThe online version of this article (10.1007/s00213-017-4792-5) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 91%

Synergistic enhancing-memory effect of donepezil and S 47445, an AMPA positive allosteric modulator, in middle-aged and aged mice

et al. 2017

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“…A03 is also described as a non-competitive NMDA receptor antagonist 38 , 39 and testing of the partial NMDA antagonist memantine did not show an increase in SirT1 levels as seen with A03. Thus, NMDA receptor antagonism alone does not appear to explain the SirT1 effect, since the limited reports on the impact of NMDA receptor antagonism on SirT1 have been mixed and model-dependent 40 , 41 . Together these data suggest that an as-yet unidentified mechanism maybe involved in the SirT1 increases seen with A03.…”

Section: Discussionmentioning

confidence: 99%

A small molecule ApoE4-targeted therapeutic candidate that normalizes sirtuin 1 levels and improves cognition in an Alzheimer’s disease mouse model

Campagna

Spilman

Jagodzinska

et al. 2018

Sci Rep

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We describe here the results from the testing of a small molecule first-in-class apolipoprotein E4 (ApoE4)-targeted sirtuin1 (SirT1) enhancer, A03, that increases the levels of the neuroprotective enzyme SirT1 while not affecting levels of neurotoxic sirtuin 2 (SirT2) in vitro in ApoE4-transfected cells. A03 was identified by high-throughput screening (HTS) and found to be orally bioavailable and brain penetrant. In vivo, A03 treatment increased SirT1 levels in the hippocampus of 5XFAD-ApoE4 (E4FAD) Alzheimer’s disease (AD) model mice and elicited cognitive improvement while inducing no observed toxicity. We were able to resolve the enantiomers of A03 and show using in vitro models that the L-enantiomer was more potent than the corresponding D-enantiomer in increasing SirT1 levels. ApoE4 expression has been shown to decrease the level of the NAD-dependent deacetylase and major longevity determinant SirT1 in brain tissue and serum of AD patients as compared to normal controls. A deficiency in SirT1 level has been recently implicated in increased tau acetylation, a dominant post-translational modification and key pathological event in AD and tauopathies. Therefore, as a novel approach to therapeutic development for AD, we targeted identification of compounds that enhance and normalize brain SirT1 levels.

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“…NMDA participates in the ornithine cycle, promoting oxygen- and carbon dioxide-induced generation of urea and enhancing liver function. Therefore, in the medical industry, NMDA is primarily used as a liver function accelerant for the treatment of liver fibrosis ( 40 , 41 ). These observations are consistent with the putrescine decrease observed in the model rat group in the present study, and this alteration may be associated with impaired amino acid metabolism.…”

Section: Discussionmentioning

confidence: 99%

Effects of Shu Gan Jian Pi formula on rats with carbon tetrachloride-induced liver fibrosis using serum metabonomics based on gas chromatography-time of flight mass spectrometry

Jiang

Qin

et al. 2017

Molecular Medicine Reports

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Liver fibrosis is a common stage in the majority of chronic liver diseases, regardless of the etiology, and its progression may lead to hepatic cirrhosis or hepatocellular carcinoma. Metabolomics, a powerful approach in systems biology, is a discipline used to qualitatively and quantitatively analyze the small molecule metabolites of cells at specific times and under certain conditions. The present study aimed to investigate serum metabolic changes following Shu Gan Jian Pi formula (SGJPF) treatment of carbon tetrachloride (CCl4)-induced liver fibrosis in rats using gas chromatography-time of flight mass spectrometry (GC-TOFMS). In addition, the potential mechanisms were explored. Rat liver fibrosis was induced by twice-weekly subcutaneous CCl4 injection for 12 continuous weeks. During the same period, the SGJPF group received 16.2 g/kg body weight SGJPF, diluted in water, once a day for 12 weeks. Rats in the control and model groups received oral administration of the same volume of saline solution. Serum samples from the control, model and SGJPF groups were collected after 12 weeks of treatment, and metabolic profile alterations were analyzed by GC-TOF/MS. Metabolic profile analysis indicated that clustering differed between the three groups and the following 12 metabolites were detected in the serum of all three groups: Isoleucine; L-malic acid; D-erythro-sphingosine; putrescine; malonic acid; 3,6-anhydro-D-galactose, α-ketoglutaric acid; ornithine; glucose; hippuric acid; tetrahydrocorticosterone; and fucose. The results demonstrated that SGJPF treatment mitigated the effects of CCl4-induced liver fibrosis on biomarker levels, thus indicating that SGJPF may have a therapeutic effect on CCl4-induced liver fibrosis in rats. The mechanism may involve the regulation of energy, amino acid, sphingolipid, cytochrome P450, glucose and water-electrolyte metabolism.

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Protective effects of NMDA receptor antagonist, memantine, against senescence of PC12 cells: A possible role of nNOS and combined effects with donepezil

Cited by 16 publications

References 41 publications

Synergistic enhancing-memory effect of donepezil and S 47445, an AMPA positive allosteric modulator, in middle-aged and aged mice

Synergistic enhancing-memory effect of donepezil and S 47445, an AMPA positive allosteric modulator, in middle-aged and aged mice

A small molecule ApoE4-targeted therapeutic candidate that normalizes sirtuin 1 levels and improves cognition in an Alzheimer’s disease mouse model

Effects of Shu Gan Jian Pi formula on rats with carbon tetrachloride-induced liver fibrosis using serum metabonomics based on gas chromatography-time of flight mass spectrometry

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