N-(3-Ethoxy-phenyl)-4-pyrrolidin-1-yl-3-trifluoromethyl-benzamide (EPPTB) prevents 3-iodothyronamine (T1AM)-induced neuroprotection against kainic acid toxicity

Landucci, Elisa; Gencarelli, Manuela; Mazzantini, Costanza; Laurino, Annunziatina; Pellegrini‐Giampietro, Domenico E.; Raimondi, Laura

doi:10.1016/j.neuint.2019.05.004

Cited by 14 publications

(11 citation statements)

References 13 publications

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“…Activation of these pathways may, in part, increase the ability of neuronal cells to survive toxic insults such as the excitotoxic treatment that was mimicked by exposing hippocampal slices to NMDA and kainic acid. In this study, NMDA and kainic acid consistently induced death of neurons of the CA1 and CA3 regions of organotypic hippocampal slices, which correlated to the reduced hippocampal levels of p-Akt that we have previously observed [32] but also of p-Erk1/2. In the presence of the both extracts, NMDA- and kainate-induced cell death was reduced and, in parallel, the levels of p-Akt and p-Erk1/2 remained high in the hippocampus.…”

Section: Discussionsupporting

confidence: 84%

Enhanced Neuroprotective Effects of Panax ginseng G115® and Ginkgo biloba GK501® Combinations In Vitro Models of Excitotoxicity

Landucci

Pellegrini‐Giampietro

Bilia

et al. 2019

IJMS

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Neurological-related disorders are seen as an increasingly important aspect of welfare. While conventional medicine is still the mainstay for the treatment of these diseases, it is becoming apparent that patients are also seeking more natural and preventative interventions. Panax ginseng G115® and Ginkgo biloba GK501® extracts alone or in combination were used in two in vitro experimental models of primary cultures exposed to excitotoxicity: rat organotypic hippocampal slices exposed to either 5 µM kainic acid or 10 µM N-Methyl-d-aspartate for 24 hours, and mixed cortical cells exposed to 300 µM NMDA for 10 min. Cell death in the Cornu Ammonis areas CA3 or CA1 subregions of slices was quantified by measuring propidium iodide fluorescence, whereas in cortical cells, it was assessed by measuring the amount of lactate dehydrogenase. In slices, treatment with extracts alone or in combination significantly attenuated CA3 and CA1 damage induced by exposure to kainic acid or NMDA, respectively. A similar neuroprotective effect was observed in cortical cells exposed to NMDA. Analysis of cell signaling pathways found that the two extracts induced an increase of the phosphorylation and they reversed the decrease of phosphorylation of ERK1/2 and Akt induced by kainic acid and NMDA in organotypic hippocampal slices. These results suggest that P. ginseng G115® and G. biloba GK501® extracts may mediate their effects by activating phosphorylation of ERK1/2 and Akt signaling pathways, protecting against excitotoxicity-induced damage in in vitro models.

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Section: Discussionsupporting

confidence: 84%

Enhanced Neuroprotective Effects of Panax ginseng G115® and Ginkgo biloba GK501® Combinations In Vitro Models of Excitotoxicity

Landucci

Pellegrini‐Giampietro

Bilia

et al. 2019

IJMS

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“…The neuronal degeneration mediated by KA involves ER stress and the activation of ER sensors [45]. In organotypic hippocampal slices, KA induces a selective death in the CA3 region [27,28,46]. We observed that at a concentration of 10 or 20 µM, TQ was able to reduce neuronal damage induced by KA (Figure 2F).…”

Section: Discussionmentioning

confidence: 78%

“…KA triggers a delayed type of excitotoxic cell death in the CA3 area of organotypic hippocampal slices through activation of ionotropic glutamate receptors [27,28]. Additionally, it has been shown that KA induces cell death through caspases activation [29], increase expression of pro-apoptotic proteins, such as Bim and Bax, which lead to a decrease in the Bcl-2-Bad ratio, paralleled release of cytochrome c and cleavage of poly(ADP-ribose)polymerase (PARP) [30].…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective Effects of Thymoquinone by the Modulation of ER Stress and Apoptotic Pathway in In Vitro Model of Excitotoxicity

et al. 2021

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Experimental evidence indicates that the activation of ionotropic glutamate receptors plays an important role in neurological disorders’ models such as epilepsy, cerebral ischemia and trauma. The glutamate receptor agonist kainic acid (KA) induces seizures and excitotoxic cell death in the CA3 region of the hippocampus. Thymoquinone (TQ) is the most important component of the essential oil obtained from black cumin (Nigella sativa L.) seeds. It has many pharmacological actions including antioxidant, anti-inflammatory, and anti-apoptotic effects. TQ was used in an in vitro experimental model of primary cultures where excitotoxicity was induced. Briefly, rat organotypic hippocampal slices were exposed to 5 µM KA for 24 h. Cell death in the CA3 subregions of slices was quantified by measuring propidium iodide fluorescence. The cross-talk between TQ, ER stress and apoptotic pathways was investigated by Western blot. In untreated slices TQ (10 µM) induced a significant increase on the PSD95 levels and it decreased the excitotoxic injury induced by KA. Additionally, TQ was able to ameliorate the KA-induced increase in unfolded proteins GRP78 and GRP94 expression. Finally, TQ was able to partially rescue the reduction of the KA-induced apoptotic pathway activation. Our results suggest that TQ modulates the processes leading to post-kainate neuronal death in the CA3 hippocampal area.

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“…When administered to rodents, T1AM induces neurological and metabolic effects similar, but also opposite to those induced by T3. Among these, T1AM activates neuroprotective signaling including the activation of the AKT and PKA signaling [2,3]; it stimulates neuronal plasticity [4,5] and induces central-mediated reduction of body temperature without activating the brown adipose tissue [6][7][8]. Most of the pharmacological effects of T1AM, including the effect on body temperature, have been described following acute administration of the amine.…”

Section: Introductionmentioning

confidence: 99%

3-Iodothyronamine Affects Thermogenic Substrates’ Mobilization in Brown Adipocytes

Gencarelli

Laurino

Landucci

et al. 2020

Biology

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We investigated the effect of 3-iodothyronamine (T1AM) on thermogenic substrates in brown adipocytes (BAs). BAs isolated from the stromal fraction of rat brown adipose tissue were exposed to an adipogenic medium containing insulin in the absence (M) or in the presence of 20 nM T1AM (M+T1AM) for 6 days. At the end of the treatment, the expression of p-PKA/PKA, p-AKT/AKT, p-AMPK/AMPK, p-CREB/CREB, p-P38/P38, type 1 and 3 beta adrenergic receptors (β1–β3AR), GLUT4, type 2 deiodinase (DIO2), and uncoupling protein 1 (UCP-1) were evaluated. The effects of cell conditioning with T1AM on fatty acid mobilization (basal and adrenergic-mediated), glucose uptake (basal and insulin-mediated), and ATP cell content were also analyzed in both cell populations. When compared to cells not exposed, M+T1AM cells showed increased p-PKA/PKA, p-AKT/AKT, p-CREB/CREB, p-P38/P38, and p-AMPK/AMPK, downregulation of DIO2 and β1AR, and upregulation of glycosylated β3AR, GLUT4, and adiponectin. At basal conditions, glycerol release was higher for M+T1AM cells than M cells, without any significant differences in basal glucose uptake. Notably, in M+T1AM cells, adrenergic agonists failed to activate PKA and lipolysis and to increase ATP level, but the glucose uptake in response to insulin exposure was more pronounced than in M cells. In conclusion, our results suggest that BAs conditioning with T1AM promote a catabolic condition promising to fight obesity and insulin resistance.

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N-(3-Ethoxy-phenyl)-4-pyrrolidin-1-yl-3-trifluoromethyl-benzamide (EPPTB) prevents 3-iodothyronamine (T1AM)-induced neuroprotection against kainic acid toxicity

Cited by 14 publications

References 13 publications

Enhanced Neuroprotective Effects of Panax ginseng G115® and Ginkgo biloba GK501® Combinations In Vitro Models of Excitotoxicity

Enhanced Neuroprotective Effects of Panax ginseng G115® and Ginkgo biloba GK501® Combinations In Vitro Models of Excitotoxicity

Neuroprotective Effects of Thymoquinone by the Modulation of ER Stress and Apoptotic Pathway in In Vitro Model of Excitotoxicity

3-Iodothyronamine Affects Thermogenic Substrates’ Mobilization in Brown Adipocytes

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