A Medicinal Chemistry Perspective on Excitatory Amino Acid Transporter 2 Dysfunction in Neurodegenerative Diseases

Fontana, Igor C.; Souza, Débora Guerini de; Souza, Diogo Onofre de; Gee, Antony D.; Zimmer, Eduardo R.; Bongarzone, Salvatore

doi:10.1021/acs.jmedchem.2c01572

Cited by 17 publications

(11 citation statements)

References 191 publications

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“…Immunofluorescence staining showed abundant co-localization of GLT1 with GFAP in the control group, indicating the expression of GLT1 in astrocytes. This finding is consistent with previous reports that GLT1 is mainly expressed in astrocytes [ 25 , 26 ]. The co-localization was reduced by 55% ( p < 0.0001) in the Abeta group, 57% ( p < 0.0001) in the Glu group, and 69% ( p < 0.0001) in the Abeta + Glu group compared to the control group.…”

Section: Resultssupporting

confidence: 94%

Sulbactam protects neurons against double neurotoxicity of amyloid beta and glutamate load by upregulating glial glutamate transporter 1

Li,

Jiang

et al. 2024

Cell Death Discov.

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Amyloid beta (Abeta) synergistically enhances excitotoxicity of glutamate load by impairing glutamate transporter 1 (GLT1) expression and function, which exacerbates the development of Alzheimer’s disease (AD). Our previous studies suggested that sulbactam can upregulate the expression levels and capacity of GLT1. Therefore, this study aims to investigate whether sulbactam improves neuronal tolerance against neurotoxicity of Abeta and glutamate load by up-regulating GLT1 in primary neuron-astrocyte co-cultures. Early postnatal P0–P1 Wistar rat pups’ cortices were collected for primary neuron–astrocyte cultures. Hoechst–propidium iodide (HO–PI) stain and lactate dehydrogenase (LDH) assays were used to analyze neuronal death. Cell counting kit 8 (CCK8) was applied to determine cell viability. Immunofluorescence staining and western blotting were used to assess protein expressions including GLT1, B-cell lymphoma 2 (BCL2), BCL2 associated X (BAX), and cleaved caspase 3 (CCP3). Under the double effect of Abeta and glutamate load, more neurons were lost than that induced by Abeta or glutamate alone, shown as decreased cell viability, increased LDH concentration in the cultural medium, HO–PI positive stains, high CCP3 expression, and high BAX/BCL2 ratio resulting from increased BAX and decreased BCL2 expressions. Notably, pre-incubation with sulbactam significantly attenuated the neuronal loss and activation of apoptosis induced by both Abeta and glutamate in a dose-dependent manner. Simultaneously, both astrocytic and neuronal GLT1 expressions were upregulated after sulbactam incubation. Taken together, it could be concluded that sulbactam protected neurons against double neurotoxicity of Abeta and glutamate load by upregulating GLT1 expression. The conclusion provides evidence for potential intervention using sulbactam in AD research.

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Section: Resultssupporting

confidence: 94%

Sulbactam protects neurons against double neurotoxicity of amyloid beta and glutamate load by upregulating glial glutamate transporter 1

Li,

Jiang

et al. 2024

Cell Death Discov.

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“…Furthermore, double immuno uorescent staining showed that GLT1 expression in astrocytes in the neuron-astrocyte co-cultures signi cantly upregulated after the sulbactam incubation. This nding is consistent with previous reports that GLT1 primarily expresses on astrocytes [48,49], and sulbactam could dose dependently upregulate GLT1 expression [23,24,50,51]. In addition, the present study also showed that GLT1 co-localized abundantly with neuronal marker MAP2 in the neuron-astrocyte co-cultures after sulbactam treatment, which meant that GLT1 expressed on neurons and its expression was upregulated by sulbactam as well.…”

Section: Discussionsupporting

confidence: 93%

“…Immuno uorescence stain showed abundant co-localization of GLT1 with GFAP in the control group, indicating the expression of GLT1 in astrocytes. This nding is consistent with previous reports that GLT1 mainly expresses in astrocytes [48,49]. The co-localization was reduced by 55% (P<0.0001) in the Abeta group, 57% (P<0.0001) in the Glu group and 69% (P = 0.0001) in the Abeta + Glu group compared to the control group.…”

Section: Glt1 Expressionsupporting

confidence: 93%

Sulbactam protects neurons against double neurotoxicity of amyloid beta and glutamate load by upregulating glial glutamate transporter 1

Li,

Jiang

et al. 2023

Preprint

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Amyloid beta (Abeta) synergistically enhances excitotoxicity of glutamate load by impairing glutamate transporter 1 (GLT1) expression and function, which exacerbates the development of Alzheimer’s disease (AD). Our previous studies have suggested that sulbactam can upregulate the expression levels and capacity of GLT1. Therefore, this study aims to investigate whether sulbactam improves neuronal tolerance against neurotoxicity of Abeta and glutamate load by up-regulating GLT1 in primary neuron-astrocyte co-cultures. Early postnatal P0-P1 Wistar rat pups’ cortices were collected for primary neuron-astrocyte cultures. Hoechst-Propidium Iodide (HO-PI) stain and lactate dehydrogenase (LDH) assays were used to analyze neuronal death. Cell counting kit 8 (CCK8) was applied to determine cell viability. Immunofluorescent staining and western blotting were used to assess protein expressions including GLT1, BAX, BCL2, cleaved caspase 3. Under double effect of Abeta and glutamate load, neurons lost more than that induced by Abeta or glutamate alone, shown as decreased cell viability, increased LDH concentration in the cultural medium, HO-PI positive stains and high cleaved caspase 3 expression and BAX/BCL2 ratio resulting from increased BAX and decreased BCL2 expression. Notably, pre-incubation with sulbactam significantly attenuated the neuronal loss and activation of apoptosis induced by both Abeta and glutamate in a dose-dependent manner. Simultaneously, both astrocytic and neuronal GLT1 expression was upregulated after sulbactam incubation. Taken together, it could be concluded that sulbactam protected neurons against double neurotoxicity of Abeta and glutamate load by upregulating GLT1 expression. The conclusion provides evidence for potential intervention using sulbactam in AD research.

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“…Glutamate is primarily transported by excitatory amino acid transporter 2 (EAAT2), which is the primary mechanism for maintaining extracellular glutamate concentrations in the CNS below excitotoxic levels. 45 Neuroprotection is mediated by EAAT2. The PPARγ transcription factor is ligand-dependent and responds both to chemical and physiological signals.…”

Section: Effects Of Yp-7 On Excitotoxicity To the Primary Cultured Hi...mentioning

confidence: 99%

Walnut-Derived Peptides Ameliorate Scopolamine-Induced Memory Impairments in a Mouse Model via Activation of Peroxisome Proliferator-Activated Receptor γ-Mediated Excitotoxicity

Shen,

Dang,

Fang

et al. 2024

J. Agric. Food Chem.

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We investigated the protective effect of walnut peptides and YVPFPLP (YP-7) on scopolamine-induced memory impairment in mice and β-amyloid (Aβ)-induced excitotoxic injury in primary hippocampal neurons, respectively. Additionally, the protective mechanism of YP-7 on neuronal excitotoxicity was explored. Mouse behavioral and hippocampal slice morphology experiments indicate that YP-7 improves the learning and memory abilities of cognitively impaired mice and protects synaptic integrity. Immunofluorescence, western blotting, and electrophysiological experiments on primary hippocampal neurons indicate that YP-7 inhibits neuronal damage caused by excessive excitation of neurons induced by Aβ. HT-22 cell treatment with peroxisome proliferator-activated receptor γ (PPARγ) activators and inhibitors showed that YP-7 activates PPARγ expression and maintains normal neuronal function by forming stable complexes with PPARγ to inhibit the extracellular regulated protein kinase pathway. Therefore, YP-7 can ameliorate glutamate-induced excitotoxicity and maintain neuronal signaling. This provides a theoretical basis for active peptides to ameliorate excitotoxicity and the development of functional foods.

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A Medicinal Chemistry Perspective on Excitatory Amino Acid Transporter 2 Dysfunction in Neurodegenerative Diseases

Cited by 17 publications

References 191 publications

Sulbactam protects neurons against double neurotoxicity of amyloid beta and glutamate load by upregulating glial glutamate transporter 1

Sulbactam protects neurons against double neurotoxicity of amyloid beta and glutamate load by upregulating glial glutamate transporter 1

Sulbactam protects neurons against double neurotoxicity of amyloid beta and glutamate load by upregulating glial glutamate transporter 1

Walnut-Derived Peptides Ameliorate Scopolamine-Induced Memory Impairments in a Mouse Model via Activation of Peroxisome Proliferator-Activated Receptor γ-Mediated Excitotoxicity

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