Inhibition of GluN2B pathway is involved in the neuroprotective effect of silibinin on streptozotocin-induced Alzheimer's disease models

Liu, Panwen; Wang, Chenkang; Chen, Wenhui; Kang, Yu; Liu, Weiwei; Qiu, Zhiyue; Hayashi, Toshihiko; Mizuno, Kazunori; Hattori, Shunji; Fujisaki, Hitomi; Ikejima, Takashi

doi:10.1016/j.phymed.2022.154594

Cited by 6 publications

(6 citation statements)

References 46 publications

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“…Curiously, this effect was prevented by BFT treatment in the STZB group. Liu et al (2023) showed that STZ decreases the levels and phosphorylation of GluN2B, indicating a dysregulation in cell membrane trafficking of GluN2B after its overactivation . In the same model used here, Moraes et al (2020) observed a reduction in GluN2B density in STZ animals and BFT-30-day treatment restored these levels.…”

Section: Resultsmentioning

confidence: 60%

“…Glutamatergic neurotransmission via NMDA receptors is crucial for synaptic plasticity and neuronal survival . The overactivation of its GluN2B subunit leads to excessive calcium influx and excitotoxicity . Memantine is used to attenuate AD symptoms, supporting the involvement of NMDA receptors in the onset and course of the disease .…”

Section: Resultsmentioning

confidence: 99%

“…45 The overactivation of its GluN2B subunit leads to excessive calcium influx and excitotoxicity. 46 Memantine is used to attenuate AD symptoms, supporting the involvement of NMDA receptors in the onset and course of the disease. 45 Despite not considering the phosphorylation and activation, we found increased levels of GluN2B, after icv-STZ.…”

Section: ■ Introductionmentioning

confidence: 99%

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Exploring the Therapeutic Potential of Benfotiamine in a Sporadic Alzheimer’s-Like Disease Rat Model: Insights into Insulin Signaling and Cognitive function

Cardinali,

Martins,

Moraes

et al. 2024

ACS Chem. Neurosci.

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Alzheimer's disease (AD) is a complex neurodegenerative process, also considered a metabolic condition due to alterations in glucose metabolism and insulin signaling pathways in the brain, which share similarities with diabetes. This study aimed to investigate the therapeutic effects of benfotiamine (BFT), a vitamin B1 analog, in the early stages of the neurodegenerative process in a sporadic model of Alzheimer's-like disease induced by intracerebroventricular injection of streptozotocin (STZ). Supplementation with 150 mg/kg of BFT for 7 days reversed the cognitive impairment in short-and long-term memories caused by STZ in rodents. We attribute these effects to BFT's ability to modulate glucose transporters type 1 and 3 (GLUT1 and GLUT3) in the hippocampus, inhibit GSK3 activity in the hippocampus, and modulate the insulin signaling in the hippocampus and entorhinal cortex, as well as reduce the activation of apoptotic pathways (BAX) in the hippocampus. Therefore, BFT emerges as a promising and accessible intervention in the initial treatment of conditions similar to AD.

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Section: Resultsmentioning

confidence: 60%

Section: Resultsmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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Exploring the Therapeutic Potential of Benfotiamine in a Sporadic Alzheimer’s-Like Disease Rat Model: Insights into Insulin Signaling and Cognitive function

Cardinali,

Martins,

Moraes

et al. 2024

ACS Chem. Neurosci.

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“…Another important point consisted in the evaluation of neuronal death after Aβ1-42 treatment, as inhibiting the over-activation of NR2B-containing NMDAR has been shown to be involved in the neuroprotective effect of silibinin on STZ-induced sporadic AD models [60]. In this sense, we observed that neurons expressing NR2A-containing NMDAR suffered less neuronal death after Aβ1-42 treatment than neurons expressing the NR2B subunit.…”

Section: Discussionmentioning

confidence: 58%

Dual Role of NMDAR Containing NR2A and NR2B Subunits in Alzheimer’s Disease

Raïch,

Lillo,

Rebassa

et al. 2024

IJMS

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Alzheimer’s disease (AD) is the main cause of dementia worldwide. Given that learning and memory are impaired in this pathology, NMDA receptors (NMDARs) appear as key players in the onset and progression of the disease. NMDARs are glutamate receptors, mainly located at the post-synapse, which regulate voltage-dependent influx of calcium into the neurons. They are heterotetramers, and there are different subunits that can be part of the receptors, which are usually composed of two obligatory GluN1 subunits plus either two NR2A or two NR2B subunits. NR2A are mostly located at the synapse, and their activation is involved in the expression of pro-survival genes. Conversely, NR2B are mainly extrasynaptic, and their activation has been related to cell death and neurodegeneration. Thus, activation of NR2A and/or inactivation of NR2B-containing NMDARS has been proposed as a therapeutic strategy to treat AD. Here, we wanted to investigate the main differences between both subunits signalling in neuronal primary cultures of the cortex and hippocampus. It has been observed that Aβ induces a significant increase in calcium release and also in MAPK phosphorylation signalling in NMDAR-containing NR2B subunits in cortical and hippocampal neurons. However, while NMDAR-containing NR2A decreases neuronal death and favours cell viability after Aβ treatment, NMDAR-containing NR2B shows higher levels of cytotoxicity and low levels of neuronal survival. Finally, it has been detected that NMDAR has no effect on pTau axonal transport. The present results demonstrate a different role between GluNA and GluNB subunits in neurodegenerative diseases such as Alzheimer’s.

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“…[1][2][3] The pathogenesis of many classical brain disorders such as, Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD), are also known to involve Glu-NMDAR overactivation-induced excitotoxicity. [4][5][6] Additionally, there appears to be a general agreement that the neuropathology of all these brain diseases is associated with some degree of nerve demyelination in specific brain regions. [7][8][9] However, studies on the role of nerve demyelination are rare in the pathogenesis of HE, except for a few reports on myelin disarray associated with acute HE.…”

Section: Introductionmentioning

confidence: 99%

The restoration of hippocampal nerve de‐myelination by methylcobalamin relates with the enzymatic regulation of homocysteine level in a rat model of moderate grade hepatic encephalopathy

Roy,

Trigun

2024

J Biochem & Molecular Tox

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This article describes how methylcobalamin (MeCbl) restores nerve myelination in a moderate‐ grade hepatic encephalopathy (MoHE) model of ammonia neurotoxicity. The comparative profiles of myelin basic protein (MBP), homocysteine (Hcy) and methionine synthase (MS: a MeCbl‐ dependent enzyme) activity versus nerve myelination status were studied in the hippocampus of the control, the MoHE (developed by administering 100 mg/kg bw thioacetamide i.p. for 10 days) and the MoHE rats treated with MeCbl (500 µg/kg BW i.p.) for 7 days. Compared to those of control rats, the hippocampal CA1 and CA3 regions of the MoHE rats showed significantly lower myelinated areas and MBP immunostaining. This coincided with the deranged myelin layering in TEM images, decreased MBP protein and its transcript levels in hippocampus of MoHE rats. However, all these parameters recovered to normal levels after MeCbl treatment. MeCbl is a cofactor of MS that catalyzes the conversion of Hcy to methionine as a feeder step of methylation reactions. We observed significantly increased serum and hippocampal Hcy levels in MoHE rats, however, these levels were restored to control values with a concordant activation of MS due to MeCbl treatment. A significant recovery in neurobehavioral impairments in the MoHE rats due to MeCbl treatment was also observed. These findings suggest that MoHE pathogenesis is associated with deranged nerve myelination in the hippocampus and that MeCbl treatment is able to restore it mainly by activating MS, a MeCbl‐dependent Hcy‐metabolizing enzyme.

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Inhibition of GluN2B pathway is involved in the neuroprotective effect of silibinin on streptozotocin-induced Alzheimer's disease models

Cited by 6 publications

References 46 publications

Exploring the Therapeutic Potential of Benfotiamine in a Sporadic Alzheimer’s-Like Disease Rat Model: Insights into Insulin Signaling and Cognitive function

Exploring the Therapeutic Potential of Benfotiamine in a Sporadic Alzheimer’s-Like Disease Rat Model: Insights into Insulin Signaling and Cognitive function

Dual Role of NMDAR Containing NR2A and NR2B Subunits in Alzheimer’s Disease

The restoration of hippocampal nerve de‐myelination by methylcobalamin relates with the enzymatic regulation of homocysteine level in a rat model of moderate grade hepatic encephalopathy

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