Prevention of excitotoxicity‐induced processing of BDNF receptor TrkB‐FL leads to stroke neuroprotection

Tejeda, Gonzalo S.; Esteban-Ortega, Gema M; Antonio, Esther San; Vidaurre, Oscar G.; Dı́az-Guerra, Margarita

doi:10.15252/emmm.201809950

Cited by 46 publications

(34 citation statements)

References 92 publications

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“…Thus, we used BDNF to stimulate eNOS-dependent neuroprotective NO synthesis in our cell model 16 . Consistent with our results, the restitution of BDNF/TrkB signaling after a stroke enhanced neuroprotection in the cerebral cortex 58 . Moreover, further recent studies have confirmed the functional implications of eNOS expression in neurons 59 .…”

Section: Discussionsupporting

confidence: 92%

eNOS-dependent S-nitrosylation of the NF-κB subunit p65 has neuroprotective effects

Caviedes¹,

Maturana²,

Corvalán³

et al. 2021

Cell Death Dis

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Cell death by glutamate excitotoxicity, mediated by N-methyl-d-aspartate (NMDA) receptors, negatively impacts brain function, including but not limited to hippocampal neurons. The NF-κB transcription factor (composed mainly of p65/p50 subunits) contributes to neuronal death in excitotoxicity, while its inhibition should improve cell survival. Using the biotin switch method, subcellular fractionation, immunofluorescence, and luciferase reporter assays, we found that NMDA-stimulated NF-κB activity selectively in hippocampal neurons, while endothelial nitric oxide synthase (eNOS), an enzyme expressed in neurons, is involved in the S-nitrosylation of p65 and consequent NF-κB inhibition in cerebrocortical, i.e., resistant neurons. The S-nitro proteomes of cortical and hippocampal neurons revealed that different biological processes are regulated by S-nitrosylation in susceptible and resistant neurons, bringing to light that protein S-nitrosylation is a ubiquitous post-translational modification, able to influence a variety of biological processes including the homeostatic inhibition of the NF-κB transcriptional activity in cortical neurons exposed to NMDA receptor overstimulation.

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Section: Discussionsupporting

confidence: 92%

eNOS-dependent S-nitrosylation of the NF-κB subunit p65 has neuroprotective effects

Caviedes¹,

Maturana²,

Corvalán³

et al. 2021

Cell Death Dis

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“…In support, we showed that microglia and astrocyte-induced neuroinflammation plays a crucial role in the development of POCD. Moreover, alteration in BDNF signaling can result in synaptic dysfunction that is associated with memory deficits observed in AD [48], Parkinson's disease (PD) [41], stroke [49], and sepsisassociated encephalopathy [50]. In the present study, we showed that anesthesia and surgery induced decreased levels of BDNF, which could be reversed by memantine and MDL-28170.…”

Section: Discussionmentioning

confidence: 47%

Dysregulation of BDNF/TrkB signaling mediated by NMDAR/Ca2+/calpain might contribute to postoperative cognitive dysfunction in aging mice

Qiu

Pan

Luo

et al. 2020

J Neuroinflammation

165

117

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Background: Postoperative cognitive decline (POCD) is a recognized clinical phenomenon characterized by cognitive impairments in patients following anesthesia and surgery, yet its underlying mechanism remains unclear. Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal plasticity, learning, and memory via activation of TrkB-full length (TrkB-FL) receptors. It has been reported that an abnormal truncation of TrkB mediated by calpain results in dysregulation of BDNF/TrkB signaling and is associated with cognitive impairments in several neurodegenerative disorders. Calpains are Ca 2+ -dependent proteases, and overactivation of calpain is linked to neuronal death. Since one source of intracellular Ca 2+ is N-methyl-d-aspartate receptors (NMDARs) related and the function of NMDARs can be regulated by neuroinflammation, we therefore hypothesized that dysregulation of BDNF/TrkB signaling mediated by NMDAR/Ca 2+ /calpain might be involved in the pathogenesis of POCD.Methods: In the present study, 16-month-old C57BL/6 mice were subjected to exploratory laparotomy with isoflurane anesthesia to establish the POCD animal model. For the interventional study, mice were treated with either NMDAR antagonist memantine or calpain inhibitor MDL-28170. Behavioral tests were performed by open field, Y maze, and fear conditioning tests from 5 to 8 days post-surgery. The levels of Iba-1, GFAP, interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), NMDARs, calpain, BDNF, TrkB, bax, bcl-2, caspase-3, and dendritic spine density were determined in the hippocampus.Results: Anesthesia and surgery-induced neuroinflammation overactivated NMDARs and then triggered overactivation of calpain, which subsequently led to the truncation of TrkB-FL, BDNF/TrkB signaling dysregulation, dendritic spine loss, and cell apoptosis, contributing to cognitive impairments in aging mice. These abnormities were prevented by memantine or MDL-28170 treatment. Conclusion: Collectively, our study supports the notion that NMDAR/Ca2+/calpain is mechanistically involved in anesthesia and surgery-induced BDNF/TrkB signaling disruption and cognitive impairments in aging mice, which provides one possible therapeutic target for POCD.

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“…The protocol was as previously reported with slight modifications. 31,32 Briefly, E17-18 fetuses from the same pregnant Sprague-Dawley rat were used for primary cultures of cortical neurons. Brains were carefully dissected with fine scissors, and cortices were isolated and the meninges were removed with fine forceps in ice-cold DMEM.…”

Section: Primary Rat Cortical Neuron Culturementioning

confidence: 99%

Morinda officinalis oligosaccharides ameliorate depressive‐like behaviors in poststroke rats through upregulating GLUT3 to improve synaptic activity

Zhu

Peng

et al. 2020

FASEB j.

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Poststroke depression (PSD) is one of the most common psychiatric diseases afflicting stroke survivors, yet the underlying mechanism is poorly understood. The pathophysiology of PSD is presumably multifactorial, involving ischemia‐induced disturbance in the context of psychosocial distress. The homeostasis of glucose metabolism is crucial to neural activity. In this study, we showed that glucose consumption was decreased in the medial prefrontal cortex (mPFC) of PSD rats. The suppressed glucose metabolism was due to decreased glucose transporter‐3 (GLUT3) expression, the most abundant and specific glucose transporter of neurons. We also found Morinda officinalis oligosaccharides (MOOs), approved as an antidepressive Chinese medicine, through upregulating GLUT3 expression in the mPFC, improved glucose metabolism, and enhanced synaptic activity, which ultimately ameliorated depressive‐like behavior in PSD rats. We further confirmed the mechanism that MOOs induce GLUT3 expression via the PKA/pCREB pathway in PSD rats. Our work showed that MOOs treatment is capable of restoring GLUT3 level to improve depressive‐like behaviors in PSD rats. We also propose GLUT3 as a potential therapeutic target for PSD and emphasize the importance of metabolism disturbance in PSD pathology.

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Prevention of excitotoxicity‐induced processing of BDNF receptor TrkB‐FL leads to stroke neuroprotection

Cited by 46 publications

References 92 publications

eNOS-dependent S-nitrosylation of the NF-κB subunit p65 has neuroprotective effects

eNOS-dependent S-nitrosylation of the NF-κB subunit p65 has neuroprotective effects

Dysregulation of BDNF/TrkB signaling mediated by NMDAR/Ca2+/calpain might contribute to postoperative cognitive dysfunction in aging mice

Morinda officinalis oligosaccharides ameliorate depressive‐like behaviors in poststroke rats through upregulating GLUT3 to improve synaptic activity

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