NLRP3 inflammasome in NMDA-induced retinal excitotoxicity

Tsoka, Pavlina; Barbisan, Paulo Rodolfo Tagliari; Kataoka, Keiko; Chen, Xiaohong Nancy; Tian, Bo; Bouzika, Peggy; Miller, Joan W.; Paschalis, Eleftherios I.; Vavvas, Demetrios G.

doi:10.1016/j.exer.2019.01.018

Cited by 27 publications

(23 citation statements)

References 72 publications

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“…In addition, the anti-inflammatory agent indomethacin has been reported to improve cognitive impairments by inhibiting microglia activation and reversing NMDAR dysfunction in aged rats [21]. On the other hand, another study has showed that NMDA-induced retinal excitotoxicity could trigger microglia recruitment and IL-1β production [36]. In our study, we found that anesthesia and surgery induced neuroinflammation and NMDAR overactivation.…”

Section: Discussionsupporting

confidence: 48%

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

155

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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Section: Discussionsupporting

confidence: 48%

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

155

117

View full text Add to dashboard Cite

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“…Light-induced retinopathy showed an increase in NLRP3 after one-month [103], which was alleviated by the deletion of Ccr2 [103], and treatment with monomethyl fumarate [104]. NMDA-induced retinal excitotoxicity also resulted in a time-dependent increase of retinal NLRP3 mRNA [105], while TXNIP knockout in Müller cell culture prevented NLRP3 production [106]. Meanwhile, a transgenic mouse with P23H on Nlrp3 −/− background had reduced cone cell death [107].…”

Section: Nod-like Receptors In the Ocular Tissuesmentioning

confidence: 99%

NOD-like Receptors in the Eye: Uncovering Its Role in Diabetic Retinopathy

Lim

Wieser

Ganga

et al. 2020

IJMS

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Diabetic retinopathy (DR) is an ocular complication of diabetes mellitus (DM). International Diabetic Federations (IDF) estimates up to 629 million people with DM by the year 2045 worldwide. Nearly 50% of DM patients will show evidence of diabetic-related eye problems. Therapeutic interventions for DR are limited and mostly involve surgical intervention at the late-stages of the disease. The lack of early-stage diagnostic tools and therapies, especially in DR, demands a better understanding of the biological processes involved in the etiology of disease progression. The recent surge in literature associated with NOD-like receptors (NLRs) has gained massive attraction due to their involvement in mediating the innate immune response and perpetuating inflammatory pathways, a central phenomenon found in the pathogenesis of ocular diseases including DR. The NLR family of receptors are expressed in different eye tissues during pathological conditions suggesting their potential roles in dry eye, ocular infection, retinal ischemia, cataract, glaucoma, age-related macular degeneration (AMD), diabetic macular edema (DME) and DR. Our group is interested in studying the critical early components involved in the immune cell infiltration and inflammatory pathways involved in the progression of DR. Recently, we reported that NLRP3 inflammasome might play a pivotal role in the pathogenesis of DR. This comprehensive review summarizes the findings of NLRs expression in the ocular tissues with special emphasis on its presence in the retinal microglia and DR pathogenesis.

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“…Discovering potential downstream mediators of the Norrin-mediated protection of retinal neurons via Lif, would further contribute to the understanding of this signaling pathway. Finally, after induction of retinal excitotoxic damage, the role of reactive microglia is being discussed [47,48]. Therefore, the exploration of the effect of Norrin on microglia cells following acute retinal damage would open novel insights in Norrin-mediated neuroprotection of the retina.…”

Section: Discussionmentioning

confidence: 99%

Norrin Protects Retinal Ganglion Cells from Excitotoxic Damage via the Induction of Leukemia Inhibitory Factor

Kassumeh

Leopold

Fuchshofer

et al. 2020

Cells

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Purpose: To investigate whether and how leukemia inhibitory factor (Lif) is involved in mediating the neuroprotective effects of Norrin on retinal ganglion cells (RGC) following excitotoxic damage. Norrin is a secreted protein that protects RGC from N-methyl-d-aspartate (NMDA)-mediated excitotoxic damage, which is accompanied by increased expression of protective factors such as Lif, Edn2 and Fgf2. Methods: Lif-deficient mice were injected with NMDA in one eye and NMDA plus Norrin into the other eye. RGC damage was investigated and quantified by TUNEL labeling 24 h after injection. Retinal mRNA expression was analyzed by quantitative real-time polymerase chain reaction following retinal treatment. Results: After intravitreal injection of NMDA and Norrin in wild-type mice approximately 50% less TUNEL positive cells were observed in the RGC layer when compared to NMDA-treated littermates, an effect which was lost in Lif-deficient mice. The mRNA expression for Gfap, a marker for Müller cell gliosis, as well as Edn2 and Fgf2 was induced in wild-type mice following NMDA/Norrin treatment but substantially blocked in Lif-deficient mice. Conclusions: Norrin mediates its protective properties on RGC via Lif, which is required to enhance Müller cell gliosis and to induce protective factors such as Edn2 or Fgf2.

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NLRP3 inflammasome in NMDA-induced retinal excitotoxicity

Cited by 27 publications

References 72 publications

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

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

NOD-like Receptors in the Eye: Uncovering Its Role in Diabetic Retinopathy

Norrin Protects Retinal Ganglion Cells from Excitotoxic Damage via the Induction of Leukemia Inhibitory Factor

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