Decreased Expression of DREAM Promotes the Degeneration of Retinal Neurons

Chintala, Shravan K.; Cheng, Mei; Zhang, Xiao

doi:10.1371/journal.pone.0127776

Cited by 4 publications

(6 citation statements)

References 31 publications

(37 reference statements)

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“…Studies have shown that, in addition to RGCs, other retinal neurons are also impacted by NMDA-induced neurotoxicity (Chintala et al, 2015; Kuehn et al, 2017). In our present study, utilizing samples at 5 days post-injury, we investigated whether treatment with MDL improved the survival of neurons in the INL in response to NMDA treatment.…”

Section: Resultsmentioning

confidence: 99%

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Targeting Polyamine Oxidase to Prevent Excitotoxicity-Induced Retinal Neurodegeneration

et al. 2019

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Dysfunction of retinal neurons is a major cause of vision impairment in blinding diseases that affect children and adults worldwide. Cellular damage resulting from polyamine catabolism has been demonstrated to be a major player in many neurodegenerative conditions. We have previously shown that inhibition of polyamine oxidase (PAO) using MDL 72527 significantly reduced retinal neurodegeneration and cell death signaling pathways in hyperoxia-mediated retinopathy. In the present study, we investigated the impact of PAO inhibition in limiting retinal neurodegeneration in a model of NMDA (N-Methyl-D-aspartate)-induced excitotoxicity. Adult mice (8–10 weeks old) were given intravitreal injections (20 nmoles) of NMDA or NMLA (N-Methyl-L-aspartate, control). Intraperitoneal injection of MDL 72527 (40 mg/kg body weight/day) or vehicle (normal saline) was given 24 h before NMDA or NMLA treatment and continued until the animals were sacrificed (varied from 1 to 7 days). Analyses of retinal ganglion cell (RGC) layer cell survival was performed on retinal flatmounts. Retinal cryostat sections were prepared for immunostaining, TUNEL assay and retinal thickness measurements. Fresh frozen retinal samples were used for Western blotting analysis. A marked decrease in the neuronal survival in the RGC layer was observed in NMDA treated retinas compared to their NMLA treated controls, as studied by NeuN immunostaining of retinal flatmounts. Treatment with MDL 72527 significantly improved survival of NeuN positive cells in the NMDA treated retinas. Excitotoxicity induced neurodegeneration was also demonstrated by reduced levels of synaptophysin and degeneration of inner retinal neurons in NMDA treated retinas compared to controls. TUNEL labeling studies showed increased cell death in the NMDA treated retinas. However, treatment with MDL 72527 markedly reduced these changes. Analysis of signaling pathways during excitotoxic injury revealed the downregulation of pro-survival signaling molecules p-ERK and p-Akt, and the upregulation of a pro-apoptotic molecule BID, which were normalized with PAO inhibition. Our data demonstrate that inhibition of polyamine oxidase blocks NMDA-induced retinal neurodegeneration and promotes cell survival, thus offering a new therapeutic target for retinal neurodegenerative disease conditions.

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Section: Resultsmentioning

confidence: 99%

“…The NMDA receptor (NMDAR) subtypes play a major role in this process, mainly by increasing intracellular calcium (Ca 2+ ). Activation of NMDAR has been shown to promote neuronal death in the retina (Shen et al, 2006; Chintala et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Targeting Polyamine Oxidase to Prevent Excitotoxicity-Induced Retinal Neurodegeneration

et al. 2019

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“…At low concentrations (<50 nM) NMDA has been shown to damage amacrine cells but bipolar cell damage has only been reported for higher concentrations (>200 nM). 78 At 20 mM NMDA concentrations, substantial bipolar and interneuron cell damage will have occurred. We observed a significant protective effect of Lip A compared to the empty liposome Lip C ( P value < 0.02).…”

Section: Resultsmentioning

confidence: 99%

Multifarious Biologic Loaded Liposomes that Stimulate the Mammalian Target of Rapamycin Signaling Pathway Show Retina Neuroprotection after Retina Damage

et al. 2018

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A common event in optic neuropathies is the loss of axons and death of retinal ganglion cells (RGCs) resulting in irreversible blindness. Mammalian target of rapamycin (mTOR) signaling pathway agonists have been shown to foster axon regeneration and RGC survival in animal models of optic nerve damage. However, many challenges remain in developing therapies that exploit cell growth and tissue remodeling including (i) activating/inhibiting cell pathways synergistically, (ii) avoiding tumorigenesis, and (iii) ensuring appropriate physiological tissue function. These challenges are further exacerbated by the need to overcome ocular physiological barriers and clearance mechanisms. Here we present liposomes loaded with multiple mTOR pathway stimulating biologics designed to enhance neuroprotection after retina damage. Liposomes were loaded with ciliary neurotrophic factor, insulin-like growth factor 1, a lipopeptide N-fragment osteopontin mimic, and lipopeptide phosphatase tension homologue inhibitors for either the ATP domain or the c-terminal tail. In a mouse model of N-methyl-d-aspartic acid induced RGC death, a single intravitreal administration of liposomes reduced both RGC death and loss of retina electrophysiological function. Furthermore, combining liposomes with transplantation of induced pluripotent stem cell derived RGCs led to an improved electrophysiological outcome in mice. The results presented here show that liposomes carrying multiple signaling pathway modulators can facilitate neuroprotection and transplant electrophysiological outcome.

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“…In neuronal cells, DREAM acts as a transcriptional repressor involved in protein folding (28), presenilin-induced β-amyloid formation (13), nitric oxide-induced inflammatory pain (29), apoptosis (30–33), and synaptic plasticity (34). Earlier work demonstrated that DREAM represses transcription of the PDYN (prodynorphin) gene in neuroblastoma cells (17).…”

Section: Function Of Dreammentioning

confidence: 99%

“…Studies using an inducible expression system in neuroglioma cells suggested that DREAM enhances apoptosis by altering the cytosolic Ca 2+ level and increasing caspase and calpain activities (31). Nonetheless, the role of DREAM in apoptosis may be cell specific since knockdown of DREAM attenuates apoptosis induced by increased cytosolic Ca 2+ levels in HeLa cells and a T-lymphocyte cell line (32), whereas down-regulation of DREAM in retinal ganglion cells promotes apoptosis (33). …”

Section: Function Of Dreammentioning

confidence: 99%

Downstream Regulatory Element Antagonist Modulator (DREAM), a target for anti-thrombotic agents

Cho

2017

Pharmacological Research

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Circulating platelets participate in the process of numerous diseases including thrombosis, inflammation, and cancer. Thus, it is of great importance to understand the underlying mechanisms mediating platelet activation under disease conditions. Emerging evidence indicates that despite the lack of a nucleus, platelets possess molecules involved in gene transcription occurring in nucleated cells. This review will summarize downstream regulatory element antagonist modulator (DREAM), a transcriptional repressor, and highlight recent findings suggesting its novel non-transcriptional role in hemostasis and thrombosis.

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Decreased Expression of DREAM Promotes the Degeneration of Retinal Neurons

Cited by 4 publications

References 31 publications

Targeting Polyamine Oxidase to Prevent Excitotoxicity-Induced Retinal Neurodegeneration

Targeting Polyamine Oxidase to Prevent Excitotoxicity-Induced Retinal Neurodegeneration

Multifarious Biologic Loaded Liposomes that Stimulate the Mammalian Target of Rapamycin Signaling Pathway Show Retina Neuroprotection after Retina Damage

Downstream Regulatory Element Antagonist Modulator (DREAM), a target for anti-thrombotic agents

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